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XVII Acute Respiratory Failure

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Lung Failure


Respiratory Failure: An Overview Michael A. Grippi

I. CLASSIFICATION OF RESPIRATORY FAILURE II. PATHOPHYSIOLOGY Hypoxemic Respiratory Failure Hypercapnic Respiratory Failure Ventilatory Supply vs. Demand III. CATEGORIES OF RESPIRATORY FAILURE Abnormalities of the Central Nervous System Abnormalities of the Peripheral Nervous System or Chest Wall Abnormalities of the Airways Abnormalities of the Alveoli IV. APPROACH TO THE PATIENT V. PRINCIPLES OF MANAGEMENT Triage Decisions Airway Management

Respiratory failure is a condition in which the respiratory system fails in one or both of its gas-exchanging functions— i.e., oxygenation of, and carbon dioxide elimination from, mixed venous (pulmonary arterial) blood. Hence, respiratory failure is a syndrome rather than a disease. Many diseases result in respiratory failure, as discussed elsewhere in this text.

Correction of Hypoxemia and Hypercapnia Search for an Underlying Cause VI. MONITORING PATIENTS WITH ACUTE RESPIRATORY FAILURE VII. COMPLICATIONS OF ACUTE RESPIRATORY FAILURE Pulmonary Cardiovascular Gastrointestinal Infectious Renal Nutritional VIII. PROGNOSIS Morbidity and Mortality in Acute Hypoxemic Respiratory Failure Morbidity and Mortality in Acute Hypercapnic Respiratory Failure

Respiratory failure may be acute or chronic. The clinical presentations of patients with acute and chronic respiratory failure usually are quite different. While acute respiratory failure is characterized by life-threatening derangements in arterial blood gases and acid-base status, the manifestations of chronic respiratory failure are more indolent and may be clinically inapparent.

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Although the causes of respiratory failure are diverse, common underlying pathophysiological mechanisms and management strategies merit a general discussion. This chapter begins with a focus on the definition of respiratory failure and underscores distinctions between acute and chronic varieties. Hypoxemic and hypercapnic respiratory failure are described, and the pathophysiological underpinnings of each type are reviewed. The concepts of ventilatory supply and demand are considered before an overview of the many categories of disease that result in respiratory failure. Finally, an approach to clinical evaluation and management is outlined, followed by a summary of complications and comments on prognosis.

CLASSIFICATION OF RESPIRATORY FAILURE As noted previously, respiratory failure is characterized by inadequate blood oxygenation or carbon dioxide removal. “Adequacy” is defined by tissue requirements for oxygen uptake and carbon dioxide elimination. In the absence of bedside techniques for direct measurement of these metabolic parameters, clinicians must rely on arterial blood gas values. Respiratory failure may be classified as hypercapnic or hypoxemic (Fig. 143-1). Hypercapnic respiratory failure is defined as an arterial Pco2 (Paco2 ) greater than 45 mmHg. Hypoxemic respiratory failure is defined as an arterial Po2 (Pao2 ) less than 55 mmHg when the fraction of oxygen in inspired air (Fio2 ) is 0.60 or greater. In many cases, hypercapnic and hypoxemic respiratory failure coexist. Disorders that initially cause hypoxemia may be complicated by respiratory pump failure (see below) and hypercapnia. Conversely, diseases that produce respiratory pump failure are frequently complicated by hypoxemia due to secondary pulmonary parenchymal

Table 143-1 Distinctions between Acute and Chronic Respiratory Failure Category


Hypercapnic respiratory failure Acute Chronic

PaCO2 >45 mmHg

Hypoxemic respiratory failure Acute Chronic

PaO2 <55 mmHg when FIO2 ≥0.60 Develops in min to h Develops over several days or longer

Develops in min to h Develops over several days or longer

processes (e.g., pneumonia or atelectasis) or vascular disorders (e.g., pulmonary embolism). Distinctions between acute and chronic respiratory failure are summarized in Table 143-1. In general, acute hypercapnic respiratory failure is defined as a Paco2 greater than 45 mmHg with accompanying acidemia (pH less than 7.30). The physiological effect of a sudden increment in Paco2 depends on the prevailing level of serum bicarbonate anion. In patients with chronic hypercapnic respiratory failure—e.g., due to chronic obstructive pulmonary disease (COPD)—a long-standing increase in Paco2 results in renal “compensation” and an increased serum bicarbonate concentration. A superimposed acute increase in Paco2 has a less dramatic effect than does a comparable increase in a patient with a normal bicarbonate level.

Figure 143-1 Classification of respiratory failure. Although depicted as distinct entities, hypercapnic and hypoxemic respiratory failure frequently coexist. Either may be acute or chronic.

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Distinction between acute and chronic hypoxemic respiratory failure may not be readily made on the basis of arterial blood gas values. The presence of markers of chronic hypoxemia (e.g., polycythemia or cor pulmonale) provides clues to a long-standing disorder, whereas abrupt changes in mental status suggest an acute event. It is important to bear in mind that even though the definition of hypoxemic respiratory failure rests on measurement of Pao2 , the major threat of arterial hypoxemia is inadequate tissue oxygenation, reflected in tissue oxygen delivery. Tissue oxygen delivery is determined by the product of cardiac output and blood oxygen content (see Chapter 13); the latter, in turn, depends on hemoglobin concentration and oxygen saturation. Therefore, factors that lower cardiac output or hemoglobin concentration, or inhibit dissociation of oxygen from hemoglobin at the tissue level, may promote tissue hypoxia without technically producing respiratory failure.

PATHOPHYSIOLOGY Respiratory failure can arise from an abnormality in any of the “effector” components of the respiratory system—central nervous system, peripheral nervous system, respiratory muscles and chest wall, airways, or alveoli (Fig. 143-2). A defect in any of the first four components, which constitute the “respiratory pump,” may cause coexistent hypercapnia and hypoxemia; at least initially, disorders of the alveoli are more apt to result in hypoxemia.

Hypoxemic Respiratory Failure As described in Chapters 10, 11, and 12, four pathophysiological mechanisms account for the hypoxemia seen in a wide variety of diseases: alveolar hypoventilation, ventilationperfusion mismatch, shunt, and diffusion limitation. Alveolar hypoventilation occurs in neuromuscular disorders that

Respiratory Failure: An Overview

affect the respiratory system. In the absence of underlying pulmonary disease, the hypoxemia accompanying alveolar hypoventilation is characterized by a normal alveolar-arterial oxygen gradient, as defined by Eq. (1): Pao2 − Pao2 = [Pio2 − Paco2 /R] − Pao2


where Pao2 = alveolar Po2 Pao2 = arterial Po2 Pio2 = inspired Po2 Paco2 = arterial Pco2 R = respiratory exchange ratio In contradistinction, disorders in which any of the other three mechanisms are operative are characterized by widening of the alveolar-arterial oxygen gradient, which is normally less than 20 mmHg. With ventilation-perfusion mismatching, areas of low ventilation relative to perfusion contribute to the hypoxemia. Similarly, with shunt, either intrapulmonary or intracardiac, deoxygenated mixed venous blood bypasses ventilated alveoli, resulting in “venous admixture.” Finally, diseases that increase the diffusion pathway for oxygen from the alveolar space to pulmonary capillary impair oxygen transport across the alveolar-capillary membrane. Although changes in minute and alveolar ventilation can change Paco2 considerably, this is not so for Pao2 . Increases in minute ventilation and, secondarily, in alveolar ventilation, modestly increase Pao2 . Indeed, at a Pao2 above 55 to 60 mmHg, the effect of increasing ventilation on oxygen content is minimal, since the oxyhemoglobin dissociation curve is flat in this range.

Hypercapnic Respiratory Failure At a constant rate of CO2 production (V˙ co2 ), Paco2 is determined by the level of alveolar ventilation. The relationship

Figure 143-2 Functional components of the respiratory system and its controller. Abnormalities in any of the effector components can result in respiratory failure. The central and peripheral nervous systems, respiratory muscles and chest wall, and airways constitute the ‘‘respiratory pump” (shaded boxes). Hypercapnia is the hallmark of respiratory pump failure, while hypoxemia constitutes the primary disturbance in alveolar disorders producing respiratory failure. (From Lanken PN: Respiratory failure: An overview, in Carlson RW, Geheb MA (eds), Principles and Practice of Medical Intensive Care. Philadelphia, WB Saunders, 1993, pp 754–763.)

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between alveolar ventilation, rate of CO2 production, and Paco2 is described by Eq. (2): ˙ = K · V˙ co2 /Paco2 Va


where ˙ = minute alveolar ventilation Va K = a constant V˙ co2 = rate of CO2 production ˙ which, ˙ 2 is constant, Paco2 is determined by Va, When Vco in turn, is dictated by two factors: minute ventilation (V˙ e ) and the relationship between V˙ e and V˙ a . The latter is determined by the proportion of V˙ e that constitutes dead space ventilation—i.e., the dead space to tidal volume ratio (Vd /Vt ): V˙ e = K · (V˙ o2 · RQ)/(Paco2 /[1 − Vd /Vt ])


where V˙ o2 = rate of O2 consumption RQ = respiratory quotient (the respiratory exchange ratio in the steady state) Vd = dead space volume Vt = tidal volume Inspection of Eq. (3) indicates that disorders reducing V˙ e or increasing the proportion of dead space ventilation may result in hypercapnia.

Ventilatory Supply vs. Demand A useful theoretical construct for understanding the pathophysiological basis for hypercapnic respiratory failure is the relationship between ventilatory supply and ventilatory demand (Fig. 143-3). Ventilatory supply is the maximal spontaneous ventilation that can be maintained without development of respiratory muscle fatigue; ventilatory supply is also known as maximal sustainable ventilation (MSV). Ventilatory demand is the spontaneous minute ventilation, which, when maintained constant, results in a stable Paco2 (assuming a fixed rate of CO2 production). Normally, ventilatory supply greatly exceeds ventilatory demand. Hence, major changes in minute ventilatory requirements (e.g., during exercise) may occur without hypercapnia. In lung disease, significant abnormalities may be present before ventilatory demand encroaches on MSV. Consequently, hypercapnia is a late finding. When ventilatory demand exceeds MSV, Paco2 increases. As a general rule, MSV is approximated as one-half the maximal voluntary ventilation, or MVV (see Chapter 34). A 70-kg adult has an MVV of about 160 L/min, an MSV of 80 L/min, and, under basal conditions, a V˙ e of approximately 6 to 7 L/min (90 ml/kg/min). Normally, therefore, there is a 10- to 15-fold difference between resting V˙ e and MSV. In disease states, the V˙ e requirement may approach a markedly

Figure 143-3 Relationship between ventilatory supply (maximal sustainable ventilation) and ventilatory demand (overall level of ventilation specified by the central nervous system controller). Relative size of the arrows indicates levels of supply and demand in each of the three circumstances illustrated. A. Normal. Ventilatory supply greatly exceeds ventilatory demand. Physiological ‘‘reserve” is maintained. B .Ventilatory supply is decreased and ventilatory demand increased (e.g., acute asthma attack). ‘‘Borderline” respiratory failure exists. C . Ventilatory demand exceeds ventilatory supply (e.g., sepsis in a patient with chronic obstructive pulmonary disease). Respiratory muscle fatigue develops, and hypercapnic respiratory failure ensues. See text for details. (From Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiology. Philadelphia, JB Lippincott, 1995, pp 267–280.)

reduced MSV. Further reductions in MSV result in ventilatory demand exceeding supply, and hypercapnia occurs. Factors that Reduce Ventilatory Supply or Increase Ventilatory Demand Disruption of any component of the efferent arm of the respiratory control system may diminish ventilatory supply (Table 143-2). While a variety of diseases produce specific abnormalities along the efferent pathway (e.g., phrenic nerve and respiratory muscle disorders), some result in respiratory

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Respiratory Failure: An Overview

Table 143-2 Factors That Diminish Ventilatory Supply Factor Decreased respiratory muscle strength Muscle fatigue Disuse atrophy


Recovery from acute respiratory failure, high respiratory rates, increased inspiratory time Prolonged mechanical ventilation, following phrenic nerve injury


Protein-calorie starvation

Electrolyte abnormalities Arterial blood gas abnormalities Fatty infiltration of diaphragm Unfavorable alteration in diaphragm length–tension relationship

Low serum phosphate or potassium concentrations Low pH, low PaO2 high PaCO2 Obesity Flattened domes of diaphragm caused by hyperinflation

Increased muscle energy requirement or decreased substrate supply High elastic work of breathing High resistive work of breathing Reduced diaphragm perfusion Decreased motor neuron function Decreased phrenic nerve output Decreased neuromuscular transmission Abnormal respiratory mechanics Airflow limitation Loss of lung volume Other restrictive defects

Low lung or chest wall compliance, high respiratory rate Airway obstruction Shock, anemia

Polyneuropathy, Guillain-Barr´e syndrome, phrenic nerve transection or injury, poliomyelitis Myasthenia gravis, use of paralyzing agents

Bronchospasm, upper-airway obstruction, excessive airway secretions After lung resection, large pleural effusion Pain-limited inspiration; tense abdominal distention due to ileus, peritoneal dialysis fluid, or ascites

muscle fatigue—the biochemical, cellular, and molecular mechanisms of which remain poorly understood. As described previously, ventilatory demand can be assessed according to Eq. (3): V˙ e = K · (V˙ o2 · RQ)/(Paco2 /[1 − Vd /Vt ])


Any factor that affects terms on the right-hand side of the equation may result in ventilatory demand exceeding supply. Selected clinical examples are given in Table 143-3.

CATEGORIES OF RESPIRATORY FAILURE Although many different diseases cause respiratory failure, they may be grouped conveniently according to primary abnormalities in the individual effector components of the respiratory system.

Abnormalities of the Central Nervous System A variety of pharmacologic, structural, and metabolic disorders of the central nervous system (CNS) are characterized by suppression of the neural drive to breathe. The resultant hypoventilation and hypercapnia may be acute or chronic. An overdose of a narcotic or other drug with sedative properties is a common cause of respiratory failure. While the most striking clinical picture occurs with an acute overdose, long-standing use of some agents (e.g., methadone) may result in chronic hypercapnia. “Structural” CNS abnormalities producing hypercapnic respiratory failure include meningoencephalitis, localized tumors or vascular abnormalities of the medulla, and strokes affecting medullary control centers. Usually, respiratory failure is observed in the context of other neurological findings.

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Table 143-3 Factors That Increase Ventilatory Demand Factor

Clinical Examples

Increased Vd /Vt

Acute asthma, emphysema, late phase of acute respiratory distress syndrome, pulmonary emboli

Increased VO2

Fever, sepsis, trauma, shivering, increased work of breathing, massive obesity

Increased RQ

Excessive carbohydrate feeding

Decreased PaCO2

Hypoxemia, metabolic acidosis, anxiety, sepsis, renal failure, hepatic failure

Source: Data from Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiolosy. Philadelphia, JB Lippincott, 1995, pp. 267–280.

A variety of metabolic derangements may produce hypercapnia through depression of respiratory control centers. Examples include severe myxedema, hepatic failure, and advanced uremia. In addition, elevation of Pco2 in the CNS results in neural depression, further enhancing CO2 retention. A common clinical setting in which elevation of Paco2 is observed is chronic metabolic alkalosis (e.g., due to diuretic use), as detailed in Chapter 14. Finally, obesity-hypoventilation syndrome is characterized by hypercapnia due to hypoventilation on a central basis. The underlying mechanisms have not yet been elucidated.

Abnormalities of the Peripheral Nervous System or Chest Wall A wide variety of disorders of the peripheral nerves, neuromuscular junction, and chest wall may be associated with hypercapnic and hypoxemic respiratory failure. While the hallmark is an inability to maintain a level of V˙ e appropriate for the rate of CO2 production, many of these disorders are complicated by impaired expiratory muscle strength, atelectasis, and aspiration. Through mechanisms outlined previously, hypoxemia develops in conjunction with the hypercapnia. Among the most common neuromuscular causes of hypercapnic respiratory failure are Guillain-Barr´e syndrome, myasthenia gravis, polymyositis, the muscular dystrophies, and a large number of metabolic muscle disorders. In addition, acute poliomyelitis and traumatic spinal cord injury are associated with hypercapnia. Development of respiratory muscle fatigue during prolonged weaning from mechanical ventilation may cause recurrent hypercapnia in the critical care setting.

Pharmacologic causes of hypercapnia in the intensive care unit are frequently encountered. Use of depolarizing and nondepolarizing paralyzing agents, particularly in conjunction with systemic corticosteroids (e.g., in management of status asthmaticus), cholinergic crisis during therapy of myasthenia gravis, and administration of aminoglycosides to patients with myasthenia are examples. Primary disorders of the chest wall constitute another important category of neuromuscular respiratory failure. The prototype is severe kyphoscoliosis. Additional examples include flail chest (see Chapter 100), extensive thoracoplasty, morbid obesity, and massive abdominal distention due to ascites or distended loops of bowel. In each of these disorders, a common pathophysiological sequence develops. Because of inadequate activation of inspiratory muscles or limited thoracic excursion, tidal volume falls. While an increase in respiratory rate compensates initially for the fall in V˙ e (and in V˙ a ), V˙ e eventually declines. In addition, the sigh mechanism is impaired, which, in conjunction with the low tidal volume, results in atelectasis and reduced lung compliance. Reduced lung compliance produces a further fall in tidal volume and an increase in the elastic work of breathing (see Chapter 9). Hence, ventilatory supply becomes limited, while ventilatory demand increases due to a rise in Vd /Vt (as a result of atelectasis and other factors noted below). An imbalance between ventilatory supply and demand arises, and hypercapnia ensues. Furthermore, an impaired gag reflex in the setting of bulbar weakness, coupled with impaired cough due to respiratory muscle involvement, may result in aspiration pneumonia and secondary hypoxemia. In addition to the pathophysiology described, structural abnormalities of the thoracic cage (e.g., severe kyphoscoliosis) are characterized by an increase in the elastic component of the work of breathing. This results in a ˙ 2 and a higher proportion of total O2 consumphigher Vo tion by the respiratory muscles (normally, less than 5 percent of V˙ o2 ).

Abnormalities of the Airways Obstructive diseases of the airways—either upper or lower— are common causes of acute and chronic hypercapnia. Examples in the upper airways include acute epiglottitis, aspirated foreign body, tracheal tumor, and narrowing of the trachea or glottis by fibrotic tissue. Disorders of the lower airways include COPD, asthma, and advanced cystic fibrosis. The underlying mechanisms are multifaceted and variable. However, several common pathophysiological pathways are operative. Airway narrowing results in a greater transthoracic pressure gradient requirement for inspiratory airflow. The resistive component of the work of breathing is increased, ˙ 2 . In adand the increase is associated with an elevation in Vo dition, tidal volume falls and dead space ventilation increases. Respiratory muscle fatigue may develop; the consequences of a shallow breathing pattern ensue.

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Finally, in some disorders (e.g., acute asthma or an exacerbation of COPD), air trapping and lung hyperinflation occur, resulting in diaphragm flattening and worsening diaphragm mechanics (see Chapters 9, 41 and 42). The overall effect is a growing imbalance between ventilatory supply and demand.

Abnormalities of the Alveoli Although diseases characterized by diffuse alveolar filling frequently result in hypoxemic respiratory failure, hypercapnia may complicate the picture. Common clinical examples in this category include cardiogenic and noncardiogenic pulmonary edema, diffuse pneumonia, extensive pulmonary hemorrhage, aspiration of stomach contents, and neardrowning. Diffuse alveolar filling creates a large right-to-left shunt as pulmonary blood flows through nonventilated or poorly ventilated regions of the lung. In addition, coexisting interstitial edema may impair diffusion across the alveolar-capillary membrane, further impairing oxygenation of mixed venous blood. In extensive, acute pulmonary disease characterized by alveolar filling, ventilatory demand is high because of hypoxemia and increases in Vd /Vt , the elastic work of breathing (due to reduced lung compliance), the resistive work of breathing (due to airway narrowing and increased airway reactivity), and the neural drive to breathe (mediated by pulmonary parenchymal vagal fibers). In conjunction with heightened ventilatory demand, ventilatory supply is reduced because of alveolar flooding, reduced lung elasticity, respiratory muscle fatigue, and, possibly, reduced blood supply to the diaphragm secondary to shock. Once again, the imbalance between ventilatory supply and demand results in hypercapnia.

APPROACH TO THE PATIENT The diagnosis of acute or chronic respiratory failure begins with clinical suspicion of its presence. Confirmation of the diagnosis is based on arterial blood gas analysis (Table 143-1). Evaluation for an underlying cause must be initiated early, frequently in the presence of concurrent treatment for acute respiratory failure. While the diagnosis of chronic respiratory failure is usually easily established with clinical findings of chronic hypoxemia (with or without findings of hypercapnia), the diagnosis of acute respiratory failure requires more careful analysis. Signs and symptoms in acute respiratory failure reflect the underlying disease process and associated hypoxemia or acidemia due to hypercapnia. Localized pulmonary findings reflecting the acute causes of hypoxemia (e.g., pneumonia, pulmonary edema, asthma, or COPD) may be readily apparent. Alternatively, the predominant findings may be systemic (e.g., hypotension due to sepsis). The principal manifestations may even be remote from the thorax—e.g., abdominal

Respiratory Failure: An Overview

pain in acute pancreatitis or leg pain due to a long bone fracture—each associated with acute (adult) respiratory distress syndrome (ARDS) (see Chapter 145). Frequently, neurological or cardiovascular symptoms and signs predominate. Neurological manifestations include restlessness, anxiety, confusion, seizures, or coma. Asterixis may be seen with severe hypercapnia. Common cardiovascular findings include tachycardia and a variety of arrhythmias. Finally, there may be few or no findings other than a complaint of dyspnea, as in some patients with hypoxemia due to pulmonary embolism. Once respiratory failure is suspected on clinical grounds, arterial blood gas analysis is performed to confirm the diagnosis, to assist in the distinction between acute and chronic forms, to assess the magnitude and metabolic impact, and to help guide management (Table 143-4).

PRINCIPLES OF MANAGEMENT The principles of management of patients in acute respiratory failure include those that are cause-specific and those that are more general. Triage of the patient to the proper clinical setting, airway maintenance, correction of hypoxemia and hypercapnia, and management of the underlying cause are of paramount importance.

Triage Decisions The first step in management is to determine the appropriate setting for care—admission to a standard inpatient facility or to an intensive or intermediate care unit. Factors that constitute the basis for this decision include the acuity of the respiratory failure; the degree of hypoxemia, hypercapnia, and acidemia; the presence of co-morbid conditions (e.g., cardiac disease or renal insufficiency); and the clinical direction that the patient takes over the first few minutes or hours of observation. At one end of the spectrum is the patient with fulminant hypoxemic respiratory failure, metabolic acidosis, and imminent cardiovascular collapse, who needs emergent intubation, mechanical ventilation, and admission to a critical care unit. At the other end of the spectrum is the patient with COPD and chronic, compensated hypercapnic respiratory failure, who requires observation in an intermediate care unit. Notably, in recent years, a number of studies have indicated that use of noninvasive mechanical ventilation may obviate the need for endotracheal intubation in selected patients with hypercapnic or acute, hypoxemic respiratory failure (other than ARDS-related). Although studies also point to the potential role of noninvasive mechanical ventilation in recurrent respiratory failure following extubation, a multicenter, randomized trial found no reduction in mortality or in the need for reintubation with its use.

Airway Management Assurance of an adequate airway is key in the patient with acute respiratory distress. Whether emergency intubation is

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Table 143-4 Changes in Arterial Blood Gases, Pao2 –Pao2 , and Ventilation in Acute Respiratory Failure Failed Respiratory System Component




PAo2 –Pao2

V˙ E

V˙ A

Central nervous system


NL or ↑†

Peripheral nervous system or chest bellows


NL or ↑†

Early phase (before respiratory failure)


“Crossover point”



NL or ↓


With development of respiratory muscle fatigue


NL or ↑§


NL to ↓

NL or ↑




NL, ↑ or ↓‡

Before respiratory muscle fatigue develops



After respiratory muscle fatigue develops



Airways In acute asthma

In COPD Non–CO2 retainer CO2 retainer


∗ Pa

o2 may decrease when pneumonia or atelectasis occurs as a complication. o2 –Pao2 ) widens when pneumonia or atelectasis occurs as a complication. ‡V ˙ E declines when frank respiratory muscle failure occurs. § Pa co2 may increase during an exacerbation. Note: ↑ = increased; ↑↑= very increased; ↓= decreased; ↓↓= very decreased; NL = in normal range. Source: Data from Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiolosy. Philadelphia, JB Lippincott, 1995, pp. 267–280. † ( Pa

required depends on the clinical circumstances described previously. For patients with chronic respiratory insufficiency, the need for intubation depends on critical arterial blood gas values and the patient’s early acute course. When progressive hypoxemia or hypercapnia is observed over the first few minutes or hours of care, intubation and mechanical ventilation are warranted.

Correction of Hypoxemia and Hypercapnia Once the airway is secured, the clinician must turn attention to the treatment of hypoxemia—the most life-threatening

aspect of acute respiratory insufficiency. The goal is to assure adequate oxygen delivery to tissues, generally achieved with a Pao2 of about 60 mmHg (assuming an adequate hematocrit and cardiac output). In patients who have coronary or cerebrovascular disease, a slightly higher level of arterial oxygenation may be desirable in order to provide a “buffer” for any sudden, unpredictable changes in gas exchange. The means by which supplemental oxygen is administered is determined by the clinical circumstances. While some patients may simply require nasal prongs or a face mask to achieve an adequate Pao2 , others are best treated with controlled-flow oxygen delivered via a Venturi mask—e.g.,

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the patient with COPD and chronic hypercapnia (see Chapters 42 and 149). Generally, if an acceptable level of oxygenation, as judged by arterial blood gases, cannot be attained using a face mask, or if administration of supplemental O2 causes hypercapnia to worsen significantly (e.g., in some patients with COPD), either noninvasive mechanical ventilation or endotracheal intubation and mechanical ventilation will be required. While correcting hypoxemia, the clinician must also address any coexisting hypercapnia and respiratory acidosis. Once again, the immediacy of correction depends on the magnitude of the acidosis and its attendant effects (e.g., elevation of serum potassium). A partly compensated respiratory acidosis in a patient with COPD usually constitutes a less urgent clinical circumstance than does profound respiratory acidosis in a patient with a drug overdose.

Search for an Underlying Cause Finally, as therapy is initiated to correct the hypoxemia, hypercapnia, and acidosis of respiratory failure, a search for the cause of the problem and its management must be undertaken. In some cases, the cause and management are straightforward (e.g., administration of a narcotic antagonist to the patient with a narcotic overdose). In others, a more protracted course may be in store (e.g., long-term ventilator management of fulminant ARDS due to sepsis). In both brief and prolonged cases of respiratory failure, attention to details of management is important in order to minimize the risks of complications of therapy, as discussed below.

MONITORING PATIENTS WITH ACUTE RESPIRATORY FAILURE Repeated assessment of the patient with incipient or resolving respiratory failure, as well as the patient with frank hypoxemic or hypercapnic failure, is critical in formulating decisions about therapy. Monitoring methods range from routine bedside observations to use of invasive techniques. For many patients with acute respiratory failure, simple observation of respiratory rate, tidal volume, use of accessory muscles, and presence of paradoxical breathing movements provides evidence of worsening respiratory failure and the need for mechanical ventilation. The patient with asthma or an acute exacerbation of COPD will frequently manifest rapid, shallow breathing and paradoxical thoracoabdominal breathing movements as respiratory mechanics deteriorate. Once placed on mechanical ventilation, the patient must be monitored carefully for ventilator-associated complications (see below). In addition, placement of indwelling arterial and venous catheters, patient immobilization, and use of a broad range of pharmacologic agents present additional potential threats to the acutely ill patient.

Respiratory Failure: An Overview

While many monitoring techniques are routine and may be universally applicable to patients in a critical care setting (e.g., pulse oximetry), others may be of particular importance in selected clinical circumstances. For example, routine assessment of static respiratory system compliance in a mechanically ventilated patient with ARDS or pulmonary fibrosis may provide an early warning of barotrauma. In the patient with status asthmaticus requiring mechanical ventilation, development of hypotension due to intrinsic positive end-expiratory pressure (PEEP) or “auto-PEEP,” as discussed in Chapters 152 and 153, may signal the need to alter ventilator settings or implement sedation or pharmacologic paralysis.

COMPLICATIONS OF ACUTE RESPIRATORY FAILURE The respiratory patient in a critical care unit must navigate not only the obstacles presented by the underlying pulmonary process, but also the hazards associated with use of mechanical devices and pharmacologic agents. Complications of acute respiratory failure may be broadly categorized as pulmonary, cardiovascular, gastrointestinal, renal, infectious, nutritional, and other (Table 143-5). For details in each of these areas, the reader is referred to other chapters in this text.

Pulmonary Common pulmonary complications of acute respiratory failure include pneumonia (discussed in detail elsewhere), pulmonary emboli, pulmonary barotrauma, pulmonary fibrosis, and complications directly related to use of mechanical devices. Pulmonary emboli have been reported in up to onefourth of patients with respiratory failure in intensive care units. The diagnosis is difficult in this setting, since patients typically have diffuse underlying lung disease, abnormal gas exchange, and many coexisting potential causes for the clinical, radiographic, and physiological consequences of pulmonary emboli. Pulmonary barotrauma, identified as the presence of extra-alveolar air in structures that do not normally contain air, may occur in patients receiving mechanical ventilation for a variety of indications. It is particularly common in patients with ARDS. Manifestations of barotrauma include pulmonary interstitial emphysema, pneumothorax, pneumomediastinum, pneumoperitoneum, subcutaneous emphysema, tension lung cysts, and subpleural air cysts. Pulmonary fibrosis may follow acute lung injury associated with ARDS. In addition, use of high inspired concentrations of oxygen may enhance development of fibrosis in the presence of acute lung injury. Based on recent studies, a strategy of “low stretch” ventilation has emerged for managing patients with acute lung injury or ARDS and is aimed at minimizing the risks of ventilator-induced pulmonary damage, as discussed in

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Table 143-5 Complications of Acute Respiratory Failure Pulmonary Pulmonary emboli Pulmonary barotrauma (interstitial emphysema, pneumothorax, subcutaneous emphysema, pneumoperitoneum, tension lung cyst, subpleural air cyst) Pulmonary fibrosis Related to Use of Mechanical Devices Complications of mechanical ventilation (infection, arterial desaturation, hypotension, barotrauma, others) Complications of insertion and maintenance of pulmonary artery catheter (pneumothorax, air embolism, arrhythmias, infection, thrombosis, pulmonary artery rupture) Complications of tracheal intubation Related to prolonged intubation attempt (hypoxemic brain injury, cardiac arrest, seizures, others) Related to right main bronchus intubation (hypoventilation, pneumothorax, atelectasis) Self- or inadvertent extubation Endotracheal tube dislodgment Endotracheal tube cuff leak Injury to pharynx, larynx, trachea Complications of tracheotomy (pneumothorax, bleeding, tube dislodgment, tracheoinnominate fistula, tracheoesophageal fistula, tracheal stenosis) Gastrointestinal Hemorrhage (including â&#x20AC;&#x153;stressâ&#x20AC;? ulceration) Ileus Diarrhea Cardiovascular Hypotension Arrhythmias Decreased cardiac output Myocardial infarction Pulmonary hypertension Renal Acute renal failure Fluid retention Infectious Nosocomial pneumonia Bacteremia Sepsis Paranasal sinusitis Nutritional Complications of underlying malnutrition (decreased respiratory muscle strength, immune suppression, others) Complications of enteral feeding (pneumothorax, pleural effusion, sinusitis, aspiration, diarrhea) Complications of parenteral feeding (pneumothorax, sepsis, hyperglycemia, hyperosmolar coma, hypophosphatemia, liver function test abnormalities) Complications of refeeding (hypercapnia) Other Psychiatric (anxiety, depression, confusion, sleep dysfunction, psychosis) Hematological (anemia, thrombocytopenia)

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Chapters 144 and 145. In addition, new approaches to the use of intravenous sedation, namely, daily interruption of the infusion, has been shown to reduce both the duration of mechanical ventilation and length of stay in the intensive care unit. Common device-related complications include those due to pulmonary artery flotation catheters, endotracheal intubation, and tracheotomy.

Cardiovascular Common cardiovascular complications in patients with acute respiratory failure include hypotension, reduced cardiac output, arrhythmias, pericarditis, and acute myocardial infarction. These complications may be related to the underlying disease process, mechanical ventilation, or use of pulmonary artery flotation catheters.

Gastrointestinal A variety of gastrointestinal complications of acute respiratory failure, particularly during mechanical ventilation, have been well described. The major ones include hemorrhage, gastric distention, ileus, diarrhea, and pneumoperitoneum. â&#x20AC;&#x153;Stressâ&#x20AC;? ulceration is extremely common in patients with acute respiratory failure. Associated risk factors include trauma, shock due to a variety of causes, sepsis, renal failure, and liver disease.

Infectious Nosocomial infections are a frequent complication of acute respiratory failure. Principal among these are pneumonia, sepsis, and urinary tract infections. Each typically occurs with the use of mechanical devices, including endotracheal and tracheotomy tubes, indwelling central venous and pulmonary artery catheters, and urinary bladder catheters. The incidence of nosocomial pneumonia in the critically ill may be as high as 70 percent for patients in intensive care units, particularly in those with ARDS. The need for prolonged mechanical ventilation is a harbinger for development of nosocomial pneumonia. Not unexpectedly, nosocomial pneumonia occurring in the medical intensive care unit is associated with a significantly increased length of stay and higher mortality. Guidelines have been developed for treatment of patients with ventilator-associated pneumonia.

Renal Acute renal failure and abnormalities in electrolyte and water homeostasis are not uncommon in critically ill patients with acute respiratory failure; the former is observed in approximately 10 to 20 percent of patients in intensive care units. Development of acute renal failure in a patient with acute respiratory failure carries a poor prognosis and a high mortality. The causes of acute renal failure are numerous and

Respiratory Failure: An Overview

include prerenal azotemia and acute tubular necrosis due to hypotension or use of nephrotoxic drugs.

Nutritional Nutritional complications of acute respiratory failure include the effects of malnutrition on respiratory performance and complications related to the administration of enteral or parenteral nutrition. Complications of enteral nutritional support relate to initial insertion of the catheter (e.g., tracheal or pleural space penetration, pneumomediastinum, pneumothorax, and pleural effusion) and its maintenance (e.g., paranasal sinusitis and aspiration). In addition, vomiting, abdominal distention, and diarrhea are common. Complications of parenteral nutrition are mechanical (e.g., pneumothorax during catheter insertion), infectious (e.g., catheter-related sepsis), or metabolic (e.g., metabolic acidosis, hyperglycemia and hyperosmolar coma, and hypophosphatemia). Hypercapnia, induced by enteral as well as parenteral nutrition, can complicate management of patients who have limited ventilatory reserve.

PROGNOSIS Interpretation of studies addressing the prognosis of patients with acute respiratory failure is subject to a number of constraints, including marked clinical variability in the patients studied, predominance of studies from intensive care units in large university teaching hospitals, and variability in treatment methods employed over the time span of studies performed. In addition, many studies report only hospital mortality, not long-term survival or quality of life. Finally, findings from large-population studies are difficult to extrapolate to prediction of outcome in a single patient. Nonetheless, several generalizations can be made regarding the prognosis of patients hospitalized with acute respiratory failure.

Morbidity and Mortality in Acute Hypoxemic Respiratory Failure As expected, mortality in hypoxemic respiratory failure depends on the underlying cause. A number of studies have addressed outcome in patients with ARDS. Mortality in ARDS appears to have improved in recent years, with overall survival now at about 60 percent. Patients who develop sepsis after trauma have a lower mortality than do patients with sepsis that complicates medical disorders. Not surprisingly, younger patients (those under the age of 70 years) have better survival rates than do older patients. Notably, patients with preexisting lung disease, higher Fio2 or PEEP requirements, or a lower Pao2 may not necessarily have a poorer chance of survival. Approximately two-thirds of patients who survive an episode of ARDS will manifest some impairment of

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pulmonary function one or more years after recovery. The abnormalities include both obstructive and restrictive defects, as well as a reduction in diffusing capacity. The pulmonary function findings do not appear to correlate with whether low or high tidal volumes were used during mechanical ventilation. Pulmonary function abnormalities that persist beyond one year after recovery are unlikely to resolve thereafter. Furthermore, despite recovery of pulmonary function, many survivors of ARDS have persistent functional disabilities one year after discharge, largely due to muscle wasting and weakness. Approximately three-fourths of survivors of ARDS have neurocognitive findings at hospital discharge; in about onehalf, the findings persist at 2 years postdischarge. Indeed, reduced quality of life and persistent neurocognitive defects represent long-term morbidities of survival in ARDS.

Morbidity and Mortality in Acute Hypercapnic Respiratory Failure In general, several parameters presage a higher mortality in patients admitted with hypercapnic respiratory failure: (1) the patient’s “physiological reserve,” as determined by concurrent cardiopulmonary, renal, hepatic, or neurological disease and the patient’s age; (2) the underlying cause of the acute deterioration; (3) the severity of the respiratory failure, as defined by arterial pH and Pco2 ; and (4) development of complications after onset of acute respiratory failure—e.g., sepsis, pneumonia, renal failure, or gastrointestinal bleeding. Cachexia and home confinement before hospitalization may also presage a poorer outcome. These harbingers appear to hold true regardless of whether the patient requires mechanical ventilation. For patients with COPD and acute respiratory failure, overall mortality has declined from approximately 26 percent to 10 percent according to more recent studies. Not unexpectedly, older patients who are significantly more acidemic, hypotensive, or uremic appear to have a higher mortality. The magnitude of the hypoxemia or hypercapnia at the time of presentation may not reliably foretell mortality.

SUGGESTED READING The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000. Bernard, GR: Acute Respiratory Distress Syndrome: A historical perspective. Am J Respir Crit Care Med 172:798–806, 2005. Cunnion KM, Weber DJ, Broadhead WE, et al: Risk factors for nosocomial pneumonia: Comparing adult criticalcare populations. Am J Respir Crit Care Med 153:158–162, 1996.

Curtis JR, Hudson LD: Emergent assessment and management of acute respiratory failure in COPD. Clin Chest Med 15:481–500, 1994. Ely EW, Wheeler AP, Thompson BT, et al: Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med 136:25–36, 2002. Esteban A, Frutos-Vivar F, Ferguson ND, et al: Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 350:2452–2460, 2004. Gammon RB, Shin MS, Groves RH Jr, et al: Clinical risk factors for pulmonary barotrauma: A multivariate analysis. Am J Respir Crit Care Med 152:1235–1240, 1995. Ghio AJ, Elliott CG, Crapo RO, et al: Impairment after adult respiratory distress syndrome: An evaluation based on American Thoracic Society Recommendations. Am Rev Respir Dis 139:1158– 1162, 1989. Grippi MA: Distribution of ventilation, in Grippi MA (ed), Pulmonary Pathophysiology. Philadelphia, JB Lippincott, 1995, pp 41–53. Herridge MS, Cheung AM, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683–693, 2003. Hopkins RO, Weaver LK, Collingridge D, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 171:340–347, 2005. Kress JP, Pohlman AS, O’Connor MF, Hall JB: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471–1477, 2000. Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiology. Philadelphia, JB Lippincott, 1995, pp 267–280. Lanken PN: Respiratory failure: An overview. In Carlson RW, Geheb MA (eds), Principles and Practice of Medical Intensive Care. Philadelphia, WB Saunders, 1993, pp 754–763. Marini JJ, Gattinoni L: Ventilatory management of acute respiratory distress syndrome: A consensus of two. Crit Care Med 32:250–255, 2004. Matthay MA: The adult respiratory distress syndrome: Definition and prognosis. Clin Chest Med 11:575–580, 1990. Milberg JA, Davis DR, Steinberg KP, et al: Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 273:306–309, 1995. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network: Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327–336, 2004. Orme, J Jr, Romney JS, Hopkins, RO, et al: Pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 167:690–694, 2003. Pepe PE, Marini JJ: Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 126:166–170, 1982.

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Piantadosi CA, Schwartz DA: The acute respiratory distress syndrome. Ann Intern Med 141:460–470, 2004. Pingleton SK: Complications of acute respiratory failure. Am Rev Respir Dis 137:1463–1493, 1988. Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685– 1693, 2005. Statement of the American Thoracic Society and the Infectious Disease Society of America: Guidelines for the

Respiratory Failure: An Overview

management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005. Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1995, 2001. Unterborn JN, Hill NS: Options for mechanical ventilation in neuromuscular diseases. Clin Chest Med 15:765–781, 1994. Weiss SM, Hudson LD: Outcome from respiratory failure. Crit Care Clin 10:197–215, 1994.

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144 Acute Respiratory Distress Syndrome: Pathogenesis Michael A. Matthay

Role of Inflammation Role of Direct Toxicity Biologic Markers

I. PATHOPHYSIOLOGY OF PULMONARY EDEMA IN ACUTE LUNG INJURY Vascular Fluid and Protein Exchange Increased Permeability Pulmonary Edema Lung Physiology


II. MECHANISMS OF ACUTE LUNG INJURY Path ological Findings Mediators Role of Infection


This chapter focuses on the pathogenesis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Chapter 145 discusses clinical features and clinical management.

PATHOPHYSIOLOGY OF PULMONARY EDEMA IN ACUTE LUNG INJURY Pulmonary edema occurs when fluid is filtered into the lungs faster than it can be removed. Accumulation of fluid may have major consequences on lung function because efficient gas exchange cannot occur in fluid-filled alveoli. Lung structure relevant to edema formation and the forces governing fluid and protein movement in the lungs has been the subject of classic and more recent reviews and chapters, as noted in the “Suggested Reading” included at the end of this discussion.

Vascular Fluid and Protein Exchange The essential factors that govern fluid exchange in the lungs are expressed in the Starling equation for the microvascular barrier: Jv = LpS[(Pc − Pi) − σd(πc − πi)]


where Jv = the net fluid-filtration rate (volume flow) across the microvascular barrier Lp = the hydraulic conductivity (“permeability”) of the microvascular barrier to fluid filtration (a measure of how easy it is for water to cross the barrier) S = the surface area of the barrier Pc = the pulmonary capillary (microvascular) hydrostatic pressure Pi = the interstitial (“perimicrovascular”) hydrostatic pressure πc = the capillary (microvascular) plasma colloid osmotic (or oncotic) pressure πi = the interstitial (perimicrovascular) fluid osmotic pressure σd = the average osmotic reflection coefficient of the barrier (a measure of the effectiveness of the barrier in hindering the passage of solutes from one side of the barrier to the other) The Starling equation predicts the development of two different kinds of pulmonary edema. Increased pressure pulmonary edema occurs when the balance of the driving forces increases,

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forcing fluid across the barrier at a rate that can no longer be accommodated by lymphatic drainage. Increased permeability pulmonary edema occurs in the presence of ALI that damages the normal barriers to fluid filtration and allows increased flux of liquid and protein into the extravascular compartments of the lungs. Thus, pulmonary edema results from increases in either hydrostatic driving pressures (increased pressure edema) or barrier conductance (increased permeability edema), or both. What distinguishes the two types is barrier permeability, which is normal in increased pressure edema, but abnormal in increased permeability edema. Fluid flow into the lungs is driven across the barrier in both types of edema by the balance of pressures. ALI or ARDS results primarily from an increase in lung vascular permeability, although some cases may be made worse by the presence of elevated lung vascular hydrostatic pressures.

into the interstitial and alveolar spaces. The ability of the lymphatics to pump the excess filtrate away is increased when the lungs are injured. Maximal lung lymph flow increases more when the microvascular wall has been injured than when hydrostatic pressure alone is increased, but even this augmented lymphatic-pumping capability is taxed at lower driving pressures. If the epithelial barrier is injured, edema may accumulate readily in alveoli, because most of the resistance to fluid and protein flow into the alveoli is in the epithelial barrier. Increased permeability edema is often rapid in onset and progression because injured barriers offer much less resistance to flow and because hydrostatic driving pressure is unopposed by increases in osmotic pressure difference. Clinically, many patients with increased permeability edema have a low intravascular hydrostatic pressure, commonly measured as a low or normal pulmonary capillary wedge pressure. In some cases, this reflects the low intravascular pressures associated with the underlying disease process, such as sepsis.

Increased Permeability Pulmonary Edema Increased permeability pulmonary edema is caused by an increase in liquid and protein conductance across the barriers in the lungs. The essential feature is that the integrity of the barrier to fluid and protein flow into the lung interstitium and the alveoli is altered. Increased permeability edema is sometimes called noncardiogenic pulmonary edema, and the resulting clinical syndromes in humans are commonly lumped together as acute lung injury or the acute respiratory distress syndrome. Accumulation of fluid and protein increases when the lung endothelial and epithelial barriers are injured. If the rate of fluid accumulation exceeds the rate at which it can be removed, increased permeability edema occurs. Because the barriers limiting fluid and protein flow into the lungs do not function normally when the lungs are injured, the lungs are not protected against edema by the usual safety factors. Although increases in fluid and protein filtration across the lung endothelium can be removed by lymphatics and drained away from the alveolar walls as in increased pressure edema, much more fluid and protein are filtered at any given sum of driving pressures because the barriers to their flow are much less restrictive than normal. Edema formation in injured lungs is very sensitive to hydrostatic driving pressures. Driving pressures are often increased when the lungs are injured because of the vasoconstrictive effects of inflammatory mediators such as thromboxanes, which may shift the main site of resistance to postcapillary venules, thus increasing hydrostatic pressure at the microvascular fluid exchange sites, or because of effects on the heart as well as on the circulation. For example, elevated left atrial pressure, pulmonary venoconstriction, or an increase in cardiac output in sepsis can increase hydrostatic pressure at the microvascular fluid exchange sites. Because the barriers are leaky, the protective osmotic pressure differences across them are lost; driving pressure is unopposed by osmotic pressure, and even normal hydrostatic pressure results in significant fluid and protein extravasation

Lung Physiology The effects of increased permeability edema on lung mechanics and gas exchange depend, in part, on the magnitude of edema accumulation. As with increased pressure edema, the major effects on pulmonary mechanics occur with alveolar flooding. In experimental lung injury, functional residual capacity is decreased as a consequence of alveolar flooding; the loss of units which can be ventilated accounts for most of the decrease in static lung compliance. Computed tomography has provided new insights into structure-function relationship in human ALI. In the early stage of lung injury, when alveolar edema predominates, the lungs are characterized by a more homogeneous alteration of vascular permeability, and edema can accumulate evenly in all lung regions with a nongravitational distribution. Measurements of pulmonary mechanics in mechanically ventilated patients with ALIs show a decrease in static lung compliance as a consequence of the loss of ventilated lung units. In addition, airflow resistance is increased as a result of decreased lung volume. Bronchospasm may add to the increase in airflow resistance and may be partially reversed in some patients by administration of inhaled bronchodilators. Chest wall compliance is reduced, probably because of alterations in the intrinsic mechanical properties of the chest wall by abdominal distention, chest wall edema, and pleural effusion. Some investigators have reported differing respiratory mechanics and response to positive end-expiratory pressure (PEEP) during mechanical ventilation in patients with ARDS originating from pulmonary disease (e.g., pneumonia, which causes consolidation) versus ARDS due to extrapulmonary disease (which causes edema and subsequent alveolar collapse). Although the effects of surface forces on decreased lung compliance in ALI were once believed to be small, results of experiments in isolated rabbit lungs indicate that increased permeability edema may produce more severe mechanical

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changes than equivalent degrees of increased pressure edema. In contrast, experiments in awake sheep have demonstrated that similar degrees of pulmonary edema, regardless of mechanism, cause similar changes in compliance and gas exchange. Other studies indicate that dynamic and static lung compliances are decreased early in evolving lung injury. Surfactant is strongly thromboplastic, and coagulation may compound surfactant depletion when plasma proteins enter the airspaces. The injured lung may release substances that can interfere with the normal, low surface tension in the alveoli. In addition, activated neutrophils may impair surfactant function in vitro and degrade major surfactant apoproteins through a combination of proteolysis and oxidantradicalâ&#x20AC;&#x201C;mediated mechanisms. In studies using bronchoalveolar lavage, human lung surfactant obtained from patients at risk for ALI and from those with established ALIs has been reported to be abnormal in chemical composition and functional activity. Abnormalities may also be caused by interactions between surfactant and edema proteins, since plasma proteins (especially fibrin monomers, but also fibrinogen and albumin) interfere with surfactant function. Proteinaceous edema fluid has been associated with surfactant inhibition in several experimental models. Gas exchange is severely compromised in increased permeability edema because of both intrapulmonary shunting of blood and ventilation-perfusion inequalities. New evidence indicates that patients with early ALI have a marked increase in pulmonary dead space fraction. This finding indicates that many ventilated lung units are not well perfused, although intrapulmonary shunting may also contribute to the elevated dead space. Not surprisingly, minute ventilation is typically twice normal (approximately 12 L/min) at the onset of ARDS.

Acute Respiratory Distress Syndrome: Pathogenesis

This section focuses on the characteristic pulmonary pathological findings in patients with ALI and ARDS and the mechanisms responsible for ALI.

The injured alveolar epithelium is swollen, disorganized, discontinuous, and, frequently, detached from basement membranes, which may be otherwise intact. The alveolar surface may be covered by hyaline membranes. Type I cells are more severely damaged than type II cells. The thin cytoplasmic extensions of cells far from the nucleus, which cover the thin side of the alveolar-capillary barrier, may be most severely affected. The interstitium is widened by edema (especially in peribronchovascular cuffs) and may be filled with leukocytes, platelets, red blood cells, fibrin, and debris (especially near the alveolar walls). The microvascular endothelium is relatively preserved; it usually shows little other than irregular, focal thickening due to cytoplasmic swelling or vacuoles and greater numbers of luminal leukocytes. After about 5 to 10 days, the exudative phase is followed by a proliferative phase. The relative contributions of the original insult, repair processes, and effects of therapies on this and subsequent phases are not well known. Some abnormalities occurring after the initial exudative phase appear to be related to effects of traditional modes of mechanical ventilation that used tidal volumes between 12 and 15 ml/kg predicted body weight. Reabsorption of some of the edema fluid characterizes the proliferative phase. Fibrin may be prominent in alveoli and interstitium, and infiltration with inflammatory cells and fibroblasts, which may have been activated very early in the course of lung injury, may be seen. The alveolar epithelium is often cuboidal and made up largely of proliferating type II cells. The air-blood barrier may be thickened by interstitial and epithelial enlargement. The pulmonary vascular bed may be partially or completely disrupted, and structural alterations may reduce its surface area. Approximately 2 weeks after the initial insult, a final stage may be observed in which fibrotic changes of the alveolar ducts, alveoli, and interstitium predominate. Alveoli may be obliterated, alveolar walls coalesced, and functional lung units lost. The lungs may be emphysema-like, with extensive bullous changes. Notably, even severe changes at any stage may be reversible during a slow recovery back toward normal lung function.

Pathological Findings


Based on several studies that included a preponderance of postmortem pathology, the light and electron microscopic appearances of human and animal lung tissue in ALI have been described. Exudative, proliferative, and fibrotic changes usually appear in sequence. The earliest changes are marked by widespread alveolar and interstitial edema and hemorrhage. Hyaline membranes, composed of precipitated plasma proteins, fibrin, and necrotic debris are frequently found (Fig. 144-1). The alveolar epithelium may be more extensively damaged than is the vascular endothelium, even if the underlying insult is bloodborne. Widespread, local areas of destruction of type I alveolar epithelial cells alternate with normal-appearing alveoli.

The most common clinical disorders associated with the development of ALI are pneumonia, sepsis, gastric aspiration, and major trauma. Other, less common causes include transfusion-associated lung injury, drug overdose, severe acute pancreatitis, and near drowning. The initiating insult to the lungs occurs either via the airways or the bloodstream. The exact mechanisms by which the lungs are injured have been the subject of intense investigation in humans, animals, and cellular systems. Human studies have provided descriptive data about the events that occur in the airspaces before and after the onset of lung injury. Studies using bronchoalveolar lavage or collection of pulmonary edema fluid


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Figure 144-1 A. A low-power light micrograph of lung biopsy specimen collected 2 days after onset of ALI/ARDS secondary to gram-negative sepsis demonstrates key features of diffuse alveolar damage, including hyaline membranes, inflammation, intra-alveolar red blood cells and neutrophils, and thickening of the alveolar-capillary membrane. B . High-power view of a different field illustrates dense hyaline membrane and diffuse alveolar inflammation. Polymorphonuclear leukocytes are imbedded in the proteinaceous hyaline membrane structure (black arrows). The white arrow points to the edge of an adjacent alveolus, which contains myeloid leukocytes. (Histological sections in A and B courtesy of Dr. K. Jones, University of California, San Francisco). C. Electron micrograph from a classic analysis of ALI/ARDS showing injury to capillary endothelium and alveolar epithelium. LC = leukocyte within the capillary lumen; EC = erythrocytes; EN = blebbing of the capillary endothelium; BM = exposed basement membrane where the epithelium has been denuded; C = capillary; A = alveolar space. (From The ARDS Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301â&#x20AC;&#x201C;1308, 2000, with permission.)

in patients following the onset of ALI have demonstrated a major acute inflammatory response beginning prior to clinical recognition of ALI. The response peaks during the first 1 to 3 days of clinically defined ALI and resolves slowly over 7 to 14 days in patients who remain intubated. These studies have shown the complexity of the evolving inflammatory responses, characterized by accumulation of acute response cytokines and their naturally occurring inhibitors, oxidants, proteinases and antiproteinases, lipid mediators, growth factors, and the collagen precursors involved in the repair process. Hypotheses regarding the mechanisms of lung injury have been tested in animal models and in vitro studies, and several reviews have summarized the findings. The existing

animal models do not completely reproduce all of the aspects of ALI in humans, in part because human ALI evolves over a longer period of time than can be studied in the laboratory. In addition, the lungs of humans are exposed not only to the initial injurious insult, but also to the therapies that are used to treat ALI, such as mechanical ventilation. Experiments using isolated cells have been helpful in testing specific concepts, but the complexity and redundancy of intact biologic systems is not reproduced in simplified experimental systems. By design, most experimental work limits study to one causative agent, thereby reducing actual clinical complexity to the simplicity of a single experimental pathway. Increased permeability edema in humans is likely to be caused by interactions among a number of different pathways acting in parallel or series.

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Studies in isolated organs and small animals in which hemodynamic variables are not measured can be difficult to evaluate. Indices of lung injury, usually measured by the appearance of markers in lungs, lavage fluid, or perfusate, are not determined solely by the barrier function of the microvasculature. Indeed, when vascular endothelium is injured, fluid and protein movement from the vascular space into the lungs is sensitive to hydrostatic driving pressures and filtration surface area. Hence, the effects of experimental interventions may be caused by changes in these parameters and not by changes in microvascular barrier function. The effects of microvascular driving pressures and surface area can be difficult to evaluate, even in large, instrumented animals. In sheep and goats, interpretation of lung lymph fluid and protein flow changes are further complicated by contributions of extrapulmonary lymphatics, physical forces acting on lymphatics, and possible intranodal modification of lymph. Data from experimental animal models suggest that at least two broad categories of mechanisms of ALI are operative: (1) those that are indirect (i.e., require the participation of intermediary mechanisms, e.g., host defenses); and (2) those that are direct (i.e., do not require intermediary mechanisms; injury probably occurs as a result of contact between an offending substance and lung tissue). These categories overlap, since once the lungs are injured, inflammatory responses occur, which may compound the primary mechanism of injury. Three major hypotheses regarding the mechanism of ALI are discussed below. Although discussed separately, they are interrelated.

Role of Infection ALI develops in 20 to 45 percent of patients with severe sepsis. Increased microvascular permeability to albumin has been shown to accompany human sepsis, and infection and the sepsis syndrome are major causes of ALI in humans. Patients who develop shock in response to known or suspected infection have a particularly high incidence of ALI, and the mortality of patients with ALI associated with infection (i.e., sepsis syndrome) is increased. ALI also appears to predispose the lungs to infection, and delayed infection is an important cause of morbidity in patients who survive the initial lung insult. The mechanism by which infection and sepsis syndrome injure the lungs is not certain. The lung injury is likely related to factors other than direct damage by bacteria or other microorganisms, since the prognosis appears unrelated to documented bacteremia or pneumonia. In experimental animals, intravenous infusions of live Pseudomonas aeruginosa or endotoxins from Escherichia coli or surgically induced peritonitis result in increased permeability pulmonary edema. Instillation of endotoxin into the airways of sheep also leads to lung inflammation with variable degrees of lung injury. P. aeruginosa produces lung injury in pigs, and E. coli endotoxin administration injures the lungs of baboons and dogs; neutrophilic alveolitis is observed in rats and mice. ALI caused by endotoxin in sheep is thought to be an inflamma-

Acute Respiratory Distress Syndrome: Pathogenesis

tory response mediated, at least in part, by neutrophils and tumor necrosis factor (TNF). Endotoxin may also affect the clotting system and metabolic functions of the lungs, as well as predispose the lungs to development of pulmonary infections by increasing adherence of bacteria to injured endothelium. Exoproducts of bacteria, such as elastase and Pseudomonas exoenzyme U, also have been shown to injure the lungs. In addition to a direct role in the pathogenesis of lung injury, bacterial products may also have an indirect role by sensitizing the lungs to the effects of mechanical stretch. Gram-negative lipopolysaccharide causes an acute inflammatory response in the lungs of humans. Bacterial endotoxin enhances the responses of human alveolar macrophages to positive pressure ventilation; pretreatment of rats with intravenous endotoxin enhances cytokine production in the lungs during mechanical ventilation ex vivo. Furthermore, mechanical ventilation using moderate or large tidal volumes increases the sensitivity of lung macrophages to endotoxin in vitro and the expression of the endotoxin recognition molecule, CD14, on lung cells in vivo. Endotoxin recognition pathways are increased in the lungs of patients with ARDS, and the biologic effects of endotoxin are amplified in the lungs of patients with lung injury. The synergism between bacterial products and mechanical stretch suggests that interrupting these pathways might limit some forms of ALI in humans. Increased permeability edema is associated with impaired antibacterial defenses. In animal models, bacterial infections worsen ALI. The cause of impaired bacterial defenses in acute ALI is not known. Bactericidal properties of the alveolar lining material might be altered in injured or flooded lungs, and alterations in surfactant concentration and function may be important. Although neutrophils may be present in large numbers in the bronchoalveolar lavage fluid of patients with ALI, evidence indicates that the function of the neutrophils is compromised.

Role of Inflammation Substantial evidence implicates host defenses and inflammatory responses in the underlying mechanism of many ALIs. Neutrophils are a vital component of host defenses, and patients with severe neutropenia are at increased risk of bacterial and fungal infections. On the other hand, neutrophils release toxic oxygen radicals, proteases, and other biologically active mediators that initiate inflammation. Other important cells in pathogenesis include alveolar and pulmonary intravascular macrophages, and eosinophils. Normally, the pulmonary circulation contains a very large pool of marginated neutrophils that change shape in order to squeeze through the lung capillaries. When neutrophils are activated, they stiffen and become less distensible. These neutrophils are retained for longer periods of time in the pulmonary microcirculation. Endothelial activation leads to increased expression of leukocyte adhesion molecules, providing a second mechanism to slow the transit of neutrophils. Trapped neutrophils respond to chemotactic

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gradients generated by chemokines produced by alveolar macrophages and mesenchymal cells and migrate into the airspaces. Activated neutrophils generate and release toxic substances (e.g., oxygen metabolites and granular constituents, such as proteases, and cationic lysosomal enzymes) that disrupt the function of the microvascular and epithelial barriers. Normally, these barriers limit liquid and protein flow out of the vascular space and into the alveolar spaces, mitigating development of permeability edema. Inflammatory responses also have the potential to induce lung cell injury by activating cell death pathways, leading to apoptosis. Bacterial products, such as Pseudomonas Exoenzyme U and mechanical stretch, may lead to direct cellular necrosis. Apoptosis is mediated by a family of death receptors, including TNF and Fas receptors. The Fas ligand (FasL) is a 45 kD peptide that is shed from the cell surface by the action of metalloproteinases. Biologically active soluble FasL (sFasL) accumulates in the lungs of patients with ARDS, inducing apoptotic death of human lung epithelial cells in vitro. Human sFasL induces epithelial cell death in the lungs of rabbits; a monoclonal antibody that activates membrane Fas causes alveolar wall apoptosis and fibrosis in the lungs of mice. Apoptosis and inflammation pathways intersect, as stimulation of membrane Fas induces cytokine production in human macrophages and inflammation in the lungs of rabbits and mice. In addition, lung injury may be able to trigger apoptosis pathways in distant organs, such as the kidney, perhaps by increasing the concentrations of circulating sFasL. Thus, inflammatory responses may trigger cell death pathways, and cell death pathways triggered by sFasL may induce inflammation in the lung alveolar environment. Recent human studies implicate apoptosis in human lung injury.

Role of Direct Toxicity Inflammation is not required for all forms of ALI. ALI or ARDS can develop in neutropenic patients. A clinical trial using granulocyte colony-stimulating factor to increase the number and activation state of circulating neutrophils in patients with severe pneumonia was not associated with an increased incidence of ARDS. Lung injuries that do not require the participation of neutrophils have been described in animal models. Direct lung injury is also thought to occur in humans. Putative agents that directly injure the lungs include mechanical forces during mechanical ventilation, toxic and corrosive chemicals and gases (e.g., hydrochloric and other acids, ozone, ammonia, chlorine, phosgene, nitrogen dioxide, the vapors of cadmium and mercury, combustion products, and oxygen, especially at high concentrations), ionizing radiation, aspiration of fresh water (near drowning) or hydrocarbon compounds (e.g., kerosine, gasoline, and dry-cleaning fluid), high temperatures (parenchymal lung burns from fires or explosions), and mechanical injuries (e.g., lung contusion from nonpenetrating chest trauma or blast injury from explosions or lightning). Many of these injuries develop rapidly, support-

ing the idea that injury is caused directly by contact with the respiratory epithelium in the airways and/or alveolar walls. Inflammatory pathways are likely to be rapidly activated following many types of direct lung injury, as probably occurs following aspiration of gastric secretionsâ&#x20AC;&#x201D;one of the most common clinical causes of ALI. Lung injury occurs rapidly, especially to the epithelium. The injury is probably related, in part, to the low pH of the aspirated stomach contents (aspiration of gastric contents with pH greater than 2.5 is relatively benign; aspiration of gastric contents with pH less than 2.5 causes severe pulmonary injury). Aspirated acid is almost immediately neutralized. However, within hours, proinflammatory mediators are released, the injured lung is infiltrated with neutrophils, fibrin accumulates in the alveolar spaces, and further structural damage is seen on histological examination.

Biologic Markers Considerable interest exists in finding a simple test of blood, urine, or bronchoalveolar lavage fluid that would identify patients at risk for, or in the earliest stages of, ALI, or that might predict clinical outcome. Although products of complement activation have been proposed as markers, their serum levels correlate poorly with lung injury. Measurement of circulating endotoxin is not appropriately sensitive or specific for the presence or risk of developing lung injury. The same is true for measurements of release or activity of angiotensin-converting enzyme. Von Willebrand factor (VWF) antigen may be useful as a plasma marker of impending ALI in patients with nonpulmonary sepsis. Recent work confirms that VWF levels are elevated in the edema fluid and plasma of patients with ALI and correlate with poor clinical outcomes. While increases in other biochemical and inflammatory markers, including surfactant protein D and interleukin-6, correlate somewhat with lung injury and mortality, no simple biologic marker currently serves in the same diagnostic capacity as do cardiac enzymes in evaluation of suspected acute myocardial infarction. Because neutrophils are implicated in the mechanism of many lung injuries, their detection in the lungs, assessment of their function, or assay of the toxic metabolites they release might be useful. For example, increased hydrogen peroxide levels have been measured in the breath and urine of patients with ALI, presumably reflecting the presence of oxygen metabolites in the injured lungs. Evidence of increased oxidant activity has been reported in bronchoalveolar lavage fluid in patients with lung injury. Finally, other mediators of inflammation in ALI have been studied. For example, increased levels of TNF are detected in blood and bronchoalveolar lavage fluid in lung injury, but an association between TNF levels and development of ARDS has not been found. Furthermore, elevated TNF levels are found in patients with severe congestive heart failure. Lipoxygenase products of arachidonic acid metabolism have been detected in pulmonary edema fluid, bronchoalveolar lavage fluid, plasma, and urine, and elastase has been

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Acute Respiratory Distress Syndrome: Pathogenesis

Figure 144-2 Multiple cellular responses and mediators contribute to alveolar-capillary membrane injury (righthand side) and the transition from normal alveolar structure and function (left-hand side) in the acute phase of ALI/ARDS. Original investigations of the pathogenesis of ALI/ARDS searched for single mediators that provided final common pathways to inflammation and alveolar edema. Current concepts of pathogenesis involve multiple molecular factors of several classes, a variety of responding cells, and an imbalance between injurious and reparative signals and pathways. See text and Ware & Matthay (2000) and Matthay & Zimmerman (2005). (Reprinted from Matthay MA, Zimmerman GA: Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319â&#x20AC;&#x201C;327, 2005, with permission.)

detected in bronchoalveolar lavage fluid in the setting of lung injury. ALI follows a wide variety of insults of varying severity. Furthermore, many abnormalities detected in ALI are found in other diverse, severe illnesses that do not involve the lungs. Therefore, the likelihood that any single marker that unequivocally identifies the risk or the presence of ALI will be found seems remote. An investigative focus on particular subgroups of patients with common causes of injury, coupled with study of much larger groups of more definitively diagnosed patients, might prove helpful. An approach that has not received much attention is investigation of the sensitivity and specificity of combinations of biologic markers. The new field of proteomics will expand this type of investigation and, perhaps, identify patterns of protein abnormalities that can be found in plasma, urine, edema fluid, and bronchoalveolar lavage in patients with ARDS.

Figure 144-2 depicts multiple pathways involved in the pathogenesis of ALI and ARDS in the context of normal and injured alveoli. Emphasis is placed on potential pathways for injury across the vascular endothelium and alveolar epithelium.

VENTILATOR-ASSOCIATED LUNG INJURY The most important development of the last 10 years in our understanding of the pathogenesis and treatment of ALI is recognition that the long-standing practice of mechanically ventilating patients with ALI or ARDS using high tidal volumes and airway pressures actually worsens the injury. Animal studies first suggested the potential contributory role of high tidal volumes and elevated airway pressures in the

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pathogenesis of lung injury; subsequently, clinical trials confirmed the findings.

Animal Studies Animal experiments have shown that ventilation using high tidal volumes may increase vascular filtration pressures; produce stress fractures of microvascular endothelium, alveolar epithelium, and basement membranes; and cause lung rupture (so-called ventilation-induced lung injury). The injury appears to be due to increased lung excursions at high volumes (“volutrauma”), rather than the high-airway pressure, per se, since it can be prevented by limiting thoracic motion (e.g., by placing the chest in a cast). The concept of volutrauma was first established in 1974 when investigators found that modestly elevated tidal volumes, especially in the absence of PEEP, caused lung edema in rats. Several years later, additional animal studies further demonstrated the potential injurious role of high tidal volumes and elevated airway pressures, an effect termed ventilator-induced lung injury (VILI). Subsequent experiments demonstrated that VILI could also induce release of several proinflammatory cytokines, injuring the lung and other organs—a process referred to as “biotrauma.” These animal studies stimulated clinical investigation that revolutionized the care of patients with ALI or ARDS.

Clinical Studies The compelling evidence from animal experiments and small clinical trials prompted clinical studies aimed at testing the potential benefit of lower tidal volumes and reduced airway pressures in management of ALI or ARDS. In a large, multicenter, National Heart Lung and Blood–sponsored trial of 861 patients, mortality was reduced from 40 to 31 percent using a tidal volume of 6 ml/kg/ideal body weight and a limited plateau airway pressure of less than 30 cm H2 O. In this trial, use of small tidal volumes was associated with a lower incidence of nonpulmonary organ failure. The protocol for carrying out the lung protective ventilatory strategy is described in detail in Table 144-1. The results of the trial have transformed the management of patients with ALI or ARDS. A follow-up clinical trial has shown that ventilation using the limited tidal volume and plateau pressure of the original study is associated with an overall reduction of mortality to 26 percent. In the follow-up study, although elevated levels of PEEP did not decrease mortality, the basic lung protective strategy was validated as effective. The beneficial mechanism underlying the low tidal volume strategy is unclear. An Italian study has shown that use of low tidal volumes in patients with ARDS attenuates the inflammatory response in both lungs and bloodstream, as measured by reductions in neutrophil and cytokine concentrations in bronchoalveolar lavage and cytokines in circulating blood. Other studies have confirmed a number of these findings. In addition, a reduction in alveolar epithelial injury appears likely, based on a decline in plasma surfactant protein

D levels. Additional clinical and experimental studies are underway. A reduction in lung endothelial and epithelial injury, attenuated inflammatory responses, reduced edema formation, and more rapid resolution of lung edema are likely part of the mechanism(s).

RESOLUTION OF ACUTE LUNG INJURY In the last two decades, considerable progress has been made in understanding the mechanisms responsible for resolution of lung edema. More limited progress has been made in understanding the resolution of lung inflammation. Considerable advances have been made in our understanding of the clearance of fluid and solute from alveoli. Active sodium and chloride transport across the alveolar and distal airway epithelial barriers into the interstitium drives edema fluid removal from the airspaces. The uninjured alveolar epithelium has a remarkable ability to rapidly clear fluid from the airspaces. Even when mild-to-moderate alveolar injury occurs, salt and water transport capacity is often preserved. In severe injury, when the barrier is disrupted, the capacity to clear edema is lost. The vascular endothelium becomes the limiting barrier between the vascular space and airspace. Clinically, the capacity to remove some alveolar edema fluid (as indicated by increase in edema fluid to plasma protein concentration ratio) in the first 12 hours following ALI is a favorable prognostic finding; the associated mortality rate is only 20 percent. In contrast, an inability to resorb alveolar edema fluid early in the course of injury is associated with a mortality of nearly 80 percent. Thus, the function of the alveolar epithelial barrier early in the course of ALI may be a useful prognostic index, serving as a marker of the severity and extent of injury. In uninjured, ex vivo human lungs, alveolar fluid clearance is increased by administration of salmeterol. In addition, experimental studies have shown that even in the presence of ALI and alveolar edema, alveolar fluid clearance can be increased pharmacologically (e.g., by catecholamines), thereby representing a potential therapeutic intervention. Clearance of protein from flooded alveoli is much slower (1 to 2 percent per hour) than clearance of fluid (10 to 20 percent per hour), resulting in an increased concentration of protein in airspaces. If the alveolar edema formed during increased lung vascular permeability clots, its removal from flooded alveoli may be slowed. Clotting may occur because extravasation of plasma into airspaces can lead to clotting system activation by surfactant or macrophage-derived procoagulants. Most of the interstitial water in pulmonary edema lies in the peribronchovascular loose connective-tissue spaces, rather than in alveolar walls. Because the lymphatic capillaries are arranged to drain only the alveolar wall interstitium, this route for edema removal is not significant for most interstitial edema. A study in goats showed that lung lymph originates mainly from alveolar wall interstitial fluid. The contribution

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Acute Respiratory Distress Syndrome: Pathogenesis

Table 144-1 National Institute of Heart, Lung, and Blood, ARDS Network: Lung Protective Ventilatory Strategy Ventilator mode

Volume assist-control

Tidal volume

≤ 6 ml/kg PBW

Plateau pressure

≤ 30 cmH2 O

Ventilation set rate, pH goal

6–35, adjusted to achieve arterial pH ≥7.30, if possible

Inspiratory flow, I:E

Adjust flow to achieve I:E = 1:1–1:3

Oxygenation goal

55 ≤Pao2 ≤80 mmHg or 88 ≤Spo2 ≤95%

FIO2 /PEEP Combinations Fio2















PEEP, cmH2 O














18, 22, 24

(Further increases in PEEP to 34 cmH2 O allowed, but not required) Weaning

Attempts to wean by pressure support required when Fio2 /PEEP ≤0.40/8

PBW = predicted body weight Male PBW = 50 + 2.3 [height (inches) − 60] or 50 + 0.91[height (cm) − 152.4] Female PBW = 45.5 + 2.3[height (inches) − 60] or 45.5 + 0.91[height (cm) − 152.4] I:E = ratio of inspiratory to expiratory duration Pao2 = partial pressure of oxygen in arterial blood Spo2 = oxyhemoglobin saturation measured by pulse oximetry Source: Adapted from Acute Respiratory Distress Syndrome Network: Ventilation with low tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000, with permission.

of the lung lymphatic system to clearance of interstitial edema in bronchoalveolar cuffs and interlobular septa is small. The maximum possible contribution by lung lymphatics to clearance of interstitial edema liquid is less than 10 percent, with airway loss of liquid through evaporation occurring at about twice the rate of lymphatic clearance. In a study of in situ perfused sheep lungs with experimentally induced low- and high-protein pulmonary edema, interstitial liquid was resorbed into the circulation in inverse proportion to its protein concentration. Only a very small fraction of interstitial edema was cleared by the lung lymphatics during recovery from either type of edema. Some fluid from the loose peribronchovascular interstitium may drain directly into the bloodstream by crossing the walls of blood vessels in the lungs. A study of isolated sheep lungs made edematous by raising vascular pressures

showed that the primary route of edema clearance is by vascular resorption (60 percent of filtered water cleared over 3 hours, including 42 percent by resorption into the bloodstream and 18 percent by lymphatic, pleural, and mediastinal drainage). Edema may also drain into the pleural space. Pleural effusions are more common in increased pressure pulmonary edema (25 to 50 percent of patients; usually on the right if unilateral). However, they occur in ALI as well (35 percent of patients). As much as 25 to 30 percent of edema fluid may leave the lungs through the pleural space. A significant portion of the interstitial edema probably follows the prevailing pressure gradient in the lungs to drain into the mediastinum, where it may be picked up by the lymphatics. Short-term alveolar protein clearance appears to proceed primarily by paracellular diffusion. The process depends

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on the size of the proteins. Most proteins are cleared intact, rather than as degraded, smaller fragments. However, a few specific proteins (e.g., vasoactive intestinal peptide and gastrin) are degraded before being cleared. Receptor-mediated clearance may play a role. An albumin-binding protein (albondin) is expressed on lung microvascular endothelial cells. An antibody to this protein reacts with cellular proteins of alveolar epithelial cells, which also appear to have albondinlike binding sites for albumin. In addition, a polymeric immunoglobulin receptor has been described. The significance of these receptors in protein clearance is, however, unclear. Finally, the general consensus is that transcytosis (transport via vesicles) is not a major mechanism for clearing bulk quantities of albumin or other proteins from the alveolar space. Over the long term, phagocytosis and catabolism by macrophages account for most protein clearance from the alveolar spaces. All insoluble, precipitated proteins are removed in this way. Macrophages are also ultimately responsible for removing senescent and dead neutrophils and other debris. The presence of a small, ciliated surface area of the distal airspaces suggests that the mucociliary route accounts for only a minor fraction of alveolar protein clearance. Complete clearance of alveolar protein from pulmonary edema by any route is slow. Little is known about the mechanisms and signals that regulate endothelial barrier function or how increased endothelial permeability is returned to normal.

CONCLUSIONS Among the major advances in respiratory medicine and physiology over the last three decades has been the acquisition of important new knowledge on the physiology of fluid, solute, and protein transport in healthy and diseased lungs. Pulmonary edema, defined as the abnormal accumulation of extravascular lung fluid, is a pathological state that occurs when fluid is filtered into the lungs faster than it can be removed. The many causes of pulmonary edema are grouped into two main pathophysiological categories: (1) increased pressure edema, which results from an increase in hydrostatic or osmotic forces (or both) that act across the barriers that normally restrict movement of fluid and solutes in the lungs; and (2) increased permeability edema, which is seen in ALI in which a breakdown of the normal barrier properties of lung endothelium or epithelium develops. Although these two different types of pulmonary edema share many features, usually they can be distinguished by careful clinical, radiological, and physiological evaluation. They also differ in treatment and prognosis. Major advances in the treatment of ALI have occurred because of the successful application of lung protective ventilatory strategies early in the course of the illness (Table 144-1).

A low tidal volume (6 ml/kg/ideal body weight), coupled with a plateau pressure limit (less than 30 cm H2 O) has resulted in the first therapy demonstrated to reduce mortality in patients with ALI. Recently, the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network published the results of the Fluid and Catheter Treatment Trial (FACTT), a large randomized trial comparing a liberal fluid management strategy to a conservative fluid management strategy in patients with ALI. Patients were also randomized to receive either a pulmonary arterial catheter or a central venous catheter for monitoring and fluid management. There were no differences in clinical outcomes between the pulmonary or central venous catheter utilization. In contrast, there was a marked difference in outcome between the liberal and the conservative fluid management arms of the study. Patients in the conservative fluid management arm had 2.5 more ventilator-free days than those in the liberal fluid management arm with concordant improvements in pulmonary physiology. There was also a 2.9 percent reduction in the 60day mortality rate in the conservative fluid management arm compared with the liberal fluid management arm, although this difference did not reach statistical significance. New insights into the pathogenesis of ALI suggest that other therapies may also prove to be efficacious in reducing mortality in this common form of severe acute respiratory failure. A major development has been the ability to conduct large, prospective, randomized, clinical trials (e.g., those sponsored by the National Heart, Lung, and Blood Institute) to test a variety of therapies important in supportive patient care, including use of mechanical ventilation, intravenous fluids, and a variety of pharmacologic agents. Such trials have led to a better understanding of the pathogenesis of human ALI and have confirmed the importance of ventilator-associated lung injury. In addition, ancillary pathogenetic studies carried out on biologic samples from clinical trials have advanced our understanding of underlying mechanisms. In the future, additional human studies will be needed to explore new therapeutic strategies suggested by basic investigation conducted in animal models of ALI.

SUGGESTED READING Albertine K, Soulier MF, Wang Z, et al: Fas and Fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol 161:1783â&#x20AC;&#x201C;1796, 2002. The ARDS Network: A trial of mechanical ventilation with higher versus lower positive end-expiratory pressures in patients with acute lung injury and acute respiratory distress syndrome. N Engl J Med 351:327â&#x20AC;&#x201C;336, 2004. The ARDS Network: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564â&#x20AC;&#x201C; 2575, 2006.

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The ARDS Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000. Dos Santos CC, Slutsky AS: Invited review: Mechanisms of ventilator-induced lung injury: A perspective. J Appl Physiol 89:1645–1655, 2000. Dreyfuss D, Saumon G: Ventilator-induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med 157:294–323, 1998. Eisner M, Parsons P, Matthay MA, et al and The ARDS Network: Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 58:983– 988, 2003. Hastings R, Folkesson HG, Matthay MA: Mechanisms of alveolar protein clearance in the intact lung. Am J Physiol Lung Cell Mol Physiol 286:L679–L689, 2004. Hirsch J, Hansen KC, Burlingame AL, et al: Proteomics: Current techniques and potential applications to lung disease. Am J Physiol Lung Cell Mol Physiol 287:L1–23, 2004. Imai Y, Parodo J, Kajikawa O, et al: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289:2104–2112, 2003. Lum H, Malik AB: Regulation of vascular endothelial barrier function. Am J Physiol 267:L223–L241, 1994. Matthay MA, Folkesson HG, Clerici C: Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 82:569–600, 2002. Matthay MA, Martin TR: Pulmonary edema and acute lung injury, in Murray JF, Nadel JA (eds), Textbook of Respiratory Medicine, 4th ed, Vol 1. Philadelphia, Elsevier Saunders, 2005, pp 322–329.

Acute Respiratory Distress Syndrome: Pathogenesis

Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319–327, 2005. Matute-Bello G, Winn RK, Jonas M, et al: Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: Implications for acute pulmonary inflammation. Am J Pathol 158:153–161, 2001. Nelson S, Belknap SM, Carlson RW, et al: A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with communityacquired pneumonia. J Infect Dis 178:1075–1080, 1998. Nuckton TJ, Alonso JA, Kallet RH, et al: Pulmonary deadspace fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 346:1281–1286, 2002. Ranieri VM, Suter PM, Tortorella C, et al: Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. JAMA 282:54–61, 1999. Robbins I, Newman JH, Brigham KL: Increased-permeability pulmonary edema from sepsis/endotoxin, in Matthay M, Ingbar, DH (eds), Pulmonary Edema. New York, Marcel Dekker, 1998, pp 203–245. Sakuma T, Folkesson HG, Suzuki S, et al: Beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am J Respir Crit Care Med 155:506–512, 1997. Ware LB, Matthay MA: Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 163:1376–1383, 2001. Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342:1334–1349, 2000.

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145 Acute Lung Injury and the Acute Respiratory Distress Syndrome: Clinical Features, Management, and Outcomes Jason D. Christie

Paul N. Lanken

I. DESCRIPTION AND DEFINITIONS Consensus Definitions of ALI and ARDS Limitations of Consensus Definitions II. EPIDEMIOLOGY Incidence and Mortality Rate Factors Influencing Risk of ALI and ARDS Factors Influencing Mortality from ALI and ARDS III. CLINICAL PRESENTATION AND DIAGNOSIS Path ology and Pathophysiology Clinical Presentation Differential Diagnosis Approach to Clinical Diagnosis

DESCRIPTION AND DEFINITIONS In 1967, Ashbaugh and co-authors described a syndrome characterized by the acute onset of dyspnea, severe hypoxemia, diffuse lung infiltrates, and decreased respiratory system compliance in the absence of evidence for congestive heart failure. The syndrome, initially called acute respiratory distress in adults (to contrast it with acute respiratory distress in neonates), is now known as the acute respiratory distress syndrome (ARDS). Following the initial report, other authors utilized various definitions that incorporated elements related to time of onset, presence of hypoxemia and radiographic infiltrates, and absence of overt congestive heart failure. In 1988, Murray and others introduced the Lung Injury Score (LIS), an assessment tool for ARDS that reflects the extent of radiographic infiltrates, severity of hypoxemia

IV. APPROACH TO TREATMENT Goals of Management Diagnosis and Treatment of Precipitating Causes and Other Comorbidities Management of Respiratory Failure V. CLINICAL COURSE, OUTCOME, AND LONG-TERM SEQUELAE Clinical Course and Duration Trends in Mortality Rates Causes of Death Long-Term Sequelae

and reduced respiratory system compliance, and level of positive end expiratory pressure (PEEP) used in mechanically ventilating affected patients. The LIS incorporates these four parameters that are graded on a scale of 0 to 4: (1) the ratio of PaO2 to FiO2 (PaO2 / FiO2 ); (2) total respiratory compliance; (3) level of PEEP; and (4) extent of radiographic infiltrates (assessed by noting the number of quadrants in the chest radiograph containing infiltrates). The LIS equals the sum of the scores for the four variables divided by four. In clinical studies, a score of 2.5 or more is generally used as a threshold for severe disease.

Consensus Definitions of Acute Lung Injury and Acute Respiratory Distress Syndrome Prior to 1994, published studies used non-uniform definitions of ARDS, prompting an American European Consensus

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 145-1 American European Consensus Conference Criteria for Acute Lung Injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) Clinical Variable

Criteria for Acute Lung Injury

Criteria for Acute Respiratory Distress Syndrome





PaO2 /FiO2 ≤ 300mm Hg

PaO2 /FiO2 ≤ 200 mmHg

Chest radiograph

Bilateral infiltrates consistent with pulmonary edema

Bilateral infiltrates consistent with pulmonary edema

Noncardiac cause

No clinical evidence of left atrial hypertension or, if measured, pulmonary artery occlusion pressure ≤ 18mmHg

No clinical evidence of left atrial hypertension or, if measured, pulmonary artery occlusion pressure ≤ 18 mmHg

Source: Bernard GR, Artigas A, Brigham KL, et al: The American-European Consensus Conference of ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818, 1994.

Conference (AECC) to develop standardized definitions for ARDS and acute lung injury (ALI): a broader category that encompasses ARDS. The AECC definitions included the acute onset of illness, bilateral chest radiographic infiltrates consistent with pulmonary edema, poor systemic oxygenation, and absence of evidence for left atrial hypertension (Table 145-1). The syndrome is ALI when the ratio of PaO2 to FiO2 (PaO2 /FiO2 ) is less than or equal to 300 and ARDS when the ratio is less than or equal to 200. The AECC coined the term ALI to facilitate diagnosing patients earlier in the course of their ARDS and identify patients who have a milder form of acute hypoxemic respiratory failure than ARDS. The AECC definitions of ALI and ARDS are intentionally broad in order to encompass different types of acute hypoxemic respiratory failure occurring in a wide variety of settings. Most patients with ALI progress to ARDS, prompting some to use the composite abbreviation ALI/ARDS to describe all patients with a PaO2 /FiO2 less than or equal to 300 who meet the other AECC criteria (Table 145-1).

Limitations of Consensus Definitions Despite standardization of definitions of ALI and ARDS, little data are available to support their reliability and validity. In fact, various components of the definitions remain problematic: (1) The chest radiograph is subject to variability in interpretation; (2) PaO2 /FiO2 may vary according to ventilator parameters, e.g., PEEP, and at extremes of FiO2 ; and (3) accuracy in excluding the presence of heart failure may be influenced by measurement methodology and timing, as discussed below. Although interpretation of chest radiographs can be inaccurate and variable among observers, formal training can reduce variability.

The PaO2 /FiO2 criterion is influenced by the level of PEEP and other transient factors, including the presence or absence of airway secretions or inadequate sedation. Increasing PEEP generally increases PaO2 at a given FiO2 . The consequent increase in PaO2 /FiO2 may result in a ratio that no longer meets inclusion criteria for ALI. Conversely, without any PEEP, values of PaO2 /FiO2 less than 300 may reflect simple atelectasis rather than ALI or ARDS. Adding PEEP may recruit sufficient atelectatic lung to raise PaO2 /FiO2 greater than 300, thereby excluding such patients from meeting this criterion for ALI. Finally, diagnostic criteria for left atrial hypertension on purely clinical grounds may be inaccurate. Use of a pulmonary artery catheter may also be inconclusive, since the pulmonary artery occlusion pressure (PAOP) in ALI/ARDS may be higher than 18 mm Hg due to intravascular volume loading, particularly in the setting of goal-directed management paradigms for sepsis (see Chapter 146). Conversely, some patients with pulmonary edema due to congestive heart failure and high left atrial pressures have normal pulmonary artery occlusion pressures by the time the catheter is inserted and PAOP is measured. Several clinical trials have used the aforementioned standardized definitions of ALI and ARDS to specify study inclusion criteria for their study populations. Using the AECC definitions of ALI and ARDS in clinical trials that have shown therapeutic benefit adds important validity to the definitions. Clinicians can generalize the results of these trials to clinical decisions involving their own patients if they meet the same criteria for ALI or ARDS as used in the clinical trial. Further refinement of the reliability and validity of definitions of ALI and ARDS are important future directions for clinical studies. More reliable definitions will not only improve estimates of the public health impact of these syndromes, but also will decrease misclassification errors that can be especially

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problematic for research aimed at clarifying mechanisms in ALI and ARDS, e.g., genetic epidemiological studies.

EPIDEMIOLOGY Over the last several decades, the epidemiology of ALI and ARDS has become more clearly delineated.

Incidence and Mortality Rate A landmark epidemiologic study of the incidence of ALI and ARDS in the United States between 1999 and 2000—the King County Lung Injury Project (conducted in King County, Washington)—represents the first broad, population-based epidemiological study of ALI and ARDS in the United States using standardized definitions. Study results included an estimated incidence of ALI of 78.9 per 100,000 person-years and an age-adjusted incidence of 86.2 per 100,000 personyears. The incidence of ARDS was estimated as 58.7 per 100,000 person-years with an age-adjusted incidence of 64.0 per 100,000 person-years. The incidence of ALI increased dramatically with age, with an incidence of 306 per 100,000 person-years for ages 75 through 84 years. By extrapolation, an estimated 190,600 cases of ALI and 141,500 cases of ARDS occur each year in the United States (Table 145-2).

Although prior estimates of the incidence of ALI and ARDS had been lower, those studies were limited by incomplete and nonvalidated data, inaccuracies in the definition of the syndromes, and use of administrative coding. Thus, the estimates from King County Lung Injury Project serve as the best indicator of the public health impact of ALI and ARDS in the United States. During the time of observation in the King County Lung Injury Project study, the mortality from ALI was 38.5 percent and from ARDS was 41.1 percent. These figures translate into an estimated 74,500 annual deaths from ALI in the United States. To put this mortality rate in perspective, more people die annually from ALI than from AIDS, asthma, and breast cancer combined. Other than lung cancer, ALI is responsible for more annual deaths than any cause of cancer, including lymphomas, leukemias, and breast, prostate, colon, ovarian, and pancreatic cancers (Table 145-3). Although the mortality rates from ALI and ARDS may have fallen since the King County Lung Injury Project was conducted in 1999– 2000 (due to usage of low tidal volume ventilation strategies), ALI and ARDS likely still have a major public health impact.

Table 145-3 Estimated Annual Number of Deaths in the US from Selected Causes

Table 145-2


Estimated Incidence, Hospital Days and Intensive Care Unit (ICU) Days for Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) in the United States (US)








Crude incidence, per 100,000 person-years



Age-adjusted incidence, per 100,000 Person-years



Estimated annual Number of cases in US


Estimated annual number of hospital days in US


Estimated annual number of days in ICU in US





From Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685, 2005.



Number of Deaths




Breast cancer




Lung cancer




Ovarian cancer


Pancreatic cancer


Prostate cancer


∗ Includes

59,000 deaths from ARDS. Source: Data for ALI and ARDS are from Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685, 2005; all other are from CDC National Center for Health Statistics (

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Furthermore, as the population of the United States becomes older, the incidence of ALI and its associated annual death rate can be expected to rise. Precipitating Causes The severe extensive lung inflammation in ALI and ARDS represents the common final pathogenetic process in response to a large variety of precipitating causes, which result in either direct or indirect (systemic) lung injury. In general, direct causes of ALI include those that originate within the lung, such as aspiration of gastric contents or viral pneumonia. Examples of indirect causes include severe systemic inflammatory response syndrome (SIRS) or severe sepsis, ingested toxins, hypotension, and ischemia-reperfusion injury. Although some causes of ALI may fit into either category (e.g., multilobar pneumonia with septic shock), the classification scheme is useful both for considering the many predisposing causes of ALI and their varying mechanisms of lung injury and for future development of therapies aimed at different categories of ALI. Table 145-4 lists precipitating causes of ALI and ARDS according to this construct.

Factors Influencing Risk of ALI and ARDS Not all patients with an underlying cause (e.g., sepsis) for ALI or ARDS develop the syndrome. In addition to inherent risk differences within at-risk populations, specific clinical variables may be important. Clinical variables found to be associated with an increased risk of ARDS include chronic alcohol abuse, hypoproteinemia, advanced age, increased severity, and extent of injury or illness as measured by injury severity score (ISS) or APACHE score, hypertransfusion of blood products, and possibly, cigarette smoking. Diabetes mellitus decreases the risk of ALI. Since many of the studies addressing this issue are retrospective or based on a single center’s experience, the consistency and generalizability of identified risk factors have not been confirmed. Nonetheless, the mechanistic underpinnings of these probable associations are the subject of ongoing research.

Factors Influencing Mortality from ALI and ARDS Clinical variables at the onset of ALI and ARDS that are associated with increased mortality include advanced age, lower PaO2 /FiO2 , high plateau pressure (i.e., low respiratory system compliance), greater extent of pulmonary infiltrates, chronic liver disease, nonpulmonary organ dysfunction, increased global severity of illness, hypoproteinemia, and greater length of hospitalization prior to onset of ALI/ARDS. In addition, an increased dead space fraction has been identified as a risk factor for increased mortality, possibly indicating the importance of early loss of the pulmonary vascular bed as a sign of greater disease severity. Although various precipitating causes of ALI and ARDS carry somewhat different prognoses,

Table 145-4 Common Direct and Indirect (Systemic) Precipitating Causes of ALI and ARDS Direct Precipitating Cause

Indirect (Systemic) Precipitating Cause∗

Aspiration of gastric fluids

Acute pancreatitis

Bacterial pneumonia (diffuse), e.g., Legionnaire’s disease

Blood transfusions with transfusion-related acute lung injury (TRALI)

Chest trauma with lung contusion

Post-cardiopulmonary bypass


Primary graft failure of lung transplantation

Pneumonia due to Pneumocystis carinii

Severe sepsis and septic shock

Toxic inhalations, e.g., smoke inhalation, inhaled crack cocaine

Toxic ingestions, e.g., aspirin, tricyclic antidepressants

Viral pneumonia, e.g., influenza, severe acute respiratory syndrome (SARS)

Trauma with multiple fractures and the fat-emboli syndrome

∗ In

indirect or systemic mechanism of lung injury, the lung injury results from deleterious effects on the alveolar epithelium by inflammatory or other mediators delivered via the pulmonary circulation (see Chapters 144 and 146 Matthay Deutschman for details). Source: Christie JC, Lanken PN: Acute lung injury and the acute respiratory distress syndrome, in Hall JB, Schmidt GA, Wood LDH (eds): Principles of Critical Care, 3d ed. New York, McGraw-Hill, 2005; p 518, reproduced with permission.

the strategy of low tidal volume ventilation utilized by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI)–sponsored ARDS Clinical Trials Network (ARDSNet) as part of its clinical trials appears to be equally efficacious in all subgroups.

CLINICAL PRESENTATION AND DIAGNOSIS The clinical presentation and diagnosis of ALI/ARDS are fundamentally related to the syndrome’s pathophysiological changes, regardless of the underlying etiology. A brief description of the pathology and pathophysiology is provided before a detailed discussion of clinical aspects of the disorder. The reader is also referred to Chapter 144 for additional details on disease mechanisms.

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Pathology and Pathophysiology

100% O2

A number of inter-related mechanisms contribute to the development and clinical course of ALI and ARDS. Inflammatory cytokines, oxygen radicals, activation of coagulation and complement, platelet and immune cell activation, generation of proteases, and abnormal fluid fluxes resulting in edema fluid generation and defective epithelial alveolar fluid clearance have all been hypothesized to play a role in the early stages. In addition, factors specific to apoptosis, edema fluid resolution, and fibrosis and repair, as well as the response to mechanical ventilation are likely to play a role in the pathophysiology of the later phases of ALI and ARDS. Pathologically and clinically, ALI can be divided into early and late phases of lung injury (Fig. 145-1). In the early phase (first few hours or days), light microscopy shows interstitial and alveolar edema, capillary congestion, and intraalveolar hemorrhage with minimal evidence of cellular injury. Electron microscopy reveals changes of endothelial cell swelling, widening of intercellular junctions, increased numbers of pinocytotic vesicles, and disruption and denudation of the basement membrane. Inflammatory cell infiltration of the lung interstitium may also be seen. Protein-rich pulmonary edema and its clinical effects are most pronounced in the early exudative phase. Hyaline membranes containing condensed fibrin and plasma proteins form over the next several days. Later in the exudative phase, inflammatory cells become more numerous within the lung interstitium, and extensive necrosis of type I alveolar epithelial cells is present.




Hyaline Membranes

PROLIFERATIVE STAGE Interstitial Inflammation

Interstitial Fidrosis.





2 3 4 5 6 7 8 9 10 11 12 13 14 TIME FOLLOWING INJURY (DAYS)

Figure 145-1 Schematic representation showing time course of evolution of the acute respiratory distress syndrome (ARDS). The early or exudative phase is characterized by a pulmonary capillary leak with interstitial and alveolar edema and hemorrhage followed by hyaline membrane formation. Within as short a period of time as 7 to 10 days, a proliferative phase may appear with marked interstitial and alveolar inflammation and cellular proliferation, followed by fibrosis and disordered healing (see text for discussion). (Reproduced with permission from Katzenstein AA, Askin FB: Surgical Pathology of Non-Neoplastic Lung Diseases, 2nd ed. Philadelphia, Saunders, 1990.)

PA O2 =650 Pvo2 = 40 mmHg Cvo = 15 ml % 2 CCO = 22 ml% 2

CaO2= 18.5 ml% PaO2= 60 mm Hg

Figure 145-2 Diagram of a two-compartment model of lung perfusion and ventilation demonstrating basis for failure of oxygenation in ALI and ARDS. When large portions of the lung are nonventilated due to alveolar collapse or flooding (hatched area), blood flow to these units with mixed venous PO2 (P¯vO2 ) of 40 mmHg and content of 15 vol percent is effectively ‘‘shunted” through the lungs without being resaturated. Thus, despite a high concentration of supplemental oxygen (100 percent in this example) and high alveolar PO2 in ventilated unit, these blood flows mix in accord with their oxygen contents, i.e., the resulting left atrial blood has an oxygen content that is the weighted mean of the oxygen content of the shunted and non-shunted blood. In this example of a 50 percent shunt, the left atrial and systemic arteries have an arterial PO2 of 60 mmHg. CaO2 = arterial oxygen content; CCO2 = capillary oxygen content; C¯vO2 = mixed venous oxygen content; PA = alveolar pressure; PaO2 = arterial PO2 ; P v¯ O2 = partial pressure of oxygen in the mixed venous blood. (Reproduced with permission Christie JD, Lanken PN: Acute Lung Injury and The Acute Respiratory Distress Syndrome, in Hall JB, Schmidt GA, Wood LDH (eds.): Principles of Critical Care, 3rd ed. New York, McGraw-Hill, 2005; p 516.)

Pathologists refer to this constellation of findings as diffuse alveolar damage (DAD). Pathophysiologically, in the exudative phase, alveolar edema and alveolar collapse, i.e., atelectasis due to loss of normal surfactant-related stabilization of alveoli, interfere with oxygenation. Surfactant is both washed out of alveoli and inactivated by the alveolar edema. The hypoxemia in ALI/ARDS is typically resistant to supplementary oxygen, reflecting an increased right-to-left shunt (Fig. 145-2). Continued perfusion of alveoli that lack ventilation because of alveolar edema ˙ Q) ˙ ratios of zero, thereby results in ventilation-perfusion (V/ defining physiological shunt. Furthermore, the effects of this type of shunt are exacerbated by shuntlike contributions from alveoli with very low ventilation-perfusion ratios. Disordered healing and proliferation of fibrous tissue dominate the late phase of ARDS or persistent ARDS, i.e., the proliferative or fibroproliferative phase. Type II alveolar cells, fibroblasts, and myofibroblasts proliferate in this phase, which can occur as early as 7 to 10 days after initial injury. The late phase of ARDS is characterized by an increased dead space fraction, high minute ventilation requirement,

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pulmonary hypertension, and further reduction in lung compliance.

Table 145-5

Clinical Presentation

Differential Diagnosis of Acute Hypoxemic Respiratory Failure (AHRF)

The development of ALI and ARDS usually follows a rapid course, occurring most often within 12 to 48 hours of the predisposing event. At its onset, patients with ALI and ARDS often become anxious, agitated, and dyspneic. Inflammatory changes in the lung decrease lung compliance, which, in turn, leads to an increased work of breathing, small tidal volumes, and tachypnea. Marked tachypnea and dyspnea are invariably present in subjects with ALI. If breathing ambient air or lowflow supplementary oxygen, patients with ALI typically have initial arterial blood gas results showing a PaO2 less than 50 to 55 mm Hg and pulse oximetry recordings of less than 85 percent arterial O2 saturation. The hallmark of ALI and ARDS is hypoxemia that is resistant to oxygen therapy because of the large right-to-left shunt (Fig. 145-2). Initially, patients may be able to compensate by hyperventilating, thereby maintaining an acceptable PaO2 with an acute respiratory alkalosis. Typically, patients deteriorate over several hours, requiring endotracheal intubation and mechanical ventilation. However, the need for mechanical ventilation is not necessary for establishing the diagnosis of ALI or ARDS. Selected patients with milder lung injury and a normal level of consciousness can be treated successfully with high-flow oxygen therapy, with or without a continuous positive airway pressure (CPAP) mask, or noninvasive assisted ventilation.

Differential Diagnosis The differential diagnoses for acute hypoxemic respiratory failure, in general (Table 145-5), and for ALI and ARDS, in particular (Table 145-6), are extensive. Identifying the specific etiology of the diffuse infiltrates in ALI or ARDS is important because several, e.g., acute eosinophilic pneumonia or diffuse alveolar hemorrhage, have specific therapies. Table 145-6 lists the major clinical and diagnostic characteristics of these disorders. The setting in which respiratory failure occurs usually provides important diagnostic information. ALI and ARDS commonly arise following development of a typical predisposing factor (Table 145-4). Sepsis, pneumonia, trauma, transfusion of blood products, and gastric aspiration account for the majority of cases. When an inciting event is obvious and diagnostic criteria (Table 145-1) are met, establishment of a clinical diagnosis of ALI or ARDS is not difficult. Under such circumstances, management can be instituted immediately. However, in the absence of a clear predisposing event, or when conflicting or ambiguous information exists, the other causes listed in Table 145-6 should be considered and relevant clues from the history and physical examination sought. For example, cardiogenic edema is most often accompanied by systolic left ventricular or valvular dysfunction, and the appropriate

1. 2. 3. 4. 5.


7. 8. 9. 10. 11.

ALI or ARDS Acute (or “flash”) cardiogenic pulmonary edema Bilateral aspiration pneumonia Lobar atelectasis of both lower lobes Severe unilateral lower lobe atelectasis, especially when patient is receiving vasodilators, such as intravenous nitrates, calcium-channel blockers, or sodium nitroprusside, that blunt hypoxic vasoconstriction Acute loss of ventilation to one lung due to complete or near-complete obstruction of its mainstem bronchus, e.g., due to a mucus plug or blood clot Loss of ventilation to one or both lungs due to large pneumothorax/pneumothoraces Loss of ventilation to one or both lungs due to large pleural effusion(s) Diffuse alveolar hemorrhage, especially in patients post–bone marrow transplantation Massive pulmonary embolus Acute opening of a patent foramen ovale in patient with preexisting pulmonary hypertension

Abbreviations: ALI = acute lung injury; ARDS = acute respiratory distress syndrome. Source: Christie JD, Schmidt G, Lanken PN: Acute respiratory distress syndrome: d349.html, July 2004. Physicians’ Information and Education Resource. Philadelphia, American College of Physicians, reproduced with permission.

history and physical findings (e.g., a heart murmur or ventricular gallop) are often present. Electrocardiographic and laboratory-based evidence (e.g., serum troponin I levels) of cardiac ischemia suggest cardiogenic edema as a likely cause. Additional important tests that help to differentiate ALI and ARDS from other causes of acute hypoxemic respiratory failure are discussed below.

Approach to Clinical Diagnosis A number of diagnostic methods are extremely valuable in evaluating suspected ALI or ARDS. Each is briefly described below. Chest Radiograph The chest radiograph is a simple and widely available test used to assess patients with acute hypoxic respiratory failure. In cases of established ALI or ARDS, the chest radiograph typically demonstrates findings of diffuse, bilateral alveolar infiltrates consistent with pulmonary edema (Fig. 145-3). However, especially early in the course of the disorder, the infiltrates associated with ALI and ARDS may be variable: mild or dense, interstitial or alveolar, patchy or confluent.

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Table 145-6 Differential Diagnosis of ALI and ARDS Disorder



Pulmonary edema due to left heart failure.

History of cardiac disease, enlarged heart on chest radiograph, third heart sound.

Rapid improvement with diuresis and/or afterload reduction.

Noncardiogenic pulmonary edema

History of one or more precipitating causes (Table 145-4), crackles absent or not prominent, normal cardiac size on chest radiograph.

Usual etiology for ALI and ARDS. Rarely some patients with ALI or ARDS have no obvious precipitating cause.

Diffuse alveolar hemorrhage (DAH)

Often associated with autoimmune diseases (e.g., vasculitis) or following bone marrow transplantation. Often patients do not have bloody sputum. Renal disease or other evidence of systemic vasculitis may be present. Hemosiderin-laden macrophages in bronchoalveolar lavage fluid can confirm diagnosis of DAH. May respond to apheresis, corticosteroids, or cyclophosphamide, depending on etiology.

May meet diagnostic criteria for ARDS (Table 145-1), but has different pathophysiology and management.

Acute eosinophilic pneumonia

Cough, fever, pleuritic chest pain, and myalgia are often present. Patients often do not have peripheral blood eosinophilia, but generally have greater than 15% eosinophils in bronchoalveolar lavage fluid. Usually responds rapidly to high-dose corticosteroid therapy.

May meet diagnostic criteria for ARDS (Table 145-1), but has diffeent pathophysiology and management.

Lupus pneumonitis

Usually associated with active lupus. May respond to high-dose corticosteroid therapy or cyclophosphamide

May meet diagnostic criteria for ARDS, but has different pathophysiology and management.

Acute interstitial pneumonia (AIP)

Slower onset than ARDS (over 4–6 weeks) with progressive course. However it may present in advanced state, mimicking ARDS.

Associated with >90% mortality. AIP includes Hamman-Rich syndrome.

Pulmonary alveolar proteinosis (PAP)

Slower onset than ARDS (over 2–12 months) with progressive course. Can be treated with whole lung lavage.

Characteristic “crazy paving” pattern on high-resolution CT scan of chest.

Bronchiolitis obliterans with organizing pneumonia (BOOP) or cryptogenic organizing pneumonia

May be precipitated by viral syndrome. Slower onset than ARDS (over >2 weeks) with progressive course. However it may present in advanced state, mimicking ARDS. May respond to high-dose corticosteroid therapy. (Continued )

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Table 145-6 (Continued ) Disorder



Hypersensitivity pneumonitis

Typically slower onset than ARDS (over weeks) with progressive course. However, it may present in advanced state, mimicking ARDS. May respond to high-dose corticosteroid therapy and removal from offending agent.

Leukemic infiltration

May be rapid in onset during active disease states. Usually leukemia is clinically apparent.

Drug-induced pulmonary edema and pneumonitis

May follow use of heroin, other opioids, overdose of aspirin, tricyclic antidepressants, or exposure to paraquat.

May progress to overt ARDS.

Acute major pulmonary embolus (PE)

Occurs acutely, occasionally accompanied by severe hypoxemia that may be resistant to O2 therapy like ARDS, and by hypotension, requiring pressors, mimicking ARDS with sepsis. Patients typically have risk factors for acute PE and may not have common precipitating causes of ARDS.

Chest radiograph in ARDS should have bilateral infiltrates consistent with pulmonary edema. Chest radiograph in acute major PE may have unilateral or no infiltrates. Acute major PE needs a confirmatory study, e.g., CT scan with pulmonary embolism protocol.


The onset is not acute, but its clinical recognition may be. Oxygenation is often impaired and the chest radiograph can be diffusely abnormal.

Historical features and the frequent presence of hilar adenopathy in sarcoidosis usually eliminate confusion with ARDS.

Interstitial pulmonary fibrosis

The onset is not acute, but its clinical recognition may be. Oxygenation is often impaired and the chest radiograph can be diffusely abnormal.

Prior chest radiographs and a history of chronic and progressive dyspnea characterize the collection of diseases causing interstitial pulmonary fibrosis.

Abbreviations: AIP = acute interstitial pneumonia; ARDS = acute respiratory distress syndrome; CT = computed tomography; DAH = diffuse alveolar hemorrhage. Source: Christie JD, Schmidt G, Lanken PN: Acute respiratory distress syndrome., July 2004. Physicians’ Information and Education Resource. Philadelphia, American College of Physicians, reproduced with permission.

In addition, the radiographic infiltrates may not correlate well with the degree of hypoxemia. For example, a patient with early ALI and ARDS may have profound hypoxemia in the setting of patchy asymmetrical infiltrates that may be interpreted as pneumonia or segmental atelectasis. Routine chest radiographs cannot reliably distinguish hydrostatic edema, i.e., cardiogenic edema, from ALI and ARDS. Nonetheless, several criteria suggest cardiogenic edema: increased heart size, increased width of the vascular pedicle, vascular redistribution toward upper lobes, the presence of septal lines, or a perihilar (“bat’s wing”) distribution of the edema. Lack of these findings, in conjunction with patchy peripheral infiltrates that extend to the lateral lung margins, suggests ALI

or ARDS. In the proper clinical setting, despite a variable radiographic appearance, the presence of bilateral infiltrates and moderate or severe hypoxemia (PaO2 /FiO2 less than or equal to 300 mmHg) should raise the possibility of ALI or ARDS. Laboratory Studies Although no laboratory test is specific for the diagnosis of ARDS, arterial blood gas analysis is essential for confirming the diagnosis of ALI or ARDS. PaO2 /FiO2 is markedly abnormal in patients with ALI and ARDS (Table 145-1). In addition to the profound oxygen therapy–resistant hypoxemia that is the hallmark of ALI and ARDS, acute respiratory alkalosis

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Figure 145-3 Chest CT and plain radiograph in ARDS. A. Chest CT scan reveals asymmetric lung injury, with dense consolidation at the right base, patchy alveolar infiltrates in the right anterior lung field, and patchy ground-glass infiltrates throughout the right lung. B . Chest radiograph obtained concurrently with chest CT scan shown in panel (A). Dense infiltrates at right base, patchy infiltrates in the right upper lung zone, and more subtle infiltrates in the left lung are demonstrated. The panels illustrate the subtle findings of lung injury that are more apparent on the CT scan than on the chest radiograph.

may also occur in the early stage. If a patient with ALI and ARDS then develops respiratory muscle fatigue, hypercapnia results. In late-stage ALI, patients typically have increased minute ventilation requirements due to an increasing deadspace fraction, despite possible improvement in oxygen exchange. In addition to arterial blood gas measurements, several other laboratory studies may be helpful in investigating other causes of respiratory failure and evaluating additional aspects of critical illness associated with ALI or ARDS. For example, cardiac enzymes (creatine phosphokinase and troponins) are useful for evaluating the presence of myocardial infarction or cardiac ischemia in patients at risk because of increased age or other factors. The results should be interpreted in conjunction with electrocardiographic findings, since elevations in cardiac enzymes, especially troponins, have been reported in patients with sepsis or septic shock in the absence of coronary artery disease. Another cardiac-related laboratory test that may be useful in this clinical context is plasma brain natriuretic peptide (BNP), which is secreted by the cardiac ventricles, and, to a lesser extent, the atria. BNP measurements are often utilized in the evaluation of acute shortness of breath in patients presenting to an emergency department. In this group, a BNP greater than 500 pg/ml indicates that congestive heart failure (CHF) is likely with a positive predictive value greater than 90 percent. In the same group, a BNP less than 100 pg/ml suggests that congestive heart is unlikely with a negative predictive value greater than 90 percent. However, interpretation of an elevated BNP in patients who are critically ill is problematic. Reports indicate that BNP increases with renal failure, and that elevations of BNP greater than 500 pg/ml may occur

in patients with sepsis and normal left ventricular function. Nonetheless, one can reasonably exclude a cardiac cause for acute pulmonary edema in patients in the intensive care unit if BNP is less than 100 pg/ml. Echocardiography Echocardiography is a useful noninvasive method to evaluate potential cardiac causes of acute hypoxemic respiratory failure. Cardiogenic pulmonary edema is suggested by echocardiographic findings of mitral valve stenosis or regurgitation, left ventricular dilatation and systolic dysfunction, or regional left ventricular wall motion abnormalities. Although these findings do not rule out coexisting lung injury, they are helpful in the initial evaluation and management, even in the presence of ALI or ARDS. Invasive Hemodynamic Monitoring Although right-heart catheterization has been performed often in patients with pulmonary edema, the benefits of the procedure are controversial and the topic of recent investigations (see Chapter 152). Several studies have demonstrated that physician interpretation of data obtained from right heart catheters is inconsistent and often erroneous. Furthermore, one observational study suggested that routine right-heart catheterization is harmful in critically ill patients with acute hypoxemic respiratory failure. The utility of the pulmonary artery occlusion pressure, also known as pulmonary artery wedge pressure (PCWP), in the diagnosis of ALI or ARDS is questionable. Studies have shown that many patients who originally met criteria for ALI or ARDS (i.e., had a pulmonary artery occlusion pressure less

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than or equal to 18 mm Hg) often have subsequent measurements with the PAOP greater than 18 mm Hg. Finally, recent results from the ARDSNet Fluid and Catheter Treatment Trial (FACCT) support the contentions that the AECC’s decision to use a PAOP of greater than 18 mmHg to exclude ALI/ARDS was arbitrary and that the threshold of greater than 18 mmHg needs re-examination. FACTT was a large, randomized clinical trial that used a two-by-two factorial design to test a fluid-conservative management strategy against a fluid-liberal management strategy in ALI and ARDS and to assess safety and efficacy of a central venous catheter (CVC) or pulmonary artery catheter (PAC) to guide fluid management. In FACTT, 29 percent of 513 patients enrolled in the PAC arm of the trial were found to have a PAOP greater than 18 mm Hg at the time of initial measurement (following passage of the catheter shortly after enrollment and randomization). Before enrollment, FACTT investigators believed that these patients lacked a primary cardiogenic cause for their pulmonary edema. Approximately one half of these subjects had PAOPs of 19 or 20 mmHg. Since the vast majority (97 percent) of this group had a normal cardiac index (greater than or equal to 2.5 L/m2 /min), and a mortality similar to other subjects in FACTT, the elevated PAOP (greater than 18 mmHg) likely reflected intravascular volume loading rather than cardiogenic pulmonary edema. Bronchoalveolar Lavage Bronchoscopy with bronchoalveolar lavage (BAL) is an important tool in the evaluation of patients who have ALI or ARDS of unclear origin. In general, BAL can be performed safely in patients with ALI or ARDS, except in those with a very low PaO2 or requiring high levels of PEEP. The principal reason for performing bronchoscopy in ALI or ARDS is to rule in or rule out acute processes that may have specific therapies. For example, acute eosinophilic pneumonia is a rare disorder characterized by diffuse eosinophilic infiltrates in the lungs (Table 145-6). When the precipitating cause for ALI or ARDS is uncertain, performance of BAL and measurement of the percent eosinophil count in the lavage fluid is helpful in establishing a diagnosis of this corticosteroid-responsive disorder. Likewise, BAL can be diagnostic for diffuse alveolar hemorrhage (see Chapter 77). In this case, the bronchoscopy may or may not reveal fresh blood in the trachea and major bronchi. However, BAL generally demonstrates a bloodtinged fluid, which contains red blood cells and hemosiderinladen macrophages. Diffuse alveolar hemorrhage may occur following bone marrow transplantation or as a result of rheumatologic or other immunologic disorders, including Goodpasture’s syndrome, Wegener’s granulomatosis, systemic lupus erythematosus, or anti-phospholipid antibody syndrome.

APPROACH TO TREATMENT Goals of Management Management of patients with ALI or ARDS can be complicated and challenging because clinicians are often faced with simultaneous failure of both respiratory and nonrespiratory organ systems (Table 145-7). Unfortunately, only a limited set of controlled clinical trials are available to support an evidenced-based approach. For example, even large, multicenter, randomized clinical trials, such as those done by ARDSNet, are limited in the number of variables that can be tested. As a result, patient management rests on a combination of relevant evidence-based medicine, extrapolations from basic and clinical research, and experience-based approaches.

Diagnosis and Treatment of Precipitating Causes and Other Comorbidities The first step in the therapy of ALI or ARDS is identification and treatment of the precipitating cause(s) and any other life-threatening medical or surgical issues (Fig. 145-4).

Table 145-7 Goals of Management of Patients with ALI and ARDS Treatment of respiratory system abnormalities Diagnose and treat the precipitating cause of ALI/ARDS, if possible (Table 145-8) Maintain oxygenation, preferably using nontoxic FiO2 (<0.7), PEEP, or mechanical ventilation Prevent ventilator-induced lung injury (VILI) by using a low tidal volume ventilatory strategy (Table 145-9) with a limit (≤30 cm H2 O) on static end-inspiratory airway pressure (plateau pressure) Keep pH in normal range without compromising goal to prevent VILI (but reverse a life-threatening acidosis, even if it prevents meeting goal to prevent VILI) Enhance patient-ventilator synchrony and patient comfort by use of sedation, amnesia, opioid analgesia, and pharmacological paralysis, if necessary Liberate or wean from mechanical ventilation when patient can breathe without assisted ventilation Treatment of non-respiratory system abnormalities Support or treat other organ system dysfunction or failure General critical care (preventive and homeostatic measures) Adequate early nutritional support

2545 Chapter 145 Patient presents with ALI/ARDS


Table 145-8 Treatable Inciting Causes of ALI and ARDS

Treat precipitating cause(s) of ALI/ARDS and other serious comorbidities

Provide other ICU supportive care

Ventilatory management of respiratory abnormalities

Provide adjuncts to ventilator management as needed

Treat inflammation and coagulation abnormalities as appropriate

Monitor patient during the course of ALI/ARDS


Rehabilitation and Recovery

Figure 145-4 Summary of treatment approach to ALI and ARDS. Note that, ‘‘Treat inflammation and coagulation abnormalities as appropriate,” is currently limited. Examples include treatment of patients with severe sepsis and multiple organ dysfunction using recombinant drotrecogin alpha (activated) and administration of replacement-dose corticosteroids in patients with severe sepsis and septic shock who have relative adrenal insufficiency. In the ARDSNet ‘‘LaSRS”clinical trial, physiological improvement, but no mortality benefit, was found with high-dose corticosteroid therapy for persistent (late phase) ARDS (see text for details). (Reproduced with permission Christie JD, Lanken PN: Acute lung injury and the acute respiratory distress syndrome, in Hall JB, Schmidt GA, Wood LDH (eds): Principles of Critical Care, 3rd ed. New York, McGraw-Hill, 2004; p 525.)

Since ALI and ARDS are syndromes based on nonspecific radiographic and physiologic criteria, establishing a diagnosis of ALI or ARDS is not equivalent to diagnosing the precipitating cause. The fact that early identification and treatment directed at the inciting cause(s) of ALI and ARDS are imperative for resolution of lung injury and respiratory failure cannot be overemphasized. Treatable inciting causes of ALI and ARDS include a variety of infectious and noninfectious disorders (Table 145-8).

Management of Respiratory Failure Management of respiratory failure in ALI or ARDS rests on assurance of adequate oxygenation and carefully crafted ventilatory strategies, as outlined below.

Infectious etiologies Bacterial or other sepsis, e.g., fungemia, responsive to antimicrobial therapy Diffuse bacterial pneumonias, e.g., Legionella species Diffuse viral pneumonias, e.g., cytomegalovirus, influenza A Diffuse fungal pneumonias, e.g., Candida species, Cryptococcus Pneumocystis carinii pneumonia Other diffuse lung infections, e.g., military tuberculosis Noninfectious etiologies Diffuse alveolar hemorrhage post–bone marrow transplantation Diffuse alveolar hemorrhage due to vasculitis, e.g., Goodpasture syndrome Acute eosinophilic pneumonia Lupus pneumonitis Toxic drug reactions, e.g., aspirin Source: Christie JD, Lanken PN: Acute lung injury and the acute respiratory distress syndrome, in Hall JB, Schmidt GA, Wood LDH (eds.): Principles of Critical Care, 3rd ed. New York, McGraw-Hill, 2004; p 525, reproduced with permission.

Maintaining Adequate Oxygenation As noted, the pathophysiological hallmark of ALI and ARDS is hypoxemia that is resistant to oxygen therapy. Maintaining adequate arterial oxygenation is the primary goal of both traditional and newer (“lung protective”) approaches to assisted ventilation. As expected with shunt physiology, administration of supplementary oxygen provided by high-flow oxygenation systems, e.g., a non-rebreather face mask, is generally ineffective in reversing the oxygenation deficit. Exceptions to this rule are some patients with mild or transient cases of ALI or ARDS that are otherwise uncomplicated by other organ system failures. In order to reduce the shunt, positive end-expiratory pressure (PEEP) is employed. When utilized in sufficient amounts, PEEP generally results in correction of the hypoxemia to patients with ALI, thereby allowing FiO2 to be lowered from high potentially toxic concentrations. Although PEEP is usually used in conjunction with mechanical ventilation, in selected cases it may be effective when applied by means of a continuous positive airway pressure (CPAP) mask or as the lower level of bilevel noninvasive ventilation. The effect of PEEP-induced improvement in arterial oxygenation is attributed predominantly to recruitment of collapsed alveoli. However, application of PEEP may also mediate a redistribution of alveolar fluid into the interstitium and decrease the absolute magnitude of shunt by reducing cardiac output.

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Acutely ill patients in intensive care units typically receive assisted ventilation via an endotracheal tube. In selected non-ARDS disorders, e.g., COPD or acute cardiogenic pulmonary edema, noninvasive ventilation has been shown to be as effective as invasive ventilation. Although the routine use of noninvasive ventilation for patients with ALI or ARDS lacks compelling evidence, the data are limited. One reason for limited study of noninvasive ventilation in ALI or ARDS is concomitant nonrespiratory organ failure (e.g., due to septic shock). Except for select subgroups, e.g., immunosuppressed patients with hypercapnic respiratory failure who are hemodynamically stable, one should generally avoid use of noninvasive ventilation for patients with ALI and ARDS.

In summary, the goals of lung-protective ventilation are to avoid injury due to overexpansion of alveoli during inspiration (so-called “volu-trauma”) and injury due to repetitive opening and closing of alveoli during inspiration and expiration (so-called “atelecta-trauma”) (Fig. 145-5). The injurious effects of mechanical ventilation on the lung have been referred to as “ventilator-induced lung injury or VILI.” The term “bio-trauma” encompasses the direct lung injury and the concomitant release of inflammatory cytokines that produce remote cell death or organ injury. Clinical strategies underlying contemporary applications of mechanical ventilation in treatment of ALI or ARDS are described below.

Lung-Protective Mechanical Ventilation As described in Chapter 153, over the past 30 years investigators have convincingly shown that large tidal volumes delivered during mechanical ventilation can injure lungs of normal animals, producing a pathologic pattern resembling ALI in humans. In animal models of acute lung injury, use of large tidal volume ventilation has been found to augment preexisting injury. In addition, repetitive opening and closing of alveoli during inspiration and expiration induces acute lung injury in normal animals. The injury can be prevented by application of sufficient PEEP. Finally, overexpansion of alveoli in normal lungs of sheep induces multiorgan failure, with recent studies of other species showing that lung overexpansion results in systemic release of proinflammatory cytokines—providing a likely mechanism for these remote deleterious effects. These observations support the concept that the lung, rather than the gut, is the “engine of inflammation.” Concurrent with the previously described observations, clinical investigators studying patients with ALI or ARDS using computed tomography observed that, in contrast to the typical diffuse-appearing pattern noted on plain chest radiographs, the pattern of consolidation, atelectasis, and normal alveoli is actually heterogeneous (Fig. 145-3). The key physiological implication of these observations is that a ventilator-delivered tidal volume is preferentially distributed to the open alveoli, which represent only a small fraction of the entire lung. Reference by Gattinoni, Pesenti and coworkers to this fraction as “the baby lung” emphasized the potential danger of delivering traditional tidal volumes of 10 to 15 ml/kg actual body weight and the associated risk for alveolar overexpansion and lung injury. Notably, tidal volumes of 10 to 15 ml/kg actual body weight (equivalent to approximately 12 to greater than 15 ml/kg predicted body weight) were used originally in critically ill patients with ALI or ARDS as a complementary strategy to PEEP in recruiting atelectatic alveoli. These productive lines of basic and clinical research strongly support the hypothesis that mechanical ventilation using limited tidal volumes should be less injurious to the lungs of patients with ALI and ARDS and should result in better outcomes (i.e., decreased mortality) compared with use of traditional, large tidal-volume ventilation.

Based on the aforementioned considerations, the ARDSNet conducted a randomized trial (ARMA) in the mid-to-late 1990s to test the hypothesis that low tidal volume ventilation, combined with limited end-inspiratory (plateau) pressure, would lower mortality and ventilator days among survivors of ARDS compared with use of traditional tidal volumes. The trial included 861 subjects. The low tidal volume arm consisted of a tidal volume of 6 ml/kg predicted body weight, as long as the end-inspiratory pressure (Pplat) was 30 cm H2 O or less; if Pplat exceeded 30 cm H2 O, the tidal volume could be decreased to as low as 4 ml/kg. The traditional tidal volume arm used a tidal volume of 12 ml/kg predicted body weight, as long as the Pplat remained less than 50 cm H2 O. Both arms included explicit goals and protocols as the bases for ventilator adjustments and determination of the time and means of weaning (Table 145-9). Important results of this clinical trial are summarized in Table 145-10. The difference in actual tidal volumes resulted from protocol-driven target tidal volumes in each study arm. As expected, the mean plateau pressure for the lower tidal volume group was less than 30 cm H2 O (25 cm H2 O), since the protocol required decreasing the tidal volume from 6 ml/kg predicted body weight to as low as 4 ml/kg if Pplat exceeded 30 cm H2 O. Of note, the traditional tidal volume group had a mean Pplat of 33 cm H2 O on study day one—a value less than the threshold of 35 cm H2 O that some clinicians had believed represented a safe threshold. Despite the fact that the clinical trial used an arbitrary threshold of 30 cm H2 O for Pplat in the lower tidal volume arm, it should not be assumed that any Pplat at or below 30 cm H2 O is safe. If a “safe” upper limit of Pplat exists, its value is unknown. Lack of such a safe threshold is supported by the finding of an absence of any significant interaction between differences in mortality and quartiles of static respiratory compliance (Fig. 145-6A) or quartiles of plateau pressures (Fig. 145-6B). These results suggest that the lower tidal volume ventilatory strategy tends to be effective across a wide range of baseline static compliances and plateau pressures. Likewise, a statistical model of mortality proportion vs. Day 1 Pplat that combined data from both arms of this clinical trial suggests that, in general, the lower Pplat the lower the associated mortality (Figure 145-7).

ARDSNet Ventilator Strategies: Low vs. Traditional Tidal Volumes

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Figure 145-5 A. Schematic inspiratory static pressure-volume (P-V) curve of the respiratory system (lung and chest wall combined) in ARDS. Lower inflection point (LIP) is approximately 14 cm H2 O, and upper inflection point (UIP) is approximately 35 cm H2 O. Abscissa is respiratory system recoil pressure; ordinate is lung volume above functional residual capacity (FRC) B. Same static P-V curve as (A), plus dynamic P-V curve of 600 mL tidal volume starting below the LIP (PEEP = 0). This tidal volume results in a plateau pressure (closed arrow) below the UIP (24 cm H2 O). Static compliance (Cstat = "V/"P = 600 ml/24 cm H2 O) is 25 ml/cm H2 O. C . PEEP of 15 cm H2 O has moved the starting point for the 600 ml tidal volume up the static P-V curve to a new FRC (open arrow), which is at the LIP. The tidal volume results in a plateau pressure of 27.5 cm H2 O (closed arrow), which is well below the UIP. Cstat ("V/"P = 600 ml/12.5 cm H2 O) is increased to 48 ml/cm H2 O. D. Dynamic P-V curve of a 1000 ml tidal volume, starting at 14 cm H2 O PEEP, results in a plateau pressure of 37.5 cm H2 O (closed arrow). Despite an increase in Cstat ("V/"P = 1000 ml/24 cm H2 O = 41.5 ml/cm H2 O), compared with Cstat derived from the 600 mL tidal volume in (B ), the plateau pressure associated with the 1000 ml tidal volume exceeds the UIP. Delivery of an inflation volume that results in a plateau pressure exceeding the UIP implies alveolar overdistension and is believed to put the lung at risk for ventilator-induced lung injury (see text). (Reproduced with permission from Lanken PN: Acute respiratory distress syndrome, in Lanken PN, Hanson CW III, Manaker S (eds): The Intensive Care Unit Manual. Philadelphia, Saunders, 2001, pp 824â&#x20AC;&#x201C;825.)

These considerations are important, since some clinicians may believe that they can achieve the improved mortality rate simply by lowering tidal volumes to the point where Pplat is at or slightly less than 30 cm H2 O, instead of following the ARDSNet low tidal volume strategy of using a tidal volume of 6 ml/kg predicted body weight. In addition, recognition of the need to use predicted, rather than actual, body weight is important, since the latter has been estimated to be about 20 percent greater than the former (due to fat and extravascular fluid). In summary, clinicians should employ the entire ARDSNet protocol (Table 145-9) rather than

selected parts in attempting to achieve comparably favorable mortality results. Lung Protection due to Higher PEEP

The initial ARDSNet trial (ARMA) described above did not address the question of whether application of higher levels of PEEP than used traditionally is beneficial. The possibility of improved outcomes using higher levels of PEEP was suggested by both basic and clinical studies conducted by Amato and colleagues in the early 1990s. To address whether higher levels of PEEP combined with low tidal volumes decreases

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Table 145-9 NIH NHLBI ARDS Clinical Trials Network Low Tidal Volume Ventilation Strategy Part I: Ventilator setup and adjustment 1. Calculate ideal body weight (IBW)∗ (also known as predicted body weight [PBW]) 2. Use Assist/Control mode and set initial TV to 8 ml/kg IBW (if baseline TV >8 ml/kg) 3. Reduce TV by 1 ml/kg at intervals ≤2 h until TV = 6 ml/kg IBW ˙ (but not >35 bpm) 4. Set initial rate to approximate baseline Ve 5. Adjust TV and RR to achieve pH and plateau pressure (Pplat) goals below. 6. Set inspiratory flow rate above patient demand (usually >80 L/min); adjust flow rate to achieve goal of I:E ratio of 1:1.0–1.3 Part II: Oxygenation goal: PaO2 = 55–80 mmHg or SpO2 = 88–95% 1. Use these incremental FiO2 -PEEP combinations to achieve oxygenation goal: FiO2




















0.5 10 0.9 18

0.6 10

0.7 10

1.0 20

1.0 22

0.7 12 1.0 24

Part III. Plateau pressure (Pplat) goal: ≤ 30 cm H2 O 1. Check Pplat (use 0.5-sec inspiratory pause), SpO2 , total RR, TV and ABG (if available) at least every 4 h and after each change in PEEP or TV. 2. If Pplat >30 cm H2 O, decrease TV by 1 ml/kg steps (minimum 4 ml/kg IBW) 3. If Pplat <25 cm H2 O and TV < 6 ml/kg, increase TV by 1 ml/kg until Pplat > 25 cm H2 O or TV = 6 ml/kg. 4. If Pplat < 20 cm H2 O and breath stacking occurs, one may increase TV in 1 ml/kg increments (to a maximum of 8 ml/kg) Part IV. pH goal: 7.30–7.45 Acidosis management: pH < 7.30 1. If pH = 7.15–7.30, increase RR until pH > 7.30 or PaCO2 < 25 mmHg (maximum RR = 35); if RR = 35 and PaCO2 < 25 mmHg, may give NaHCO3 . 2. If pH < 7.15 and NaHCO3 considered or infused, TV may be increased in 1 ml/kg steps until pH > 7.15 (Pplat goal may be exceeded) Alkalosis management: pH > 7.45: Decrease RR, if possible ∗ Male

IBW = 50 + 2.3 [height (inches) − 60]; female IBW = 45.5 + 2.3 [height (inches) − 60] Abbreviations: ABG = arterial blood gas; RR = respiratory rate on ventilator; SpO2 = Oxygen saturation by pulse oximetry; TV = tidal volume; V˙E = minute ventilation. From the NIH NHLBI ARDS Clinical Trials Network (Complete protocol is available at Source: Lanken PN: Acute respiratory distress syndrome, in Lanken PN, Hanson CW III, Manaker S (eds): The Intensive Care Unit Manual, Philadelphia, Saunders Co., 2001, p. 828, reproduced with permission.

mortality, the ARDSNet conducted a second ventilator clinical trial (ALVEOLI) in which each of two groups received the same low tidal volume ventilatory strategy, but one group was treated using an additional 4 to 5 cm H2 O of PEEP. Mortality rates at day 60 were below 30 percent for both groups and were not significantly different, even after adjustment for imbalances in baseline variables. Similarly, ventilator-free days were not significantly different. Therefore, at present, whether maintenance of PEEP above a certain point (corresponding to the lower inflection point in Fig. 145-5) improves clinical outcome is unknown. Recent studies by Gattinoni and

co-workers showed that, while some patients with ALI have little or no recruitment (opening previously collapsed or fluid filled airspaces) with increased levels of PEEP, in others PEEP shows marked recruitment. This suggests that future clinical trials using higher PEEP be restricted to subjects with ALI in whom PEEP increments can reliably result in recruitment. Recommended Core Ventilator Management

We recommend that as the core ventilator management in ALI and ARDS clinicians follow the ARDSNet low tidal volume ventilatory strategy (Table 145-9). Because higher levels of

2549 Chapter 145


Table 145-10 Results of NIH NHLBI ARDS Clinical Trials Network Low Tidal Volume vs. Traditional Tidal Volume Clinical Trial (“ARMA”)

Variable or Outcome


Low Tidal Volume Ventilatory Strategy Mean ± SD

Tidal volume on day 1

mL/kg PBW

6.2 ± 0.9

11.8 ± 0.8


Plateau pressure on day 1

cm H2 O

25 ± 7

33 ± 9


PEEP on day 1

cm H2 O

9.4 ± 3.6

8.6 ± 3.6


158 ± 73

176 ± 76


PaO2 :FiO2 on day 1

Traditional Tidal Volume Ventilatory Strategy Mean ± SD

p Value

PaCO2 on day 1


40 ± 10

35 ± 8


Death before discharge or 180 days





Breathing without assistance at day 28





No. of ventilator-free days by day 28

12 ± 11

10 ± 11


No. of days without failure of nonpulmonary systems by day 28

15 ± 11

12 ± 11


Abbreviations: PBW = predicted body weight (see footnote of Table 145-9 for details); PEEP = positive end expiratory pressure; SD = standard deviation; ventilator-free days by day 28, number of days alive and not receiving assisted ventilation between days 1 and 28. Source: Acute Respiratory Distress Syndrome Network. New Engl J Med 342:1301, 2000.

PEEP have not yet been found to improve outcomes, unless new evidence arises to the contrary, we also recommend that clinicians follow the same combinations of FiO2 and PEEP used in the first ARDSNet trial, ARMA (Table 145-9). Because of constraints of sample size, the ARDSNet trial tested the low-volume strategy only against use of tidal volumes of 12 ml/kg predicted body weight. Notably, a strategy using 6 ml/kg has not been shown to be superior to a strategy using tidal volumes of 8 to 10 ml/kg. However, based on the previous descriptions of ventilator-induced lung injury and bio-trauma, we believe it is prudent for clinicians to strictly follow the ARDSNet protocol as their core management strategy in ALI or ARDS. Modifications should be considered only in special cases, e.g., when contraindications for permissive hypercapnia exist (Table 145-11). Other Approaches to Ventilator Management In addition to the low-volume protocol described, several additional approaches may be used in the management of ALI or ARDS and are discussed briefly below. Pressure Control Mode

The ARDSNet low tidal volume strategy used the volumeassist-control mode—a familiar device setting and the only

ventilator intervention that has been shown thus far to improve long-term survival in patients with ALI and ARDS. However, other modes of ventilation can also provide low tidal volume ventilation, including pressure control ventilation (PCV). PCV can limit maximal peak airway pressure as well as end-inspiratory pressure (Fig. 145-8A) and, hence, is favored by some clinicians. However, the end-inspiratory pressure in PCV can be underestimated. For example, using PCV with an inspiratory pressure of 30 cm H2 O and a PEEP of 10 cm H2 O, the end-inspiratory pressure is 40 cm H2 O (the sum of the two pressures). Some may misinterpret this combination as equivalent to a Pplat of 30 cm H2 O and assume that it is a “safe” value according to interpretation of ARDSNet results. As discussed previously, however, no Pplat is known to be safe, even when end-inspiratory pressure is calculated correctly. Furthermore, use of PCV to mimic both tidal volume and Pplat used in the ARDSNet trial remains problematic. The benefit seen from using the ARDSNet strategy may have been due as much to the use of low tidal volume as to lower Pplat. Inverse ratio ventilation (IRV) with PCV is based upon an inspiratory time (I) greater than expiratory time (E), i.e., I:E greater than 1 (Fig. 145-8B). Some case reports identify

2550 Acute Respiratory Failure 0.6

Lower tidal volumes Traditional tidal volumes



0.4 0.3 0.2 0.1 0.0 0.15–0.40




Quartile of Static çompliance (ml/cm of water/kg of predicted body weight) A

Vt = 6 ml/kg


Mortality %



ARR = 15.3% 95%Cl: 2 to 30%

Vt = 12 ml/kg

ARR = 9.4% 95%Cl: −3 to 22%

ARR = 4.3% 95%Cl: −9 to 17%

ARR = 2.9% 95%Cl: −11 to 17%



Pplat 16.0 to 26.0 (101)

Pplat 10.0 to 20.0 (99)

Pplat 20.3 to 24.7 (95)

Pplat 26.3 to 31.0 (104)

Pplat 25.0 to 28.3 (97)

Pplat 31.7 to 37.3 (95)

Pplat 29.0 to 47.0 (97)

Pplat 37.7 to 69.0 (99)

0 1

2 3 Quartile of Pplat



Figure 145-6 ARDSNet ARMA study. A. Mortality rates (mean ± SE) according to quartile of static respiratory system compliance before randomization and subsequent treatment group. Data represent a subset of 861 subjects enrolled, including 257 patients assigned to the low tidal volume ventilatory strategy and 260 to the high tidal volume strategy. Mortality in the low tidal volume group was at least 30 percent lower than for those receiving traditional tidal volumes in each of the lowest three quartiles. Although the low tidal volume strategy was not advantageous for patients in the quartile with the highest static compliance, a test for interaction between treatment group and static compliance quartile at baseline was not statistically significant. Results support the concept that the low tidal volume ventilation strategy is beneficial for patients with ALI or ARDS across a spectrum of static compliances, not just for those with the stiffest lungs. (Reproduced with permission from Acute Respiratory Distress Syndrome Network. N Engl J Med 342: 1301, 2000.) B. Mortality according to quartiles of end-inspiratory pressure (plateau pressure, Pplat) and treatment group on study day 1 in 787 subjects for whom Pplat data are available (including 270 subjects for whom pre-randomization static compliance measurements were not available). Pplat was measured using protocol-dictated tidal volumes (rather than clinician-determined tidal volumes, as used in assessing static respiratory system compliance). Subjects with the stiffest lungs are likely to have Pplat in the fourth quartile (far right). Range of Pplat (cm H2 O) and number of subjects (parentheses) are shown in each bar of the graph (ARR = absolute risk reduction; CI = confidence interval). Lower tidal volume ventilation appears to benefit patients with ALI or ARDS across a range of Pplat. The hypothesis that a ‘‘safe” upper limit exists for Pplat, below which ventilator-induced lung injury does not occur, is not supported by the data. (Reproduced with permission from Hager DN, Krishnan JA, Hayden DL, et al: Am J Respir Crit Care Med 172:1241, 2005.)

2551 Chapter 145 1

Table 145-11

.9 Mortality Proportion



Contraindications for Permissive Hypercapnia and Acute Respiratory Acidosis

.7 .6 .5 .4

Increased intracranial pressure from any cause (trauma, mass lesion, malignant hypertension)

.3 .2 .1

Acute cerebrovascular disorders, e.g., stroke 0

20 40 60 Day 1 Plateau Pressure (cm H2O)


Figure 145-7 Lowess (locally weighted regression and smoothing) plot (bandwidth, 0.4) of mortality proportion and day 1 plateau pressure (Pplat, cm H2 O) for 787 patients enrolled in the ARDSNet ARMA study. Plot includes same subjects and Pplat shown in Fig. 145-6B. When expressed using this estimating method, the data do not support a safe upper limit for Pplat, the presence of which would be suggested by a leveling in mortality proportion, rather than a further decrease, as the plot demonstrates. The Lowess method is a nonparametric smoother that uses overlapping neighborhoods of data to estimate a local effect. A bandwidth of 0.4 means that 20 percent of the data on either side of a given Pplat contribute to a local estimate of mortality at that Pplat; data at the high and low ends of the curve represent fewer observations. As data are smoothed using a tricubic weight function, points furthest from the Pplat of interest are assigned the least weight and approach zero. (Reproduced with permission from Hager DN, Krishnan JA, Hayden DL, et al: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 172:1241, 2005.)

patients with refractory hypoxemia who responded to PCVIRV. This may be due to effects of auto-PEEP (intrinsic PEEP) or other mechanisms involving alveolar recruitment following prolonged exposure to IRV. IRV with auto-PEEP plus applied PEEP may compromise cardiac output and increase the risk of nonpulmonary organ dysfunction. Clinicians should consider using PCV-IRV only as a “salvage” mode of ventilation (Table 145-12).

Acute or chronic myocardial ischemia Severe pulmonary hypertension Right ventricular failure Uncorrected severe metabolic acidosis Sickle cell anemia Tricyclic antidepressant overdose Patients taking beta-blockers Pregnancy (due to potential for decreased fetal blood flow from vasodilation-induced steal syndrome; in addition, shift to the right of the O2 dissociation curve decreases the maternal-fetal gradient for O2 )

BIPAP and APRV can be expected to decrease the use of neuromuscular blocking agents in patients with ALI or ARDS since both allow spontaneous breathing and potentially less patient-ventilator dyssynchrony. However, whether such newer modes of ventilation are better than, equal to, or worse than the ARDSNet lower tidal volume ventilatory strategy remains unknown. Until more clinical evidence supports their superiority or equivalency, their routine use cannot be recommended.

Modes That Allow Spontaneous Breathing during Positive Pressure Ventilation

High Frequency Oscillatory Ventilation Mode

Two ventilatory modes of modern microprocessor-based devices that permit spontaneous breathing to occur at any phase of the respiratory cycle during assisted ventilation include biphasic airway pressure (BIPAP) and airway pressure release ventilation (APRV). In each, airway pressure cycles between higher and lower levels of PEEP at preset time intervals. Controlled studies using these ventilator modalities are limited. One report found that use of APRV in patients with ARDS decreased intrathoracic pressure, improved ventilation-perfusion mismatch and cardiac output, and decreased shunt and dead space fractions compared with pressure support ventilation (matched for the same airway pressure limits or minute ventilation). However, clinically important outcomes were not compared.

The U.S. Food and Drug Administration has approved an adult high frequency oscillatory ventilator (HFOV) for management of patients with ARDS. Theoretically, HFOV may be regarded as the ultimate low tidal volume ventilator with a capacity to ventilate a patient using a very small tidal volume midway between the upper and lower inflection points of the pressure-volume curve (Fig. 145-5). Clinically, use of HFOV has been shown to be equivalent to “usual” care. However, the trial comparing HFOV with usual care was conducted at a time when usual care did not include low tidal volume ventilation. Since its application generally requires neuromuscular paralysis, HFOV is unlikely to be utilized in patients with mild ALI or ARDS because of the risk of paralytic agent–related quadriparesis and lack of

2552 Part XVII

Acute Respiratory Failure

ALI and ARDS. In some cases, the physiological or pharmacologic basis for the measure’s beneficial effect is apparent; in others, the mechanism is unknown. Overview


Use of adjuncts to lung protective ventilation is generally based on extrapolations from animal or basic studies, or from clinical studies using physiological markers as surrogates for clinically meaningful endpoints, e.g., mortality or ICU length of stay or ventilator-free days. However, extrapolation from such studies to clinical practice is problematic. For example, the only intervention that thus far proved to result in improved survival in ALI and ARDS—the ARDSNet low tidal volume ventilatory strategy—also resulted in patients in the low-volume group with significantly lower PaO2 /FiO2 after enrollment compared with those receiving traditional tidal volume ventilation (Table 145-10). If the trial had used improvement in PaO2 /FiO2 as a surrogate marker for better survival, the results would have been interpreted as showing that low tidal volume ventilation results in higher not a lower mortality. In general, both efficacy and safety data supporting use of the following adjunctive therapies in ALI or ARDS are lacking. Thus, these interventions should be used cautiously, if at all. Permissive Hypercapnia


Figure 145-8 Schematic depiction of pressure, flow, and volume waveforms during pressure control ventilation (PCV) with applied PEEP. Abscissa is time and ordinates (from top to bottom) are proximal airway pressure (Pprose ), inspiratory flow and volume above functional residual capacity (FRC). Other abbreviations: I, inspiration, "FRC, change in FRC. A. The inspiratory-to-expiratory (I:E) time is about 1:2. The pressure waveform resembles pressure support ventilation, and the flow pattern is characterized by marked deceleration. Applied PEEP increases FRC (PEEP effect). B. I:E time is reversed (I > E), representing pressure-controlled inverse ratio ventilation (PC-IRV). As a result, the next breath starts before expiratory flow has returned to zero (open arrows), resulting in auto-PEEP and dynamic hyperinflation. The latter is superimposed on the increased FRC due to the applied PEEP. (Reproduced with permission from Lanken PN: Acute respiratory distress syndrome, Lanken PN, Hanson CW III, Manaker S (eds): The Intensive Care Unit Manual. Philadelphia, Saunders, 2001, p 829.)

efficacy data comparable to the ARDSNet protocol used in ARMA (Table 145-9). Some clinicians may use high frequency ventilation as a “salvage” mode (Table 145-16). However, its use, even in those circumstances, is not supported by controlled clinical trials. Adjuncts to Lung Protective Mechanical Ventilation A number of adjunctive measures to mechanical ventilation have assumed importance in the management of patients with

Permissive hypercapnia is defined as clinician-allowed hypercapnia during assisted ventilation, despite an ability to achieve a level of minute ventilation sufficient to maintain a normal PaCO2 (36 to 44 mmHg). Because patients may develop hypercapnia during lower tidal volume ventilation, which is recommended as the core ventilator strategy, permissive hypercapnia should no longer be considered an “adjunct.” (Although the ARDSNet lower tidal volume strategy did stipulate maintenance of minute ventilation while decreasing tidal volume in order to decrease the secondary rise in PaCO2 , permissive hypercapnia was allowed as a consequence of the protocol. The response to the resulting respiratory acidosis was left to the local investigator’s discretion.) Fluid Management

The ARDSNet Fluid and Catheter Treatment Trial (FACTT), which used a two-×-two factorial design, tested the hypothesis that a management strategy of fluid restriction (conservative fluid management) would improve clinically important outcomes in ALI compared with more generous fluid management strategy (liberal fluid management). Although the strategy of liberal fluid management was based upon a protocol to determine fluid balance, patients’ net fluid balance during the first 7 days of the trial resembled that resulting from the non–protocol-directed care in the first two ARDSNet clinical trials (ARMA and ALVEOLI). FACTT investigators developed a detailed fluid management protocol that, except for patients in shock (MAP less

2553 Chapter 145

than 60 mmHg or on vasopressors for hypotension), used four basic input variables (assessed every 1 to 4 hours) to determine the fluid management instructions: (1) mean arterial blood pressure (MAP); (2) urine output; (3) effectiveness of circulation; and (4) intravascular pressure (central venous pressure [CVP] or pulmonary artery occlusion pressure [PAOP]). In both arms of the study, the protocol goals were MAP greater than 60 mmHg (or vasopressor independence); urine output greater than 0.5 ml/kg predicted body weight/hour; and evidence for effective circulation, including a cardiac index greater than or equal to 2.5 L/min/m2 in patients with pulmonary artery catheters (PACs) or, in those with central venous catheters (CVCs), absence of physical examination findings indicating hypoperfusion of extremities. In the group randomized to conservative fluid strategy, the target intravascular pressure was a CVP less than 4 mmHg or PAOP less than 8 mmHg. In contrast, for those randomized


to the liberal fluid strategy, targets were a CVP of 4 to 8 mmHg or PAOP of 8 to 12 mmHg. Despite marked differences in cumulative net fluid balance between the conservatively and liberally managed groups, the two showed no statistically significant difference in mortality at 60 days, which was the study’s primary outcome (Table 145-12). Nonetheless, compared with the liberal strategy, the conservative strategy resulted in statistically significant improvements in several clinically important outcomes, including decreased duration of assisted ventilation and length of stay in the intensive care unit (Table 145-12). Moreover, the conservative strategy did not worsen the incidence of shock, number of days in shock, frequency or extent of other organ system failures, or rate of use of dialysis. These results support the use of a conservative fluid strategy in managing patients with ALI or ARDS who are not in shock.

Table 145-12 Results of ARDSNet FACTT (Fluids and Catheter Treatment Trial): Conservative Fluid Management Stategy vs. Liberal Fluid Management Strategy Result Cumulative net fluid balance from day 1 to day 7 (ml) All patients Patients in shock at entry Patients not in shock at entry

Conservative Strategy (n = 503) −139 ± 491 2904 ± 1008 −1576 ± 519

Liberal Strategy (n = 497)

p Value

6992 ± 502 10, 138 ± 922 5287 ± 576

<0.001 <0.001 <0.001

Death at 60 days (%)




Ventilator-free days from day 1 to Day 28∗

14.6 ± 0.5

12.1 ± 0.5


ICU-free days from day 1 to day 28∗

13.4 ± 0.4

11.2 ± 0.4


3.9 ± 0.1 3.4 ± 0.2 5.5 ± 0.1 5.7 ± 0.1 5.6 ± 0.1

4.2 ± 0.1 2.9 ± 0.2 5.6 ± 0.1 5.5 ± 0.1 5.37 ± 0.1

0.04 0.02 0.45 0.12 0.23

10 11.0 ± 1.7

14 10.9 ± 1.4

0.06 0.96

Organ-failure-free days from day 1 to day 7∗,† Cardiovascular failure‡ CNS failure§ Renal failure‡ Hepatic failure‡ Coagulation abnormalities‡ Dialysis to day 60 Patients (%) Days of dialysis

Plus-minus values are means ± SE. Abbreviations: CNS = central nervous system. was an a priori secondary outcome. Death at 60 days was the primary outcome. † Definitions of organ failure: Cardiovascular failure = systolic blood pressure <90 mmHg or receiving a vasopressor other than dopamine at 5 µg/kg/min or less; CNS failure = Glasgow Coma Scale of 12 or less; renal failure = serum creatinine ≥ 2 mg/dl (177 µmol/L); hepatic failure = serum bilirubin ≥ 2 mg/dl (34 µmol/L); coagulation abnormalities = platelet count of 80,000/µl or less. Number of days without organ failure is determined by subtracting the number of days with organ failure from the lesser of 28 or from number of days until death. ‡ This difference was not significant from day 1 through day 28. § This difference was still statistically significant from day 1 through day 28. ∗ This

2554 Part XVII

Acute Respiratory Failure

Table 145-13 Results of ARDSNet FACTT (Fluids and Catheter Treatment Trial): Use of Pulmonary Arterial Catheter (PAC) vs. Use of Central Venous Catheter (CVC) to Direct Fluid and Hemodynamic Management Protocols


Pulmonary Artery Catheter Group (n = 513)

Central Venous Catheter Group (n = 487)

Death at 60 days (%)




Ventilator-free days from day 1 to day 28∗

13.2 ± 0.5

13.5 ± 0.5


ICU-free days from day 1 to day 28∗

12.5 ± 0.5

12.0 ± 0.4


Number of catheters inserted†

2.47 ± 0.05

1.64 ± 0.04


Number of complications per catheter

0.08 ± 0.01

0.06 ± 0.01


Total number of catheter-related complications per group†


p Value


±values are means ± SE. ∗ This was an a priori secondary outcome. Death at 60 days was the primary outcome. † This includes the sheath for PAC, PAC, and CVC for subjects in the PAC group and sheath (n = 6) and CVC for subjects in the CVC group.

Hemodynamic Management

Using the trial’s two-×-two factorial design, the ARDSNet FACTT investigators also compared the safety and efficacy of PACs with CVCs in directing fluid and hemodynamic protocols, as described. Mortality and other important clinical outcomes, such as ventilator-free days, ICU-free days, and organfailure-free days by study day 28 were no different in patients managed with a PAC versus a CVC (Table 145-13). However, use of the PAC was associated with a significantly higher complication rate during catheter insertion—primarily, cardiac arrhythmias. The excess events were attributed principally to the need for passing both a sheath and catheter; none of the adverse events was fatal. Based on the results, the FACTT investigators recommend using a CVC to guide a hemodynamic and fluid management. However, in specific cases, clinicians may elect to use a PAC in selected circumstances, e.g., in addressing the response to volume resuscitation, determining the adequacy of cardiac output, measuring the oxygen saturation of mixed venous blood, calculating the degree of intrapulmonary shunt, or searching for equalization of diastolic pressures during suspected cardiac tamponade. Prone Positioning

About two-thirds of patients with ALI or ARDS improve their oxygenation after being placed in a prone position. Mechanisms that may explain the improvement include: (1) increased functional residual capacity; (2) change in regional diaphragmatic motion; (3) perfusion redistribution;

and (4) improved clearance of secretions. Studies of the distribution of ventilation-to-perfusion ratios in animal models suggest that gravity is less influential on the distribution of perfusion in the prone rather than supine position. This finding, coupled with the observation that edema fluid migrates to the dependent portions of the lung (as demonstrated on computed tomography) in patients with ALI who have been turned prone, suggested that ventilation-perfusion relationships might be favorably altered in the prone position. Patients managed in the prone position need special attention to prevent pressure necrosis of the nose, face, and ears. Extra care is also needed to ensure security and patency of the endotracheal tube. Pressure on the eye may result in retinal ischemia, especially in hypotensive patients. Others may experience cardiac arrhythmias or hemodynamic instability when turned prone. In a large clinical trial of prone positioning in patients with ALI and ARDS published in 2001 by Gattinoni and colleagues, subjects were randomly placed prone for 6 or more hours daily for 10 days or were left in the supine position. Although the investigators found that oxygenation was transiently improved with prone positioning, they demonstrated no survival advantage. A more recent study of prone positioning in children with ALI also demonstrated lack of benefit. Because no controlled clinical trial has showed improved survival with prone positioning, and because the technique carries known risks, even in experienced hands, it cannot be recommended for routine use in patients with ALI or ARDS. However, some clinicians may opt to use

2555 Chapter 145

prone positioning as salvage therapy for severe hypoxemia (Table 145-16).


ported that recruitment maneuvers improve oxygenation in patients on relatively low levels of PEEP, receiving large tidal volumes, or maintained on paralytics. Because no controlled clinical trials demonstrate efficacy in clinically relevant end points and there are potentially adverse effects, routine use of recruitment maneuvers is not recommended in ALI or ARDS. Likewise, in the absence of data showing efficacy, routine use of ventilator “sighs” exceeding peak pressures of 30 cm H2 O (the threshold used in the ARDSnet clinical trial that showed improved survival) is also not recommended. Some clinicians may use recruitment maneuvers with higher pressures as part of salvage therapy for patients with severe refractory hypoxemia (Table 145-16).

Recruitment Maneuvers

Lung recruitment maneuvers are defined as the application of continuous positive airway pressure (CPAP) aimed at “recruiting” or opening totally or partially collapsed alveoli. The alveoli are then kept inflated during expiration using an appropriately high level of PEEP. In one study of a “lung protective” strategy utilizing low tidal volume ventilation and extra-high PEEP, recruitment manuvers were performed by maintaining a CPAP level of 35 to 40 cm H2 O for 30 seconds. Others advocate application of equivalent or higher pressures for longer periods. No controlled clinical trial supports the efficacy of recruitment maneuvers alone to improve clinically important outcomes, such as mortality or ventilator-free days. Studies of recruitment maneuvers have generally used physiological end points, e.g., improvement in oxygenation. In a subset of patients treated with high levels of PEEP in the ARDSnet trial comparing high versus low PEEP in ARDS, no clinically relevant improvements in arterial saturation were noted. However, complications such as transient hypotension and slight drops in arterial saturation during the manuver were reported. On the other hand, other clinical studies have re-

Inhaled Nitric Oxide

In 1993 Roissant and colleagues published a study of inhaled nitric oxide (NO) as a novel therapy for ARDS. Given via inhalation, NO selectively vasodilates pulmonary capillaries and arterioles that subserve ventilated alveoli, diverting blood flow to these alveoli and away from areas of shunt. Lowering of the pulmonary vascular resistance, accompanied by lowering of the pulmonary artery pressure, appears maximal at very low concentrations (0.1 ppm) in patients with ARDS. Beneficial effects on oxygenation take place at somewhat higher inspired concentrations of NO (1 to 10 ppm).

Table 145-14 Results of ARDSNet Late Steriod Rescue Study (“LaSRS”) in Patients with Persistent ARDS: A Priori Protocol-Defined Outcomes and Adverse Events MethylprednisoloneTreated Group

Placebo-Treated Group

Mortality at day 60 (%) (95% CI)

28.6 (20.8–38.5)

29.2 (20.8–39.4)

No. of ventilator-free days at day 28

11.2 ± 9.4

6.8 ± 8.5


No. of ICU-free days at day 28

8.9 ± 8.2

6.2 ± 7.8


No. of serious adverse events associated with myopathy or neuropathy




27 66 35 23

36 66 8 25


Variable or Outcome

60-Day mortality according to time from onset of ARDS (means) 7–13 days (%) No. of patients >14 days (%)∗ No. of patients ± values

p Value 1.0


are mean ± SD. = 0.02 for the interaction with treatment-group assignment (Wald’s test). Abbreviations: SD = standard deviation; ventilator-free days by day 28, number of days alive and not receiving assisted ventilation between days 1 and 28; ICU-free days by day 28, number of days alive and not in ICU between days 1 and 28 Source: Acute Respiratory Distress Syndrome Network. N Engl J Med 354:1671, 2006.


2556 Part XVII

Acute Respiratory Failure

Rapid inactivation of NO by hemoglobin prevents unwanted systemic hemodynamic side effects, but also requires continuous delivery of gas through the ventilator circuit. Thus, if continuous delivery of NO is interrupted (e.g., during patient transport or due to NO supply exhaustion), precipitous and life-threatening hypoxemia and right-sided heart failure may occur. Inhaled NO has been studied in one large contolled clinical trial in patients with ALI and ARDS (not due to sepsis) who had no other organ failures. Inhaled NO did not improve survival, although some patients experienced transient improvements in oxygenation. Based on this trial, the routine use of inhaled NO in ALI is not recommended. Some clinicians may consider using inhaled NO as a salvage intervention (Table 145-16). However, a much less costly alternative, inhaled prostacyclin (epoprostenol/ilo- prost), is available. The initial daily cost of inhaled NO is several thousands of dollars, while the daily cost of inhaled prostacyclin is several hundreds of dollars. Although less well studied than inhaled NO, inhaled prostacyclin seems to improve oxygenation to the same degree in a majority of patients with ALI or ARDS. Tracheal Gas Insufflation

Tracheal gas insufflation (TGI) consists of delivering fresh gas through a modified endotracheal tube at a point just above the carina. The additional gas flow (i.e., flow provided in addition to the standard tidal volumes delivered by the ventilator) tends to remove CO2 -rich gas from the trachea and smaller airways. It has the effect of reducing anatomic dead space. Although acute lung injury decreases the ability of TGI to reduce PaCO2 , permissive hypercapnia and higher PaCO2 values increase its relative effectiveness. For example, in one study of patients with ARDS, TGI using 100 percent humidified oxygen, delivered throughout the respiratory cycle at a flow of 4 L/min, lowered PaCO2 from 108 to 84 mmHg. Because TGI carries a number of potential risks (e.g., tracheal erosion, oxygen toxicity related to an increased FiO2 , and hemodynamic compromise or barotrauma due to TGIinduced auto-PEEP and a larger tidal volume than the ventilator is set to deliver), its routine use is not recommended. However, once again, some clinicians may employ it as a salvage intervention for patients with high levels of PaCO2 (e.g., greater than 100 mmHg). Extracorporeal Membrane Oxygenation (ECMO) or Extracorporeal CO2 Removal (ECCO2 R)

The use of extracorporeal gas exchange, such as ECMO or ECCO2 R, is based on the hypothesis that more patients will survive if the lung is allowed to recover from its injury by â&#x20AC;&#x153;restingâ&#x20AC;? it by using extracorporeal gas exchange temporarily. Although this hypothesis was initially stimulated by the desire to decrease the risk of pulmonary oxygen toxicity, its assessment can now be justified in regard to the techniquesâ&#x20AC;&#x2122; potential roles in reducing ventilator-induced lung injury (VILI). In the 1970s, a large-scale study on use of ECMO in patients with severe ARDS demonstrated that it offered no

survival benefit to patients whose mortality was extremely high (approximately 90 percent). Similarly, a randomized controlled trial in severely ill patients with ARDS reported in 1994 did not find improved survival using ECCO2 R. Despite these findings, some clinicians believe that ECMO, with its continually improving technology, may be beneficial in subgroups of patients with ARDS when treated before 7 days of mechanical ventilation. A number of related techniques also have been utilized, including veno-venous ECMO to assist in CO2 elimination. Some specialized centers continue to offer ECMO to adults with severe ARDS and consider the technique as a safe life-saving salvage intervention (Table 145-16). Corticosteroids

The general consensus among intensivists is that corticosteroids have little or no role to play in treating the acute phase of ALI or ARDS. However, the role of corticosteroids in later phases of ALI or ARDS has been controversial. A number of small case series suggest that high-dose corticosteroid therapy may be beneficial during the proliferative phase of ARDS, based on the rationale of preventing lung scarring that occurs during this phase of ALI as a result of alveolar inflammation. Potential risks include immunosuppression of debilitated, instrumented patients managed in environments harboring multiple antibiotic-resistant organisms and potential long-term neuromuscular weakness associated with use of high-dose corticosteroids and paralytic agents. In 2006, the ARDSNet investigators published results of a double blind, random, controlled clinical trial (Late Steroid Rescue Study or LaSRS) designed to evaluate benefits and risks of moderately high doses of corticosteroids in 180 patients with persistent ARDS (ARDS lasting 7 to 21 days) (Tables 145-15 and 145-16). It found no differences in 60- or 180-day mortality rates. Although parameters of respiratory function, including PaO2 /FiO2 , plateau pressure, respiratory system compliance, and time to, and rate of, liberation from mechanical ventilation improved after corticosteroid administration, the corticosteroid treated group included more patients who returned to assisted ventilation. Furthermore, no statistically significant differences between treated and untreated groups in ICU or hospital days by 180 days were observed. In addition, more adverse events related to weakness occurred in the treated group than in those receiving placebo. Finally, patients treated with corticosteroids after 14 days of persistent ARDS had a significantly increased mortality (Table 145-15). Hence, the results of this study do not support the routine use of steroids for late-phase ARDS in general, and they argue against their use if ARDS has been present for 14 days or longer. Beta-Agonists

Basic research supports the hypothesis that beta-agonists may improve the outcomes of patients with ALI or ARDS. Betaagonists stimulate removal of fluid from flooded alveoli by stimulating the epithelial sodium pump and promoting active

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Table 145-15 Results of ARDSNet Late Steroid Rescue Study (“LaSRS”) in Patients with Persistent ARDS: Post-hoc Analyses of Outcomes and Adverse Events at 180 Days Variable or Outcome

MethylprednisoloneTreated Group

Placebo-Treated Group

180-Day mortality (%) (mean) (95% CI)

31.5 (22.8–41.7)

31.9 (23.2–42.0)


No. of days of assisted ventilation in survivors up to 180 days (median) (interquartile range)






No. of days of ICU stay in survivors up to 180 days (median) (interquartile range)





No. of days of hospitalization in survivors up to 180 days (median) (interquartile range)





180-Day mortality according to time from onset of ARDS (means) 7–13 days (%) No. of patients >14 days (%)∗ No. of patients

27 66 44 23

39 66 12 25

p Value



0.14 0.01


= 0.006 for the interaction with treatment-group assignment (Wald’s test). Abbreviations: SD = standard deviation. Source: Acute Respiratory Distress Syndrome Network. N Engl J Med 354:1671, 2006.

transport of sodium out of the alveoli (with water following passively according to osmotic gradients). This mechanism is possible, however, only with an intact epithelial membrane. Following preliminary reports suggesting that use of betaagonists may be effective in fluid removal in patients with ALI or ARDS, the ARDSNet clinical investigators began a large, randomized, double-blinded, controlled clinical trial of inhaled albuterol to test the hypothesis in 2006. Their results are pending. Experimental Adjuncts to Lung-Protective Ventilation Two experimental adjuncts to lung-protective ventilation deserve comment: use of exogenous surfactant and partial liquid ventilation. Exogenous Surfactant

Both animal and human studies have shown that in ALI surfactant levels are decreased or proportions of various surfactants are abnormal, resulting in decreased surface tensionlowering activity. Surfactant therapy in infants with respiratory distress syndrome (RDS) due to prematurity improves

gas exchange and lung mechanics, decreases the requirement for CPAP, lessens barotraumas, and improves survival. However, results of trials using surfactant therapy in adults with ALI or ARDS have been disappointing to date. The first large, prospective, randomized controlled trial of inhaled surfactant in patients with ARDS due to severe sepsis was reported in 1996 and showed no benefit. Concerns about appropriate dosing of the agent, alternative modes of agent delivery, timing of therapy, types of subjects treated, and the precise surfactant formulation employed prompted investigators to view the study as inconclusive with regard to advising against use of exogenous surfactant in adults with ARDS. However, another large randomized, controlled trial reported in 2004 also found no improvement in survival; additional trials are underway. In contrast, in children (infants to adolescents), one encouraging report on use of exogenous surfactant in ALI or ARDS demonstrated improvement in overall mortality, but not in ventilator-free days, which was the study’s primary end point. Further positive studies in children likely will be necessary to gain FDA approval for this indication.

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Table 145-16 “Rescue” or “Salvage” Interventions Used in Patients with ARDS and Severe Hypoxemia Resistant to Conventional Mechanical Ventialation and PEEP Corticosteroids Extracorporeal CO2 removal (ECCO2 R) Extracorporeal membrane oxygenation (ECMO) High frequency oscillatory ventilation (HFOV) Inhaled nitric oxide (NO) or inhaled prostacyclin (epoprostenol/iloprost) Pressure controlled inverse ratio ventilation (PC-IRV) Prone positioning Recruitment maneuvers Tracheal gas insufflation (TGI)

Currently, exogenous surfactant for adults is available only as an experimental agent. Partial Liquid Ventilation

Clinical studies on use of partial liquid ventilation using oxygen-carrying perfluorocarbons instilled into the trachea of adults and children with ALI suggest that this mode of therapy has the potential to improve gas exchange. Partial liquid ventilation may improve oxygenation in part because the perfluorocarbon, by virtue of the hydraulic column created, is able to recruit dependent alveoli that PEEP is not. A practical problem with the technique is that agent used (perflubron) is radiodense, thereby complicating interpretation of chest radiographs in detecting infection or in following resolution of the ALI or ARDS. One clinical trial reported in 2006 reported that patients treated with partial liquid ventilation showed trends to worse survival, longer ventilator-free days and more complications.

CLINICAL COURSE, OUTCOME, AND LONG-TERM SEQUELAE The clinical course and outcomes of ALI and ARDS have been better delineated in recent years. Both pulmonary and nonpulmonary outcomes have been investigated.

Clinical Course and Duration The course of illness varies considerably in severity and duration among patients. ALI and ARDS may last for a few days or even less (e.g., ARDS from opioid exposure, with the patient recovering rapidly after the initial insult). Alternately, ARDS from other causes may last several months and involve a prolonged ICU course. Patients can recover or die at any point in the course of ALI or ARDS. The median duration of mechanical ventilation is approximately 9 days. Up to 20 percent of patients remain on mechanical ventilation for longer than 2 weeks, and about 10 percent still require assisted ventilation at 28 days (representing approximately 15 percent of those still alive at 28 days). Notably, as shown in LaSRS, a longer duration of mechanical ventilation for ALI/ARDS does not translate into a higher mortality. Most ARDS-related deaths occur within the first 2 weeks, with one-third occurring by day 7, two-thirds by day 14, and three-fourths to four-fifths by day 28. The mortality rate of patients on mechanical ventilation after 2 to 4 weeks of persistent ARDS is about 30 percent over the ensuing 2 to 6 months. These rates are similar to the overall mortality rate (at 180 days) for patients enrolled in ARDSNet clinical trials in which low tidal volume ventilation was used. The findings highlight the importance of continued supportive care in the ICU and vigilance aimed at reducing nosocomial complications.

Trends in Mortality Rates Mortality rates for patients with ARDS have decreased since the early 1980s. In one hospital using the same definition of ARDS throughout the period analyzed, the mortality rate was 68 percent in 1982, 29 percent in 1996, and in the mid–30 percent range in 1997 and 1998. Obviously, the decrease cannot be ascribed to widespread application of low tidal volume ventilation strategies, since the decline was observed prior to publication of the ARDSNet ARMA study in May 2000. The improvement is likely attributable to improvements in general ICU care, including prevention of nosocomial pneumonias and other infections, earlier institution of enteral nutrition, routine use of stress ulcer prophylaxis, and improved ICU teamwork. Notably, however, the case fatality rate for patients with ARDS due to sepsis remained the same over this time frame, while that for patients with ARDS due to trauma or other causes decreased significantly. Mortality rates for patients with ALI but without ARDS (see previously described definitions in Table 145-1) are lower by about one-third than for those with ARDS. The decreased mortality presumably reflects the decreased severity of the oxygenation defect in ALI compared with ARDS (Table 145-1).

Causes of Death Approximately one-third of ARDS-related deaths occur in the first 7 days. Most are related to the underlying disease

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or injury, i.e., to events occurring before the onset of ARDS. The majority of patients who die succumb after 7 days, with these late deaths also commonly due to the underlying injury or illness. Other causes include complications occurring contemporaneously with or after the onset of ARDS. The most common cause of death in this group of patients is sepsis and associated multiple organ system failure. Of note, only a relatively small fraction of patients—10 to 20 percent of all patients with ARDS—die a respiratory death due to irreversible hypoxemia or refractory respiratory acidosis. Therefore, not surprisingly, clinical trials of interventions aimed selectively at improving gas exchange (e.g., use of inhaled nitric oxide or exogenous surfactant) have not demonstrated improved survival.

Long-Term Sequelae Recent studies indicate that many survivors of ALI have medical problems and a compromised quality of life both of which persist well beyond their initial ICU stay. Impaired pulmonary, neurologic, musculoskeletal, cognitive, and psychosocial functions have been documented in ALI survivors. Furthermore, survivors have a poorer quality-adjusted survival than do critically ill subjects without ALI. Research into these disorders is in the early stages; the etiology and pathophysiology of are incompletely understood. Recognition of the problems affecting ALI survivors and referral for appropriate evaluation and therapy constitute important components of overall care. With improved therapy of ALI resulting in greater survival rates, clinicians should anticipate an increase in the prevalence of long-term sequelae. Health-Related Quality of Life Health-related quality of life (HRQL) has become increasingly recognized as important to the evaluation of patient-centered outcomes in recovery from a variety of illnesses. A number of studies have evaluated HRQL in ALI survivors. Tools used to assess HRQL include the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), St. George’s Respiratory Questionnaire, Quality of Well Being Scale, and Sickness Impact Profile. Each has illustrated impaired quality of life in survivors of ALI compared with various control populations, including critically ill subjects without ALI and patients with chronic diseases (including cystic fibrosis). In general, impairments in HRQL improve over the first 3 months following discharge from the ICU and appear to plateau by 1 year. Studies of interventions to improve HRQL are under way. Pulmonary Sequelae Studies of pulmonary function following ALI and ARDS are affected by inconsistent disease definitions, methodological problems due to lack of patient follow-up, and heterogeneity of preexisting pulmonary diseases. Consequently, a range of lung function impairments has been reported following recovery. Although a proportion of survivors of ALI may have


impaired diffusion capacity or restrictive or obstructive abnormalities, restoration of normal lung function occurs in a substantial proportion. In the Toronto ARDS Outcomes study, restrictive and diffusion abnormalities observed at 3 months improved toward normal by 1 year. Given the severely impaired physical function domains reported in HRQL surveys and the relatively mild pulmonary impairment, investigation has more recently focused on other limitations and causes of symptoms in ALI survivors (see below). Physical and Neuromuscular Sequelae In the previously noted Toronto ARDS Outcomes study, persistent physical impairment in survivors of ARDS was assessed. Despite improvement in pulmonary function at 1 year following their ICU stay, this cohort had low exercise capacity, weakness, and decreased muscle mass. Risk factors for these findings included multiorgan dysfunction in the ICU, prolonged duration of ARDS, treatment with corticosteroids during the ICU stay, and increased co-morbid disease burden. Although the basis for many of the abnormalities is not clear, a number of patients demonstrated a range of abnormalities, including critical illness polyneuropathy, ICU-acquired myopathy (critical illness myopathy), entrapment neuropathy, and heterotopic ossification. Cognitive and Psychological Sequelae Cognitive impairments can cause major limitations in the ability to return to work, affect mood, and lead to increased health care expenditures. Study of long-term cognitive function in ARDS survivors indicates that many have impaired memory, reduced attention, and decreased concentration and processing speed. The abnormalities were associated with the number and severity of hypoxemic episodes in the ICU. Similar to physical abnormalities, cognitive dysfunction seemed to be worse in the first 3 months following hospital discharge; it improved until 1 year and then reached a plateau. Depression and anxiety are frequent following ARDS. Several studies indicate that the prevalence of depression symptoms is as high as 50 percent following recovery. These emotional problems are likely multifactorial, including prior hypoxic brain injury and delirium and subsequent limitation of physical function. In addition, some authors have suggested the presence of a major component of post-traumatic stress disorder (PTSD) in survivors of ALI. Because these disorders are potentially treatable using pharmacological, behavioral, and cognitive therapies, clinicians should ask ARDS survivors about possible depression and anxiety, which, in turn, may improve HRQL. Finally, in accord with the concept that the ICU team treats patients as well as their families, clinicians need to be aware that familial caregivers of patients who are survivors of ALI or ARDS experience long-term health effects. In particular, they are at increased risk for emotional distress (associated with various factors, including patient depression) and a lower HRQL over all domains tested on the Medical

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Outcomes Short Form 36. Clinicians providing long term follow-up care for patients with ALI or ARDS should aim to ensure adequate social and other support for their familial caregivers.

SUGGESTED READING Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301, 2000. Ammann P, Fehr T, Minder EI, et al: Elevation of troponin I in sepsis and septic shock. Intensive Care Me 27:965, 2001. Ashbaugh DG, Bigelow DB, Petty TL, et al: Acute respiratory distress in adults. Lancet 2:319, 1967. Bernard GR AA, Brigham KL, et al: The American-European Consensus Conference of ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818, 1994. Bernard GR: Acute respiratory distress syndrome: A historical perspective. Am J Respir Crit Care Med 172:798, 2005. Cameron JI, Herridge MS, Tansey CM, et al: Well-being in informal caregivers of survivors of acute respiratory distress syndrome. Crit Care Med 34:81, 2006. Chan KPW, Stewart TE, Mehta S: High-frequency oscillatory ventilation for adult patients with ARDS. Chest 131:1907, 2007. Duane PG, Colice GL: Impact of noninvasive studies to distinguish volume overload from ARDS in acutely ill patients with pulmonary edema: Analysis of the medical literature from 1966 to 1998. Chest 118:1709, 2000. Fan D, Needham M, Stewart TE: Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA 294:2889, 2005. Gattinoni L, Caironi P, Pelosi P, et al: What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 164:1701, 2001. Gattinoni L, Pesenti A: The concept of “baby lung”. Int Care Med 31:776, 2005. Hager DN, Krishnan JA, Hayden DL, et al: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 172:1241, 2005. Herridge MS, Cheung AM, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683, 2003.

Hopkins RO, Weaver LK, Collingridge D, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 171:340, 2005. Jefic D, Lee JW, Jefic D, et al: Utility of B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in evaluation of respiratory failure in critically ill patients. Chest 128:288, 2005. Moss M, Mannino DM: Race and gender differences in acute respiratory distress syndrome in the United States: An analysis of multiple-cause mortality data (1979–1996). Crit Care Med 30:1679, 2002. Murray JF, Matthay MA, Luce JM, et al: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 138:720, 1988. Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685, 2005. Perkins GD, McAuley DF, Thickett DR, et al: The betaagonist lung injury trial (BALTI): A randomized placebocontrolled clinical trial. Am J Respir Crit Care Med 173:281, 2006. Stapleton RD, Wang BM, Hudson LD, et al: Causes and timing of death in patients with ARDS. Chest 128:525, 2005. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network: Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327, 2004. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671, 2006. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: The fluid and catheter treatment trial (FACTT): pulmonary artery catheter versus central venous catheter guided treatment of acute lung injury. N Engl J Med 354: 2213, 2006. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Comparison of two fluid management strategies in acute lung injury: the fluid and catheter treatment trial (FACTT). N Engl J Med 354:2564, 2006. Ware LB, Matthay MA: Acute pulmonary edema. N Engl J Med 353:2788, 2005.

146 Sepsis, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome Stuart F. Sidlow  Clifford S. Deutschman


The systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) are diseases of medical progress. Prior to advances in critical care medicine that have characterized the past three decades, SIRS and MODS were unknown. However, our ability to treat shock, manage acute renal insufficiency, support patients in pulmonary failure, and even to transplant organs such as the liver has unmasked these new syndromes. Indeed, initial reports on MODS, which, at the time was called sequential system failure or multiple system organ failure, heralded the ability to rescue patients from such diverse catastrophic events as ruptured abdominal aortic aneurysm, severe trauma, pancreatitis, multiple transfusions, and progressive infections. Attempts to manage MODS have led, in turn, to a host of important biochemical, metabolic, and physiological discoveries. This chapter defines the clinical findings that constitute sepsis, SIRS, and MODS and places these disorders in con-

‘‘ Two-Hit’’ Hypothesis Connectionist Hypothesis Other Hypotheses VII. MANAGEMENT Pulmonary Dysfunction Source Control Perfusion Management Rational Use of Inotropes and Vasopressors Metabolic Management Novel Medications VIII. CONCLUSION

text by relating them to a continuum of clinical abnormalities and syndromes. In addition, the natural history of these disorders is reviewed briefly. Several pathogenic hypotheses, management strategies, and intriguing new forms of therapy are examined.

DEFINITIONS, NATURAL HISTORY, AND EPIDEMIOLOGY The characteristic response to inflammatory stimuli, including surgery and trauma, classically has been referred to as the stress response (Fig. 146-1)—the evolutionary importance of which is facilitation of survival and tissue repair. Initially, an orchestrated neural-endocrine-humoral response directs substrate delivery to the most vital organs— the heart and brain. This response is accomplished through

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Table 146-1 Diagnostic Criteria SIRS Temperature >38◦ C or <36◦ C Heart rate >90 beats/minute Respiratory rate >20 breaths/min or Pco2 <32 mmHg WBC >12×109 /L or <2×109 /L or >10% immature forms Sepsis SIRS + identified or suspected infection Sever Sepsis Sepsis + dysfunction of 1 or more organ systems Septic Shock Sepsis + hypotension (BP <90 mmHg or a reduction of >40 mmHg from baseline in the absence of other causes) despite adequate fluid resuscitation and perfusion abnormalities (e.g., lactic acidosis, oliguria, altered mental status) MODS No current definitions Figure 146-1 Diagrammatic representation of the two classic patterns of MODS pathogenesis. Percentages indicate the proportion of patients following the pathway. Patients develop respiratory insufficiency after an initial insult. In some cases (left side of diagram) this persists for 2 to 3 weeks, and the patients then rapidly develop abnormalities of other organ systems. Over the course of the next week, patients either recover or die. In a second group of patients, multiple-organ dysfunction rapidly follows the onset of respiratory insufficiency. These abnormalities persist for 2 to 3 weeks. Over the next week, patients then either recover or die.

vasoconstriction, fluid retention, and translocation of intracellular water to the vasculature. In the absence of exogenous support, death from shock ensues if these endogenous mechanisms are inadequate. Following resuscitation from the initial period of shock, hypermetabolism develops. The driving force behind this second phase is repair of damaged tissue, with white blood cells serving as the primary effectors of the process. To support the increased white blood cell mass, substrate is mobilized from endogenous sources and glucose reserves are rapidly depleted. Because white blood cells are obligate glucose users, muscle (both skeletal and smooth) is broken down to provide precursors for hepatic gluconeogenesis. In addition, amino acids are used to synthesize structural proteins and enzymes. Energy to support the liver, heart, and other organs is derived from fat and amino acids, since utilization of glucose by tissues other than blood cells and neurons is blocked. Generalized capillary recruitment and leak allows glucose delivery to the avascular tissue of the wound. The amount of fluid in the extracellular compartment, par-

From Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250–1256, 2003.

ticularly in the extravascular matrix, increases dramatically. Continued fluid retention and movement of water out of cells fill the dilated, leaky vasculature. Vasodilatation is accompanied by an increase in cardiac output, which further facilitates delivery of substrate. By the fourth day after injury or surgery, neovascularization of damaged tissue occurs. Along with a sharp increase in substrate delivery to the tissue of the newly vascularized wound, a decrease occurs in capillary leak accompanied by generalized increases in vascular tone and in the mobilization and excretion of fluid in the matrix. Water also returns to cells. In most cases, the patient recovers uneventfully. In an unknown percentage of patients, the inflammatory process becomes persistent, progressing to the systemic inflammatory response syndrome, or SIRS. This process is defined by the presence of two or more of the criteria listed in Table 146-1. Because these are normal responses postsurgery or following trauma, these criteria must persist beyond days 3 to 5 for the disorder to be termed SIRS. Although SIRS is a useful term in comparing studies in the literature, some have challenged the notion that it is a useful diagnostic entity. One alternative approach is the socalled “PIRO” classification system (Table 146-2), which considers Predisposition, Infection, Response, and Organ Dysfunction in evaluating patients in the context of a systemic

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Table 146-2 The PIRO system for Staging Sepsis Domain





Premorbid illness with reduced probability of short-term survival. Cultural or religious beliefs, age, sex.

Genetic polymorphisms in components of inflammatory response (e.g., TIR, TNF, IL-1, CD14): enhanced understanding of specific interactions between pathogens and host diseases.

In the present, premorbid factors impact on the potential attributable morbidity and mortality of an acute insult; deleterious consequences of insult heavily dependent on genetic predisposition (future).

Insult infection

Culture and sensitivity of infecting pathogens; detection of disease amenable to source control.

Assay of microbial products (LPS, mannan, bacterial DNA): gene transcript profiles.

Specific therapies directed against inciting insult require demonstration and characterization of that insult.


SIRS, other signs of sepsis, shock, CRP.

Nonspecific markers of activated inflammation (e.g., PCT or IL-6) or impaired host responsiveness (e.g., HLA-DR); specific detection of target of therapy (e.g., protein C, TNF, PAF).

Both mortality risk and potential to respond to therapy vary with nonspecific measures of disease severity (e.g., shock); specific mediator-targeted therapy is predicated on presence and activity of mediator.

Organ dysfunction

Organ dysfunction as number of failing organs or composite score (e.g., MODS, SOFA, LODS, PEMOD, PELOD).

Dynamic measures of cellular response to insult—apoptosis, cytopathic hypoxia, cell stress.

Response to preemptive therapy (e.g., targeting micro-organism or early mediator) not possible if damage already present; therapies targeting the injurious cellular process require that it be present.

TLR, Toll-like receptor; TNF, tumor necrosis factor; IL, interleukin; LPS, lipopolysaccharide; SIRS, systemic inflammatory response syndrome; CRP, C-reactive protein; PCT, procalcitonin; HLA-DR, human leukocyte antigen-DR; PAF, platelet-activating factor; MODS, multiple-organ dysfunction syndrome; SOFA, sepsis-related organ failure assessment; LODS, logistic-organ dysfunction system; PEMOD, pediatric multiple-organ dysfunction; PELOD, pediatric logisticorgan dysfunction. source: Table created using data from Angus et al (2003); Gerlach et al (2003); Vincent, Opal et al (2003); and Vincent, Wendon et al (2003).

inflammatory response. While not yet widely accepted, this classification system has the potential to address some of the concerns over the SIRS designation. Whatever one calls the syndrome that develops when inflammation becomes persistent, the clinical entity does exist, often driven by an underlying source, such as a nidus of infection or in undrained hematoma. Such occurrences generally reflect extensive trauma, delayed resuscitation, surgery complicated by extensive, rapid blood loss, or inflammation, as occurs with pancreatitis or aspiration pneumonitis. If a clear source of infection is present, the disorder is classified as sepsis. Further details are summarized in Table 146-3. Although sepsis or SIRS may be complicated by hypotension, lactic acidosis, acute lung injury, or oliguria, obvious organ dysfunction is not present. When organ dysfunction does

arise, the syndrome is termed “multiple-organ dysfunction syndrome”, or MODS.

STRESS RESPONSE, SIRS, SEPSIS, AND MODS Virtually all organs become dysfunctional in MODS. However, defining which abnormalities in individual organs constitute dysfunction is problematic. Although many different criteria have been used, none are universally accepted. Indeed, two Consensus Conference Committees of the American College of Chest Physicians (ACCP) and the Society for Critical

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Table 146-3 General Criteria for Organ Dysfunction System




Hypoxia/hypercarbia requiring assisted ventilation for 3–5 d

ARDS requiring PEEP >10 cm H2 O and Fio2 >0.5


Bilirubin 2–3 mg/dl or other LFTs twice normal, PT elevated to twice normal

Jaundice with bilirubin >8–10 mg/dl


Oliguria (<500 ml/d) or increasing creatinine (2–3 mg/dl)



Intolerance of GI feeding >5 d

Stress ulceration with need for transfusion, acalculous cholecystitis


PTT >125% of normal, platelets <50,000–80,000 per mm3






Mild sensory neuropathy

Combined motor and sensory deficit


Decreased ejection fraction, persistent capillary leak

Hypodynamic state not responsive to pressors

ARDs = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure; LFTs = liver function tests; PT = prothrombin time; PTT = partial thromboplastin time; DIC = disseminated intravascular coagulation; CNS = central nervous system; PNS = peripheral nervous system. source: From Deitch EA: Multiple organ failure: Pathophysiology and potential future therapy. Ann Surg 216:117–134, 1992.

Care Medicine (SCCM) declined to recommend the adoption of specific definitions. The basis for this position may reflect the understanding that just as MODS falls along a continuum of abnormalities, so, too, is there spectrum of abnormalities in each organ system. Furthermore, the transition from adaptive response to organ dysfunction may be clinically obscure, and distinctions among sepsis, SIRS, and MODS are often simply semantic. Some generally used criteria for organ dysfunction in other systems are detailed in Table 146-3. However, these criteria reflect the gaps in our understanding of MODS. More detailed investigations into the pathobiology of MODS should provide more useful diagnostic criteria.

CLINICAL PATTERNS OF SIRS AND MODS Two well-defined forms of SIRS/MODS are recognized (Fig. 146-1). In either, development of acute lung injury or the acute respiratory distress syndrome (ARDS) is of key importance to the natural history. ARDS is the earliest manifestation in almost all cases. In the more common form of SIRS/MODS, damage to the lungs predominates and often is the only evidence of

organ dysfunction until very late in the disease. This predominantly pulmonary form of MODS is identical to ARDS, which is described in depth elsewhere (see Chapters 144 and 145). However, it is important to point out that the natural history of patients with this type of MODS is well established. Most often, these patients present with an initiating pulmonary affliction (e.g., pneumonia, aspiration, lung contusion, neardrowning, exacerbation of COPD, lung hemorrhage, or pulmonary embolism) that progresses to a condition that meets the diagnostic criteria for ARDS. Ventilator-dependent pulmonary dysfunction, often accompanied by encephalopathy and a mild coagulopathy, persists for some time. At some point, the patient either begins to recover or progresses to develop fulminant dysfunction in other organ systems, most often hepatic, renal, or cardiovascular. A large proportion of patients with multiple organ involvement do not survive. The pulmonary origin of this form of SIRS/MODS is useful diagnostically since the population at risk can often be defined; data indicate a better prognosis in this subgroup. Diagnosis of the second form of SIRS/MODS is more problematic. Although the earliest manifestation of the syndrome continues to be pulmonary, most often there is an underlying source that is remote from the lung. This group consists of patients who have experienced major trauma (including isolated head injuries, intra-abdominal sepsis,

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extensive blood loss, pancreatitis, vascular catastrophes, such as ruptured or dissecting aneurysms, and a host of other conditions). Acute lung injury and ARDS develop early, but dysfunction in other organs soon becomes evident. Most studies have found the liver to be the next most commonly involved organ. Indeed, if one considers bleeding associated with an elevated prothrombin time to reflect a hepatic abnormality, the liver may well become dysfunctional even in cases classified as primary pulmonary MODS. Gastrointestinal, cardiovascular, and renal dysfunction are cited equally as the next most common signs of organs failure. Compensated organ dysfunction persists for some time before the patient either recovers or deteriorates further and dies. The diversity of the population at risk makes early diagnosis of the second form of SIRS/MODS difficult. Furthermore, since many of these patients have undergone surgical procedures, development of mild hypoxemia and increased lung water—normal findings after surgery—may obscure early recognition of ARDS. Thus, SIRS/MODS may not be appreciated until dysfunction in several organ systems has become well established. Improvements in our ability to support patients with MODS have led to recognition of a third syndrome—referred to (for lack of a better term) as “chronic critical illness.” At some point, critically ill patients may become quite stable (i.e., unchanging), but their physiology remains remarkably abnormal. Typically, they require exogenous support of major organ systems. A “hyperimmune” state gives way to one of immunosuppression. Most hormonal systems cease to work properly either because of resistance to hormonal effects or to depletion of hormonal synthesis and storage. These abnormalities reflect a state of endocrine “burn-out” that currently has no specific treatment.

EPIDEMIOLOGY Accurate determination of the incidence of SIRS/MODS is difficult, predominantly a reflection of the diverse etiologies of the syndromes. The incidence of primary pulmonary SIRS/MODS (i.e., ARDS) is estimated to be in excess of 150,000 cases per year. With regard to the second form of SIRS/MODS, the estimated number of cases in the United States is 750,000 per year. The incidence of MODS following trauma that necessitates admission to the ICU may be as high as 14 percent. Mortality from MODS remains distressingly high. Estimated mortality from ARDS per se is approximately 35 to 40 percent. Involvement of additional organ systems increases the likelihood of a poor outcome; the presence of dysfunction in three or more organ systems virtually ensures death. Some investigators have reported lower mortality rates; others have shown that mortality is a function of the duration of organ failure. The incidence and mortality of MODS may be increasing. Although there is a lack of consensus in this

regard, clearly, once the disease has progressed to the point of multi-organ failure, the patient is at substantial risk for death.

PATHOPHYSIOLOGY The major factor limiting treatment of MODS is the lack of a clear understanding of the underlying pathophysiological defect. In fact, if not viewed carefully, the changes associated with SIRS/MODS may simply resemble an extension of those observed after uncomplicated stress. Thus, patients recovering from major surgery undergo increases in metabolic rate, oxygen consumption, and carbon dioxide production. Relative glucose intolerance and hyperglycemia also occur. The vasculature is dilated, and the cardiac output increases to promote oxygen transport. In fact, lactate production may increase, reflecting the overall increase in metabolism rather than tissue hypoxia. Although simple stress and SIRS/MODS have in common altered intermediary metabolism, a hyperdynamic circulation, and systemic signs of inflammation, two important distinctions have been consistently observed. First, noted previously, they differ in time course. Whereas postoperative hypermetabolism runs its course over 5 to 7 days and resolves with neovascularization, the time course of SIRS/MODS is longer, usually 3 to 4 weeks. The second distinction consists of subtle differences in metabolic and physiological parameters. In simple stress and early SIRS, the increase in metabolic demand can be met by an increase in oxygen supply or in oxygen extraction. However, as the disease progresses toward MODS, the ability to extract, and possibly, utilize, oxygen is lost in some tissue beds. This situation is unstable, because oxygen demand on the cellular level is increased. Similarly, in simple stress there appears to be a block in peripheral glucose utilization. Glucose intolerance becomes more pronounced in SIRS/MODS, possibly because of a defect in the enzyme pyruvate dehydrogenase, which catalyzes conversion of pyruvate to acetyl coenzyme A (acetyl CoA). As a result, increases in tissue metabolic demand cause an increase in the activity of the Krebs cycle and in the generation of lactate (aerobic glycolysis). Consequently, serum lactate increases in direct proportion to the increase in pyruvate. If a microcirculatory perfusion deficit develops, increases in lactate exceed increases in pyruvate. These changes in glucose metabolism become progressively less responsive to modulation by insulin. Ultimately, futile cycling occurs of alanine and lactate between the liver and periphery. The onset of hepatic dysfunction is heralded by increments in serum lactate that are disproportionate to the increments in pyruvate. Fat metabolism is markedly altered as well. Stress is characterized by levels of ketosis that are disproportionately low for the degree of starvation. It also elicits an increase in hepatic gluconeogenesis, which, in turn, causes hyperinsulinemia.

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Stress is associated with lipolysis, decreased lipogenesis, and increased oxidation of long- and medium-chain triglycerides. In early SIRS/MODS, lipogenesis undergoes further decrease. However, oxidation of long-chain triglycerides by the liver also decreases, in association with a decrease in expression of key beta-oxidative enzymes. Ultimately, fat intolerance arises as the liver continues to fail. In the setting of SIRS/MODS, with significant abnormalities of both glycolysis and beta-oxidation, amino acids become an important source of fuel. As oxidation of amino acids increases, so does urea production. Exogenous protein can be an important energy source, but ultimately, hepatic failure compromises ureagenesis and limits this energy source, as well. On the physiological level, vasodilatation and peripheral edema become more pronounced. Cardiac output increases as afterload decreases, but ultimately, the heart also fails as energy sources are depleted. Renal mechanisms are then called upon to conserve fluid and to excrete urea. The generalized edema limits the ability to concentrate the urine maximally, thereby leading to two incompatible goals. As a result, the renal system also becomes dysfunctional. One additional hallmark of progressive SIRS/MODS is a loss of the normal hormonal modulation of cellular processes. Thus, insulin-mediated glucose uptake decreases and blood pressure becomes unresponsive to all but the most potent vasopressors, while a glucagon-induced alteration in gluconeogenesis disappears. The mechanisms by which these changes occur are unknown. A large number of hypotheses have been advanced to explain the pathophysiology of SIRS/MODS. From these have emerged two general concepts concerning etiology. In one, the predominant effect is in the microcirculation: along with an overall decrease in peripheral vascular tone, demand and supply at the microcirculatory level are mismatched, resulting in misdistribution of flow. In the second, the defect is predominantly one of cellular and, indeed, mitochondrial, metabolism. All hypotheses invoke a process that “activates” an inflammatory cascade that “mediates” end-organ responses. In time, these responses become dysfunctional. It is generally accepted that dysfunction in some way results from an inability to meet metabolic demands because of either inadequate flow or direct metabolic block.

HYPOTHESES OF UNDERLYING MECHANISMS A number of hypotheses have been advanced regarding the underlying basis of SIRS/MODS.

Cytokine Hypothesis Cytokines are mediators produced and secreted by a number of cells, most notably inflammatory and endothelial cells.

These mediators bind to receptors on the cell membrane and initiate intracellular events that alter cell behavior. The cell whose behavior is altered may be the same cell that produces the cytokine (autocrine), a nearby cell (paracrine), or a distant cell (endocrine). Cytokines activate a number of intracellular signal transduction pathways. The ultimate effect may be direct (e.g., activation of membrane channel or an intracellular protein) or may result in stimulation of gene expression. Cytokines that have been implicated in SIRS/MODS include tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, and interferon-γ (INF-γ). Following simple stress, TNF-α or IL-1 are produced by inflammatory cells drawn to the site of injury or inflammation and by local endothelial cells. These cytokines are then released into the circulation and affect distant organs. The behavior of TNF-α on the liver serves as a useful paradigm. A 26-kD form of TNF-α is produced by local cells and is expressed on the cell surface. This form of TNF-α is, through unknown mechanisms, active in control of debridement and infection at the local level. Ultimately, however, 26-kD TNF-α is cleaved by a matrix metalloproteinase to a 17-kD circulating form. The blood carries the 17-kD form from remote organs. The 17-kD form is capable of not only producing vasodilatation (perhaps, via a nitric oxide-linked pathway), but also of stimulating other inflammatory and noninflammatory cells. For example, in the liver, TNF-α stimulates resident macrophages (Kupffer cells) to produce more TNF-α, as well as other cytokines, such as IL-1 and especially IL-6. TNF-α, IL-1, and IL-6 then induce hepatocytes to express the genes for a number of proteins called acute-phase reactants. These secreted proteins have diverse activities that help control the inflammatory response. Since low levels of TNF-α (and IL-1) are released from the initial site of inflammation, the process should be self-limited. In the cytokine theory of MODS, over-production of TNF-α, IL-1, or IL-6 and resultant uncontrolled inflammation are postulated. The net result is prolonged, uncontrollable vasodilatation and damage to viable organs by activated macrophages and other inflammatory cells. In support of this theory, high levels of circulating TNFα, IL-1, IL-6, and INF-γ have been found in fulminant septic shock (e.g., as in disseminated meningococcemia). Similarly, in animal models in which endotoxin is administered intravenously, serum levels of TNF-α and IL-1 are increased. Studies in animals and human volunteers indicate that TNF-α is probably the most proximal mediator, initiating the expression and release of the other cytokines. TNF-α is cytotoxic to a number of cells, initiating programmed cell death (apoptosis) in culture. Antibodies to TNF-α are protective in lethal endotoxemic and bacteremic animal models, while certain intracellular proteins can block TNF-α–induced apoptosis. Finally, administration of TNF-α to animals results in a syndrome that mimics septic shock, whereas giving low doses of this cytokine to humans mimics certain metabolic aspects of SIRS. Substantial data indicate, however, that this view of SIRS/MODS is simplistic.

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In animal models of bacterial peritonitis, neutralizing TNF-α in the serum increases mortality. Reported levels of cytokines in the blood of septic patients vary considerably among studies. Also, clinical trials of anti-TNF-α in human SIRS have been disappointing. Recent data indicate that serum levels do not reflect tissue levels, and that the cellassociated, 26-kD form (and not the 17-kD circulating form) of TNF-α mediates organ injury. Evidence from studies of IL6 knockout mice indicates that this cytokine is an important component of hepatic regeneration; therefore, it may be protective, rather than injurious. Since a host of other mediators and pathways are activated in SIRS, a reasonable conclusion is that cytokines are important mediators of certain aspects of SIRS/MODS, but that other factors are at work.

Microcirculatory Hypothesis The common link in the microcirculatory hypothesis is that the failure of cells or organs to receive adequate levels of oxygen or some important nutrient or substrate triggers SIRS/MODS. Low blood flow, as is likely to occur in hypotension or shock, contributes to cellular dysfunction. However, the release of vasoactive mediators and vascular congestion secondary to microthrombi and leukocytes are also held to be important. Reperfusion of ischemic tissue may be as important a determinant of tissue injury as decreased flow itself. In particular, the generation of oxygen free radicals and peroxidation of membrane lipids following reperfusion may contribute to tissue injury. Sources of free radicals include the conversion of molecular oxygen to superoxide by xanthene oxidase, activated leukocytes, mitochondria, and prostaglandin synthase. The first two sources are probably the most important. Circulatory shock, microvascular compromise, and free radical generation are likely to affect the endothelium directly. Endothelial cells are active in free radical formation, provide a point of attachment for leukocytes, and may be exquisitely sensitive to hypoxia. Furthermore, they not only produce, but are also affected by, vasoactive mediators. These interactions provide the link between the cytokine and microvascular hypotheses. Cytokines activate endothelial cells to elaborate other vasoactive substances and to express surface proteins that promote leukocyte adhesion; endothelial cells are also important participants in the formation of microthrombi. In support of the microvascular hypothesis, circulatory shock often occurs before MODS; autopsy data indicate the presence of microvascular injury in patients with MODS; and microthrombi containing platelets, neutrophils, and fibrin are common in MODS. Antibodies to CD18, which block leukocyte adhesion, do occur in circulatory shock and are protective in some forms of ischemia-reperfusion injury; they are not protective against liver injury or leukocyte adherence in experimental sepsis. The microthrombi, microvascular constriction, and free radicals are valuable in limiting the spread of infection.

Gut Hypothesis The syndrome that is now designated as SIRS once was believed to be the result of uncontrolled infection, presumably due to the endotoxin released by gram-negative bacteria. However, organisms other than gram-negative bacteria have been implicated, and in many patients, neither microorganisms nor a source of bacteria can be identified. The gut hypothesis contends that inflammation is due, in part, to bacteria in the gastrointestinal tract (or their associated endotoxin) that translocate to the mesenteric lymph nodes, liver, and circulation. Various insults have been shown to lead to such translocation of bacteria or endotoxin, and the intestinal barrier is disrupted in many clinical situations that can precede MODS. As a rule, translocation involves a combination of insults, including an alteration in the indigenous gastrointestinal flora, that results in bacterial overgrowth, impaired host defenses, and physical disruption of the intestinal barrier. The gut hypothesis overlaps the cytokine and microcirculatory hypotheses. Bacteria or endotoxin activates white blood cells and induces production of cytokines. Each can alter the behavior of both endothelial cells and the coagulation system, leading to microvascular aggregation and production of free radicals, which can, in turn, create a self-sustaining cycle that culminates in MODS. Exposure to intestinal flora activates hepatic macrophages (Kupffer cells), releases cytokines, and damages hepatic cells, reinforcing the hypothesis that translocated bacteria are important in the pathogenesis of SIRS/MODS.

‘‘Two-Hit’’ Hypothesis A second insult, subsequent to an initial “hit,” may be of major importance in the pathogenesis of SIRS/MODS. According to this hypothesis, an initial period of hypotension “primes” the trauma patient for SIRS/MODS (i.e., the initial insult activates other processes that amplify the effects of the initial event, however mild). Priming could involve activation of white blood cells or platelets, disruption of the intestinal mucosal barrier, or the induction of free radicals and the enzymes (such as xanthene oxidase) that produce these reactive species. Although this hypothesis overlaps with others, such as the cytokine, microcirculatory, and gut hypotheses, animal studies in which a single insult is followed by a second, more severe insult have shown that the first “hit” is actually protective.

Connectionist Hypothesis By viewing biologic systems as composed of oscillators, with the oscillations reflecting a continuously changing series of external events, we can regard the loss of either the external stimuli or the ability to respond to these stimuli as pathological. On the basis of this approach, and with the application of nonlinear modeling, the transition from SIRS to MODS has been depicted as an erosion in the ability of different organs to

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communicate with each other. For example, in experimental sepsis, hepatocellular metabolic pathways, such as glucogenesis, respond inadequately to hormonal stimulation. Similarly, beat-to-beat cardiac variability in human volunteers is lost during experimental endotoxemia. The connectionist hypothesis supplements, rather than substitutes for, the hypotheses presented above.

Other Hypotheses Other hypotheses are being explored. For example, one possibility under investigation is that the seemingly diffuse abnormalities in SIRS and MODS may be related to deficits in hepatic metabolism. Consistent with this hypothesis is the observation that gluconeogenesis, beta-oxidation, and ureagenesis are impaired in septic animals. These alterations are due, in part, to a decrease in the transcription of genes coding for key enzymes in each pathway. Furthermore, when important transcription factors are examined, a potential link between pulmonary and hepatic dysfunction becomes clear. Similarly, another theory holds that dysfunction at the mitochondrial level may be responsible for the improper response in MODS—specifically, inadequate oxygen utilization by cells may be operative. This mechanism, coupled with inadequate oxygen delivery (as described in the microcirculatory hypothesis) results in a mismatch between oxygen demand or supply and oxygen utilization. Recent studies reveal a defect in cytochrome oxidase, the terminal complex in the electron transport chain, in septic myocardium. Regardless of which is the dominant “cause” or “effect” of SIRS or sepsis, the net result is that dysfunction of multiple systems results in physiological detriment to the patient and threatens survival.

MANAGEMENT Management of patients with SIRS/MODS is challenging and focuses on treatment of major end-organ damage.

Pulmonary Dysfunction Pulmonary dysfunction most often takes the form of secondary ARDS. This topic is covered in depth in Chapter 145.

Source Control The key to prevention and elimination of SIRS/MODS is source control. The clinician must exhaustively search for and eliminate the nidus of inflammation, whether it is a hematoma, abscess, wound infection, or sinusitis. This is critical to reversing the process. While conducting the search for the offending source or microorganism, empiric use of broadspectrum antibiotics is advised; subsequently, the regimen is

tailored based on culture and sensitivity reports from the microbiology laboratory.

Perfusion Management In the face of inflammation, perfusion should be optimized. It is nearly impossible to restore the body to pre-insult hemodynamic status until the inflammatory response has run its course. Supportive care is key. That inadequate tissue perfusion potentiates SIRS and may catalyze progression to MODS should be recognized. This is especially true for the kidneys, which are sensitive to hypoperfusion, even in the absence of underlying renal pathology. Moreover, hypoperfusion of the kidneys activates the renin-angiotensin-aldosterone system. Since angiotensin II is the major determinant of portal perfusion of the liver, and since hepatic dysfunction figures prominently in MODS, disturbances in the renin-angiotensinaldosterone system may contribute to disturbance in hepatic function. Disturbances in ventilation-perfusion relationships secondary to pulmonary hypoperfusion may contribute to arterial hypoxemia. Fluids should be administered liberally in SIRS/MODS. Determination of the appropriate volume of fluid to administer is problematic, however, largely because end-organ function, the best index of adequate perfusion, is already impaired. One practical rule of thumb is to achieve a stroke volume of approximately 1 ml/kg of body weight. If the administration of fluid does not increase stroke volume, cardiac dysfunction is probably present and administration of additional fluid is not likely to be helpful.

Rational Use of Inotropes and Vasopressors Animal and human studies indicate that SIRS/MODS renders the cardiovascular system relatively resistant to the effects of native and synthetic catecholamines. Therefore, powerful agents are required to achieve any hemodynamic effect. Also, the vasodilatation may represent a compensatory response to a metabolic defect; hence, induced vasoconstriction may worsen this defect. One practical expedient is to treat hypotension when evidence of myocardial ischemia develops, usually at a diastolic pressure of about 40 mmHg. Norepinephrine is the drug of choice. This agent constricts somatic (muscle) beds, but it appears to spare the splanchnic circulation, thereby transferring fluid from the periphery to the central, visceral compartment. As a second-line therapy to increase visceral tone once maximum effect using norepinephrine has been achieved, a low, nontitrated dose of vasopressin at 0.01 to 0.04 units/h may be added. Endogenous vasopressin release is diminished in sepsis, suggesting a role for vasopressin “replacement,” rather than “therapy.” Dopamine, which had long been a preferred agent in sepsis, is no longer advocated, since it is a nonspecific agonist and may cause maldistribution of flow. Dopamine has been demonstrated to be detrimental to renal function. If cardiac output remains low despite adequate fluid resuscitation and vasopressor therapy, an inotrope,

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Supplemental oxygen ± endotracheal intubation and mechanical ventilation

Central venous and arterial catheterization

Sedation, paralysis (if intubated), or both

<8 mm Hg


Crystalloid Colloid

8–12 mm Hg


<65 mm Hg >90 mm Hg

Vasoactive agents

>65 and <90 mm Hg



>70% Transfusion of red cells until hematocrit >30%


>70% Inotropic agents


Goals achieved Yes Hospital admission

Figure 146-2 Goal-directed therapy for septic shock. (From Clinical Practice Guidelines, Hospital of the University of Pennsylvania.) Resuscitation in Septic Shock: Hemodynamic Considerations in Goal-Directed Therapy Resuscitation should continue with predetermined end points: 1. 2. 3. 4.

Target mean arterial pressure (MAP) of 65 mmHg Urinary output of >0.5 ml/kg/h Central venous pressure (CVP) of 12–15 mmHg Stroke volume (SV) of 0.7–1.0 ml/kg

If early aggressive fluid resuscitation does not restore MAP within 30 min (refractory shock), add norepinephrine. If norepinephrine dose exceeds 10 µg/min, add nontitrated dose of vasopressin at 0.04 µg/min. If patient remains hyperdynamic with impaired myocardial contractility, add inotrope with goal SV of 0.7–1.0 ml/kg. Dobutamine is first line, followed by epinephrine. Impaired myocardial contractility is defined as decreased ejection fraction (EF), ventricular dilation, impaired contractile response to volume loading, or low peak systolic/end-systolic volume ratio. End points for assessing resuscitation are arterial blood pressure, heart rate, urinary output, and skin perfusion. From Clinical Practice Guidelines, Hospital of the University of Pennsylvania, Philadephia, PA.

such as dobutamine, may be added to increase cardiac contractility. Recent studies emphasize goal-directed therapy in the management of sepsis (Fig. 146-2). This includes promptly achieving a mean arterial pressure (MAP) greater than 65 mmHg, a central venous pressure (CVP) of 8 to 12 mmHg,

a venous oxygen saturation (SvO2 ) greater than 70 percent, a hemoglobin concentration greater than 10 g/dl, and a lactate concentration less than 4.0 mm. After initial resuscitation, unless there is active cardiac disease, acute hemorrhage, or continuing lactic acidosis, a hemoglobin concentration of 7 g/dl is acceptable.

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Metabolic Management As SIRS progresses to MODS, the intrinsic metabolic defect associated with the disorder worsens. Although glucose intolerance is apparent very early in the course of the disease, progressive hyperglycemia may develop. Additionally, there is progressive azotemia as amino acids are deaminated and carbon skeletons enter the Krebs cycle. Ultimately, hepatic dysfunction becomes so severe that even this process becomes impaired. The intrinsic defect appears to be a decrease in the transcription of genes encoding certain key enzymes in metabolic pathways. Although compensation can occur early in the course, ultimately this fails. To meet caloric needs, most clinicians rely on a formula that is relatively hypocaloric and protein-rich. The resultant increase in blood urea nitrogen is generally well tolerated in adequately hydrated patients. This contrasts with the results of overfeeding with fat or glucose. However, if the increase in blood urea nitrogen is a manifestation of uremia, rather than an isolated consequence of protein overfeeding, dialysis may become necessary. We believe that administration of exogenous insulin should be avoided early in SIRS/MODS. Most often, the need is precipitated by use of fluids that contain exogenous glucose. Employment of tight glycemic control is controversial in sepsis, although it has been shown to be effective overall in critically ill patients. These studies show an improvement primarily in patients in the ICU for more than 5 days. Thus, it is our belief that “insulin resistance” represents one additional manifestation of “endocrine burn out” in chronic critical illness. In the acute phase of critical illness, insulin may lower serum glucose levels, but it does so by driving glucose into fat cells. Insulin does not increase glucose oxidation in any tissue. Moreover, even though insulin may block catabolism of skeletal muscle, it does not have this effect on smooth muscle. Therefore, vascular and gastrointestinal smooth muscle may be mobilized, worsening the defects in these organ systems. Use of corticosteroids in sepsis is another controversial topic. Patients requiring high doses of vasopressors may have a component of adrenal insufficiency. However, the criteria for defining adrenal insufficiency in critically ill patients are difficult to define. If normal diagnostic criteria are met (low baseline cortisol or failure to increase serum levels 30 to 60 minutes following administration of adrenocorticotropic hormone [ACTH] or an ACTH analogue), corticosteroid administration is reasonable. Adrenal insufficiency, too, may be a manifestation of endocrine burnout in chronic critical illness.

Novel Medications Recent studies have evaluated the use of recombinant human Activated Protein C (rhAPC) in patients who are in severe sepsis or MODS. The rationale for use is that the inflammatory response results in a procoagulant state. By reversing this response, patients may have a greater survival rate. Indeed,

in carefully selected subgroups (those who are less severely ill, with Acute Physiology, Age, and Chronic Health Evaluation (APACHE) scores under 25), administration of rhAPC modestly increases survival. Furthermore, low-risk patients do not benefit. The specifics of renal replacement therapy are beyond the scope of this chapter. However, in acute renal failure from MODS, the replacement of choice is early continuous venovenous hemodialysis (CVVHD). Hemodynamic stability is greater with CVVHD than with intermittent hemodialysis. In addition, animal studies have demonstrated a shortened course of sepsis using hemodiafiltration. Unfortunately, these results have not been confirmed in human studies.

CONCLUSION SIRS/MODS represent a major cause of mortality and morbidity. The nature of the underlying pathological defect is unknown. Current treatment is supportive and centers on assurance of adequate ventilation and oxygenation, appropriate fluid resuscitation, metabolic support, an intensive search for an excisable or drainable inflammatory site, and avoidance of secondary organ injury.

SUGGESTED READING Abraham E, Laterre PF, Garg R, et al: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353:1332–1341, 2005. Andrejko KM, Deutschman CS: Altered hepatic gene expression in fecal peritonitis: Changes in transcription of gluconeogenic, beta-oxidative, and ureagenic genes. Shock 7:164–169, 1997. Angus DC, Burgner D, Wunderink R, et al: The PIRO concept: P is for predisposition. Crit Care 7:248–251, 2003. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310, 2001. Annane D, Sebille V, Troche G, et al: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283:1038–1045, 2000. Beale RJ, Hollenberg SM, Vincent JL, et al: Vasopressor and inotropic support in septic shock: An evidence-based review. Crit Care Med 32:S455–S465, 2004. Bernard GR, Margolis BD, Shanies HM, et al: Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): A single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 125:2206–2216, 2004. Dellinger RP, Carlet JM, Masur H, et al: Surviving Sepsis Campaign guidelines for management of severe

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sepsis and septic shock. Crit Care Med 32:858–873, 2004. Deutschman CS, De Maio A, Clemens MG: Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene. Am J Physiol 269:R584–R591, 1995. Gerlach H, Dhainaut JF, Harbarth S, et al: The PIRO concept: R is for response. Crit Care 7:256–259, 2003. Godin PJ, Fleisher LA, Eidsath A, et al: Experimental human endotoxemia increases cardiac regularity: Results from a prospective, randomized, crossover trial. Crit Care Med 24:1117–1124, 1996. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150, 2003. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250–1256, 2003. Levy RJ, Piel DA, Acton PD, et al: Evidence of myocardial hibernation in the septic heart. Crit Care Med 33:2752– 2756, 2005. Levy RJ, Vijayasarathy C, Raj NR, et al: Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis. Shock 21:110–114, 2004.

Pelosi P, D’Onofrio D, Chiumello D, et al: Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur Respir J Suppl 42:48s–56s, 2003. Regel G, Grotz M, Weltner T, et al: Pattern of organ failure following severe trauma. World J Surg 20:422–429, 1996. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377, 2001. Van den Berghe G, Wilmer A, Hermans G, et al: Intensive insulin therapy in the medical ICU. N Engl J Med 354:449– 461, 2006. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359–1367, 2001. Vincent JL, Mercan D: Dear Sirs, what is your PCT? Intensive Care Med 26:1170–1171, 2000. Vincent JL, Opal S, Torres A, et al: The PIRO concept: I is for infection. Crit Care 7:252–255, 2003. Vincent JL, Wendon J, Groeneveld J, et al: The PIRO concept: O is for organ dysfunction. Crit Care 7:260–264, 2003.

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147 Acute Respiratory Failure in the Surgical Patient Robert M. Kotloff

I. IDENTIFICATION OF THE HIGH-RISK PATIENT Type of Operative Procedure Chronic Obstructive Pulmonary Disease Smoking Predicting Risk of Respiratory Failure II. IMPACT OF ANESTHESIA AND POSTOPERATIVE ANALGESIA ON PULMONARY FUNCTION General Anesthesia Neuraxial Anesthesia Postoperative Analgesia

IV. CAUSES OF POSTOPERATIVE RESPIRATORY FAILURE Atelectasis Pneumonia Acute Lung Injury Phrenic Nerve Injury and Diaphragmatic Dysfunction Pulmonary Embolism Obstructive Sleep Apnea V. USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION


Advances in surgical technique, anesthesia and analgesia, and postoperative supportive care have facilitated application of sophisticated surgical procedures to an expanding spectrum of patients. Emboldened by diminished operative mortality rates, clinicians are increasingly willing to subject older and sicker patients to rigorous, but potentially life-saving, surgical interventions. In most instances, the success or failure of the surgery is defined not in the operating room, but postoperatively, when the adverse effects of surgery may first become apparent and when intercurrent complications may jeopardize the patient’s well-being. The respiratory system is particularly vulnerable to the effects of general anesthesia and surgery, and postoperative respiratory impairment is common. While generally mild and well-tolerated in otherwise healthy, young patients, postoperative respiratory compromise may have serious consequences in the elderly and in patients with preexisting lung disease. Potentially devastating postoperative complications,

such as pneumonia, aspiration, and acute respiratory distress syndrome (ARDS) may lead to respiratory failure independent of the patient’s presurgical status. Overall, pulmonary complications account for approximately 25 percent of postoperative deaths. This figure is, in fact, conservative, since many patients with respiratory failure can be supported on mechanical ventilation, only to die of other nonrespiratory complications (e.g., sepsis, gastrointestinal bleeding, and multi-organ failure). In addition to their effect on mortality, respiratory complications exact a toll in lengthening ICU and hospital stay, delaying convalescence, and escalating the cost of care. Therefore, clinicians who provide preoperative evaluation and postoperative care must be familiar with the factors that predispose to pulmonary impairment in the surgical patient. Many of these concepts are considered in Chapter 38. This chapter focuses on the most serious of the perioperative respiratory complications—acute respiratory failure.

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IDENTIFICATION OF THE HIGH-RISK PATIENT In a review of over 7000 patients undergoing various gastrointestinal, urological, gynecological, and orthopedic procedures, respiratory failure requiring mechanical ventilation beyond 24 h occurred in only 0.8 percent. Among 81,719 patients undergoing both elective and emergency noncardiac procedures in hospitals belonging to the Veterans Affairs (VA) health system, respiratory failure (defined as mechanical ventilation beyond 48 h after surgery or need for reintubation) occurred in 3.4 percent. Though the overall risk of respiratory failure in these studies is relatively low, it is clear that risk varies markedly, depending on a number of factors related to the procedure and the patient. While risk of postoperative respiratory failure is negligible in the young, healthy nonsmoker undergoing elective knee surgery, it is significant in the elderly patient with underlying chronic obstructive pulmonary disease (COPD) undergoing emergent repair of a thoracoabdominal aortic aneurysm. Factors that have been most thoroughly studied in association with postoperative respiratory failure are discussed in greater detail below.

Type of Operative Procedure Procedures that involve the upper abdomen or thorax are associated with the highest rates of postoperative pulmonary complications, including respiratory failure (Table 147-1). In large part, the risk is attributable to the profound derangement in pulmonary mechanics that accompanies these procedures (see below). Thoracoabdominal aneurysm repair carries the greatest risk of postoperative respiratory failure.

Given the need for both abdominal and thoracic incisions, as well as division of the diaphragm and costal margin, this observation is not surprising. Other procedures with significant risk include abdominal aortic aneurysm repair, upper gastrointestinal surgery, thoracotomy, and open heart surgery. Lower abdominal procedures carry a much smaller risk than those involving the upper abdomen; procedures involving the extremities carry a negligible risk. In some cases, the surgical approach can be modified to lessen the risk of postoperative pulmonary complications in patients who are marginal operative candidates because of advanced age or co-morbid conditions. For example, use of a transverse abdominal incision appears to carry less risk than a vertical midline incision. Cholecystectomy performed by laparoscopic technique is associated with a lower incidence of pulmonary complications compared with the conventional open approach. For thoracic procedures, median sternotomy and muscle-sparing lateral thoracotomy are better tolerated than posterolateral thoracotomy. However, these approaches provide more limited access to the thorax than does the standard thoracotomy incision, and they are generally inadequate for resection of the left lower lobe or for tumors involving the posterior chest wall, diaphragm, or superior sulcus. Additionally, removal of bulky tumors via the muscle-sparing approach may be problematic. Video-assisted thoracoscopic surgery (VATS) also appears to be a less morbid thoracic procedure (Chapter 37). Studies suggest that VATS results in reduced postoperative pain and hospital length of stay compared with thoracotomy and may cause less early impairment in lung function. Whether this procedure carries a diminished risk of postoperative pulmonary complications has not been definitively established.

Chronic Obstructive Pulmonary Disease

Table 147-1 Incidence of Respiratory Failure Following Various Surgical Procedures Procedure

Incidence of Postoperative Respiratory Failure

TAAA repair


AAA repair


Lung resection




All types∗


TAAA = thoracoabdominal aortic aneurysm; AAA = abdominal aortic aneurysm; CABG-coronary artery bypass grafting. ∗Refers to general survey of gastrointestinal, urological, gynecological, and orthopedic procedures.

In the previously noted study of over 80,000 patients undergoing noncardiac surgery in VA hospitals, multivariate analysis revealed that a history of COPD was an independent risk factor for postoperative respiratory failure. Overall, the risk of respiratory failure associated with COPD (odds ratio of 1.8) was considerably lower than that associated with the type of surgery (odds ratio of 14.3 for abdominal aortic aneurysm repair and 8.1 for thoracic surgery). Notably, preoperative pulmonary function parameters were not examined in this study, precluding assessment of the relationship between severity of COPD and risk of postoperative respiratory failure. Studies focusing on outcomes following specific, highrisk procedures shed additional light on the risks posed by COPD. The incidence of respiratory failure following thoracotomy and lobectomy or pneumonectomy exceeds 50 percent for patients with COPD and a predicted postresection forced expiratory volume in 1 sec (FEV1 ) less than 40 percent of normal, but it is minimal for those with more adequate pulmonary reserve. Within the subset of patients with a predicted postresection FEV1 less than 40 percent, those who maintain an acceptable functional status (as indicated by peak oxygen consumption of greater than or equal to 10 to

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15 ml/kg/min on cardiopulmonary exercise testing) appear to have a low risk of respiratory failure following definitive lung resection procedures. The use of VATS in combination with less extensive resection of lung tissue (e.g., wedge resection or segmentectomy) appears to be well tolerated by patients with severe lung disease, with only a 4 percent incidence of respiratory failure and a 1 percent mortality rate documented in one recent study of 100 patients with an FEV1 less than 35 percent predicted. Studies of the risk posed by COPD among patients undergoing thoracoabdominal aortic aneurysm repair have yielded conflicting results. In one prospective study of over 1400 patients, COPD was found to be an independent risk factor for respiratory failure, defined as the need for mechanical ventilation in excess of 48 h. Respiratory failure developed in 53 percent of patients with COPD and in only 23 percent of patients without this disorder. The risk of respiratory failure correlated linearly with preoperative spirometry, precluding identification of a particular set of “threshold” values. In contrast, two other studies of thoracoabdominal aneurysm surgery employing similar statistical methods did not identify COPD as a significant predictor of postoperative respiratory failure. The impact of COPD on outcome following coronary artery bypass grafting (CABG) has also been examined. In one study, patients with a history of COPD had higher rates of mechanical ventilation exceeding 48 h (18.9 percent vs. 3.7 percent) and reintubation (13.5 percent versus 3.7 percent) compared with age-matched controls. In a recent study of over 8000 consecutive patients undergoing CABG, the incidence of postoperative respiratory failure was 5.6 percent. Among preoperative characteristics, COPD was identified as a risk factor for respiratory failure, with an odds ratio (OR) of 1.9. This was, nonetheless, considerably less than the risk posed by such factors as renal insufficiency (OR 3.9), congestive heart failure on admission (OR 4.1), and emergency (rather than elective) surgery (OR 5.8). Following major abdominal vascular surgery, including abdominal aortic aneurysm repair and aortobifemoral bypass grafting, approximately 25 percent of patients require ventilatory support for more than 24 h. While an extensive smoking history and low preoperative Pao2 are predictive of the need for prolonged postoperative ventilatory support, the severity of COPD, as defined by preoperative spirometry, is not. Indeed, no prospective evaluation of patients undergoing abdominal surgery of any type has shown that pulmonary function studies can reliably identify patients at increased risk of serious postoperative pulmonary complications. What conclusions can be drawn from this complex and conflicting body of literature? Clearly, the presence of severe COPD with a predicted postoperative FEV1 of less than 30 to 40 percent in association with poor functional status should be viewed as an absolute contraindication to thoracotomy and extensive lung resection (lobectomy or pneumonectomy). COPD appears to increase the risk of respiratory failure to a far lesser degree following other types of surgical procedures. Acknowledging current uncertainties about the full contri-

Acute Respiratory Failure in the Surgical Patient

bution of COPD to postoperative risk in these settings, the presence of significant lung disease should prompt a careful analysis of the necessity of the surgery planned. However, it should not preclude surgery deemed likely to extend patient survival or to markedly improve quality of life. Patients with COPD scheduled for surgery should undergo a preparatory pulmonary regimen intended to optimize lung function and minimize airway secretions. This regimen should include smoking cessation, institution or intensification of inhaled bronchodilator therapy, and use of oral antibiotics in the presence of purulent secretions or a “loose” cough. Patients should be instructed on the use of incentive spirometry or cough and deep breathing techniques prior to surgery. A short course of oral corticosteroids should be considered in patients who have a significant bronchospastic component to their disease. Such a preparatory regimen is simple and inexpensive and has been shown to have a favorable impact on the incidence of postoperative pulmonary complications. Other than the assurance of strict compliance with the regimen, there is no reason to believe that hospitalization is superior to outpatient preparation of the patient.

Smoking Smoking has been shown to be a risk factor for postoperative pulmonary complications in general and for prolonged ventilatory support in particular. Smoking does not appear simply to be a surrogate marker of COPD; rather it poses risk that is independent of the magnitude of pulmonary impairment. Detrimental effects of smoking include bronchial irritation with resultant excessive airway secretions, impairment in mucociliary clearance, and elevation of carboxyhemoglobin levels with consequent impairment in oxygen uptake and tissue oxygen utilization. While preoperative smoking cessation has been shown to diminish the risk of postoperative pulmonary complications, a minimum of 8 wk of abstinence is required to achieve this risk reduction (see Chapter 38 for additional details).

Predicting Risk of Respiratory Failure Recently, a multifactorial risk index for predicting postoperative respiratory failure was published. The model was derived from analysis of the VA population of over 80,000 patients undergoing noncardiac surgery and was validated in a second VA population of nearly 100,000 patients. Preoperative variables independently predictive of an increased risk of postoperative respiratory failure (mechanical ventilation for greater than 48 h or reintubation) were identified by multivariate analysis, and each variable was assigned a point value reflecting the relative risk that it posed (Table 147-2). Based upon the total number of points, patients were assigned to one of five risk classes that predict the overall probability of respiratory failure (Table 147-3). The model performed well when validated in the second cohort of patients. However, as it was derived from a population of male patients cared for at VA facilities and did not include cardiac procedures, its applicability to

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other patient populations is uncertain. Therefore, additional studies are required before use of this predictive index can be endorsed.

Table 147-2 Respiratory Failure Risk Index Preoperative Predictor

Point Value

Type of surgery Abdominal aortic aneurysm Thoracic Neurosurgical, upper abdominal, peripheral vascular Neck

27 21 14 11

IMPACT OF ANESTHESIA AND POSTOPERATIVE ANALGESIA ON PULMONARY FUNCTION An additional important consideration in patients undergoing surgical procedures is the effect of anesthesia on pulmonary function.

Emergency surgery


Albumin (<30 g/L)


General Anesthesia

Blood urea nitrogen (>30 mg/dL)


Partially or fully dependent functional status


History of COPD


Age (years) ≥70 60–69

6 4

Use of general anesthetic agents is associated with a number of well-characterized alterations in pulmonary mechanics, gas exchange, and respiratory drive. In the controlled environment of the operating room, these physiological derangements are clinically inconsequential and easily overcome by simple adjustments of the ventilator. However, lingering effects of general anesthesia after completion of surgery may impede efforts to extubate the patient or may precipitate respiratory failure in the recovery room. Administration of general anesthesia, whether by the inhaled or intravenous route, results in an almost immediate loss of diaphragmatic and intercostal muscle tone, a cephalad shift of the diaphragm, and a decrease in the transverse thoracic diameter. These dimensional alterations in thoracic volume result in a 20 percent reduction in functional residual capacity (FRC) and in development of compressive atelectasis. As demonstrated using computed tomography (CT) to image patients during and after general anesthesia, patients develop crescent-shaped areas of atelectasis in dependent areas of the lung within 10 min of induction. Atelectatic areas comprise approximately 2 to 10 percent of total lung volume and disappear with the application of positive end-expiratory pressure (PEEP). Dependent atelectasis develops after administration of either inhalational or intravenous anesthetics. A notable exception is ketamine, a drug that is unique in its maintenance of respiratory muscle tone. The degree of atelectasis appears unaffected by whether the patient is breathing spontaneously or is mechanically ventilated. Areas of dependent atelectasis perturb the normal balance of ventilation and perfusion in the lung. Persistent perfusion of nonventilated atelectatic areas results in an increase in the shunt fraction, which may approach 15 percent. The magnitude of shunt correlates directly with the volume of atelectatic lung and may be further magnified by impairment of hypoxic pulmonary vasoconstriction induced by certain inhalational anesthetics. Elderly patients, those who are obese, and patients with underlying COPD are most likely to develop clinically apparent hypoxemia in response to general anesthesia; the effect may persist into the early postoperative period.

Source: Adapted from Arozullah MA, et al: Multifactorial risk index for predicting, postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 22:242–253, 2000.

Table 147-3 Respiratory Failure Index Scores and Predicted Probability of Postoperative Respiratory Failure Class

Point Total

Predicted Probability of PRF
















Source: Adapted from Arozullah MA, et al: Multifactorial risk index for predicting, postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 22:242–253, 2000.

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The inhaled anesthetic agents in common usage are respiratory depressants that blunt the response to both hypoxemia and hypercapnia. These agents depress the ventilatory response to CO2 in a dose-dependent fashion. They have a negligible effect on the hypercapnic response at the low concentrations encountered during emergence from anesthesia. In contrast, hypoxemic drive is markedly attenuated even at very low, subanesthetic concentrations of the volatile agents. As a result of deposition of these agents in muscle and fat, concentrations sufficient to depress hypoxic drive persist for several hours after termination of anesthesia. This can result in significant postoperative respiratory depression in patients who, by virtue of chronic hypercapnia, are dependent upon a hypoxic ventilatory drive to breathe.

Neuraxial Anesthesia It is common practice for those providing preoperative assessment of high-risk patients to recommend the use of neuraxial (i.e., spinal or epidural) anesthesia, predicated on the impression that this route of administration lessens the adverse impact of anesthesia on the respiratory system. Neuraxial anesthesia does possess a number of favorable physiological features. In contrast to the effects of general anesthesia, neuraxial anesthesia preserves diaphragmatic innervation and function. External intercostal muscle paralysis is induced by thoracic levels of neuraxial anesthesia, but the level is generally two dermatomes below the sensory level because of the lesser sensitivity of motor neurons to the effects of the anesthetic agent. Hypoxic pulmonary vasoconstriction is unaffected by neuraxial anesthesia, and the ventilatory response to CO2 is unimpaired; indeed, the CO2 response may be heightened. Despite the ostensibly favorable effects of neuraxial anesthesia on respiratory mechanics and respiratory drive, a clinically significant benefit over general anesthesia has not been consistently demonstrated. Pending further studies, neuraxial anesthesia should not be viewed as clearly superior to general anesthesia in the compromised patient.

Postoperative Analgesia Postoperative analgesia is an essential component of the care of the surgical patient. Analgesia is important not only in ensuring patient comfort, but also in mitigating the adverse effects of pain on respiratory function and airway clearance. Inadequate pain relief can lead to splinting and patient reluctance to cough and deep breathe; the end result is promotion of retained secretions, atelectasis, hypoxemia, and, possibly, pneumonia. For major surgical procedures, particularly those involving the chest and upper abdomen, administration of opiates via the parenteral or epidural route has become the analgesic method of choice. Studies comparing the effect of epidural and parenteral opiates on pulmonary function are conflicting. While most have documented the superior analgesic effect of the epidural route, this has not invariably translated into improvement in respiratory mechanics and gas exchange or a lower incidence of postoperative

Acute Respiratory Failure in the Surgical Patient

pulmonary complications. This suggests that factors other than pain (see below) contribute significantly to alterations in pulmonary function that accompany thoracic or abdominal surgery. Nonetheless, this should not lead to the false impression that pain control is superfluous; failure to adequately control pain will exacerbate postoperative pulmonary dysfunction. The use of narcotic analgesia in the postoperative period is associated with a small, but not insignificant, risk of precipitating respiratory depression. The reported incidence of respiratory depression varies based on the criteria employed. A meta-analysis of published studies revealed an incidence of 0.3 percent defined by the need to administer naloxone, 3.3 percent defined by the presence of hypercapnia, and 17 percent defined by oxygen desaturation. The risk may be slightly lower in association with the epidural, as opposed to parenteral, route of administration. Elderly patients are particularly susceptible to the respiratory depressant effects of opiates, likely reflecting an impaired ability to metabolize these agents. Respiratory depression in the postoperative patient is most likely to occur during the initial 24 h following surgery. It is typically accompanied by a decreased level of consciousness and a slow respiratory rate. Treatment consists of administration of naloxone in 0.1 to 0.4 mg aliquots. Ventilation should be supported with a face mask and Ambu bag, reserving intubation for failure of naloxone to swiftly rectify the problem.

IMPACT OF SURGERY ON POSTOPERATIVE PULMONARY FUNCTION Surgery involving the upper abdomen and thorax results in a pronounced impairment in pulmonary function in the postoperative period. The impairment is more severe and prolonged than that due to administration of general anesthesia alone. Typically, upper abdominal and thoracic procedures are associated with a fall in lung volumes, development of atelectasis, and hypoxemia. These adverse effects commonly necessitate short-term administration of low-flow, supplemental oxygen, but when severe, or when accompanied by underlying lung disease, may precipitate respiratory failure.

Upper Abdominal Surgery Vital capacity declines by 50 percent within 24 h following upper abdominal surgery. Although the vital capacity improves with time, marked impairment persists for as long as 7 d after the surgery. In contrast, vital capacity falls by only 25 percent following lower abdominal procedures; it returns to normal by the third postoperative day. Underlying these profound changes after upper abdominal surgery is the development of diaphragmatic dysfunction, as reflected in a reduction in transdiaphragmatic pressure with tidal respirations and in a shift from abdominal to rib cage breathing.

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Two main theories have been proposed to explain the observed impairment in diaphragmatic function. One theory is that there is a primary alteration in diaphragmatic contractility induced by local irritation, inflammation, surgical trauma, or pain. This theory has been rendered improbable with the demonstration that external stimulation of the phrenic nerves produces normal peak transdiaphragmatic pressure in patients recovering from upper abdominal surgery. In other words, when maximally stimulated, the diaphragm functions in a normal fashion. The alternative, and currently favored, theory proposes that diaphragmatic dysfunction results from diminished phrenic nerve output. The basis for the attenuation in neural drive remains a matter of speculation, although several putative pathways can be rationally eliminated. For example, general anesthesia is known to depress output from the central respiratory centers, as well as to inhibit synaptic transmission. However, as noted previously, the effects of general anesthesia on diaphragmatic tone are transient and modest. Additionally, the degree of dysfunction observed after upper abdominal procedures is not seen following general anesthesia for procedures on the lower abdomen and extremities. An inhibitory arc initiated by abdominal nociceptors for pain is unlikely, given that achievement of adequate pain control by epidural opiates fails to consistently improve pulmonary function or to normalize diaphragmatic performance. In contrast, the epidural administration of anesthetic agents such as bupivacaine does ameliorate diaphragmatic dysfunction following upper abdominal surgery. Since these agents produce sympathetic blockade in addition to pain control, it has been argued that visceral sympathetic afferents are responsible for providing an inhibitory signal that downgrades central neural drive and phrenic nerve activity, thereby leading to impaired diaphragmatic function. Supporting the notion of a reflex inhibitory arc mediated by visceral afferents is the demonstration in experimental animals that mechanical gallbladder stimulation strongly inhibits electromyographic activity and motion of the diaphragm.

Cardiac Surgery Although CABG—the most commonly performed cardiac surgical procedure—has been most intensively scrutinized with respect to its impact on the respiratory system, other related cardiac procedures (e.g., valve replacement) are likely to have similar effects. Lung volumes decrease by approximately 30 percent after CABG; their return to preoperative values may take several months. Lung function may decline to a greater degree when internal mammary harvesting and grafting are employed. Gas exchange is also impaired after CABG, as evident in the development of hypoxemia and significant widening of the alveolar-arterial oxygen gradient. In 125 patients who had daily room air arterial blood gas determinations prior to and following CABG, Pao2 fell from approximately 75 mmHg preoperatively to a nadir of 55 mmHg on postoperative day 2. The PaO2 improved, but remained below preoperative values, at the end of the first postoper-

ative week. A similar pattern and magnitude of decline in oxygenation have been demonstrated in other studies, with the development of hypoxemia associated with an increase in calculated shunt fraction from 3 percent preoperatively to a peak of 19 percent postoperatively. The increase in shunt fraction is readily accounted for on the basis of atelectasis, which is invariably present postoperatively, especially on the left side. A number of factors have been implicated in the development of post-CABG pulmonary dysfunction and atelectasis. Alterations in chest wall compliance and motion may result from division of the sternum, harvesting of the internal mammary artery, and traumatic injury to the costovertebral joints and first rib induced by retraction. Intraoperative lung retraction may directly injure the left lower lobe, leading to contusion and atelectasis, and, perhaps, accounting for the predilection for radiographic infiltrates on the left side. An alternative explanation for post-CABG left lower lobe atelectasis is intraoperative injury to the left phrenic nerve and consequent diaphragmatic paralysis or paresis. The phrenic nerve is vulnerable to stretch and ischemic injury during sternal retraction, dissection of the left internal mammary artery, or prolonged distention of the pericardium. Additionally, thermal injury to the nerve may occur with the cardioplegic technique of instilling iced slush into the open pericardial sac. The actual incidence of phrenic nerve dysfunction after CABG is best defined in studies employing electrophysiological techniques, which have documented unequivocal evidence of phrenic nerve injury in 10 percent of patients. This suggests that phrenic nerve injury accounts for only a minority of the observed cases of left lower lobe atelectasis. Finally, cardiopulmonary bypass (CPB) may contribute to pulmonary impairment after cardiac surgery. The duration of CPB has been linked to the severity of postoperative atelectasis; whether this relationship is causal is unclear. It has been hypothesized that the use of CPB leads to abnormal surfactant production—possibly due to ischemic, thermal, or toxic injury to the alveolar epithelium—predisposing to the development of atelectasis. More clearly established is the ability of the bypass pump to induce a capillary leak syndrome, marked by extravasation of fluid into the alveolar interstitium and, rarely, into the airspaces. This process is thought to result from exposure of blood to nonendothelial surfaces, resultant activation of neutrophils, complement and other inflammatory cascades, and sequestration of neutrophils within the microvasculature. While this rarely may lead to full-blown ARDS (see discussion below), the consequences are usually more subtle, manifesting as a widened arterial-alveolar oxygen gradient and diminished lung compliance. The recent introduction of “off-pump” CABG has permitted a greater appreciation of the adverse impact of CPB on postoperative lung function. For example, a recent large, multicenter comparative analysis from the United Kingdom of CABG with or without CPB demonstrated significant reductions in the rates of prolonged mechanical ventilation (more than 24 h), reintubation or tracheostomy, and ARDS or pulmonary edema

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or pneumonia among the group that underwent off-pump CABG.

Lung Resection Unique to lung resection surgery is the immediate loss of lung function due to removal of lung parenchyma. The magnitude of the loss can be estimated reliably from preoperative quantitative lung scanning in conjunction with standard spirometry (Chapter 38). The impact of lung resection on pulmonary function is further magnified in the perioperative period by other factors. For example, the standard posterolateral thoracotomy incision represents significant chest wall trauma, with rib retraction and resection, and transection of intercostal, latissimus dorsi, trapezius, and serratus anterior muscles. As a result, total respiratory compliance may fall by as much as 75 percent; work of breathing increases; and lung volumes decline dramatically, out of proportion to the surgical loss of functional lung. Following standard thoracotomy and lung resection (either lobectomy or wedge resection), FEV1 and FVC fall to 25 percent of preoperative values at 1 hour, and to 30 percent at 24 h. When a more limited, muscle-sparing incision is used, the impact on pulmonary function is markedly attenuated. As with cardiac and upper abdominal surgery, atelectasis is frequently present after lung surgery and results in impaired oxygenation. Phrenic nerve activity remains normal and diaphragmatic function during tidal breathing is preserved, although maximal diaphragmatic strength may be reduced.

CAUSES OF POSTOPERATIVE RESPIRATORY FAILURE The development of acute respiratory failure in the surgical patient should prompt a systematic assessment of the likely causes (Table 147-4). In approaching this life-threatening problem, one must consider the nature and magnitude of preexisting pulmonary disease, type of surgery performed, drugs administered intra- and postoperatively, and predominant derangement in gas exchange (i.e., hypoxemia or hypercapnia). In conjunction with important information derived from the physical examination and chest radiograph, the analysis should readily identify factors responsible for, or contributing to, respiratory failure. The following discussion focuses on the more common or unique causes of postoperative respiratory failure in the surgical setting.

Atelectasis Atelectasis is the most common pulmonary complication encountered in the surgical patient, particularly following thoracic and upper abdominal procedures. As discussed previously, anesthesia and surgical manipulation act in concert to produce regional atelectasis through incompletely defined

Acute Respiratory Failure in the Surgical Patient

Table 147-4 Causes of Postoperative Respiratory Failure Factors extrinsic to the lung  Depression of central respiratory drive (anesthetics, opioids, sedatives)  Phrenic nerve injury or diaphragmatic dysfunction  Obstructive sleep apnea Factors intrinsic to the lung  Atelectasis  Pneumonia  Aspiration of gastric contents  Acute lung injury (ARDS)  Volume overload or congestive heart failure (CHF)  Pulmonary embolism  Bronchospasm or COPD mechanisms, including diaphragmatic dysfunction and diminished surfactant activity. The atelectasis is typically basilar and segmental in distribution, obscuring the hemidiaphragms radiographically. A distinct and less common cause of postoperative atelectasis is plugging of central airways by retained secretions. This problem is encountered in the surgical patient whose efforts to clear secretions are compromised by depressed consciousness, inadequate pain control, or a weak, ineffective cough. When situated in a mainstem bronchus, mucus plugs can result in collapse of an entire lung; more distal obstruction leads to lobar collapse. An abrupt termination of the proximal bronchial air shadow and the absence of air bronchograms within the atelectatic portion of the lung are clues to the possible presence of mucus plugging. While often clinically insignificant, postoperative atelectasis may lead to severe hypoxemia and respiratory distress. The magnitude of hypoxemia is dictated by the extent of atelectasis, the presence and severity of underlying lung disease, and the integrity of the hypoxemic pulmonary vasoconstrictive response. Impairment of hypoxemic pulmonary vasoconstriction by vasodilatory drugs, commonly administered to surgical patients for treatment of underlying hypertension or ischemic heart disease, prevents the compensatory diversion of blood flow away from nonventilated areas of the lung and magnifies the shunt fraction. Respiratory distress due to atelectasis usually evolves insidiously over the first several postoperative days. Supplemental oxygen requirements increase in association with worsening basilar infiltrates noted on the chest radiograph. The clinicoradiographic picture may be indistinguishable from that of pneumonia. While fever and leukocytosis suggest infection, these signs are common and nonspecific. When atelectasis is due to central airway occlusion by mucus plugs, hypoxemia and respiratory distress may develop quickly. A chest radiograph obtained immediately after the onset of symptoms may be surprisingly unrevealing if sufficient time has

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not passed to permit resorption of gas from the airspaces of the nonventilated lung. Careful examination of the patient, however, will reveal an absence of breath sounds over the involved lung, providing an important clue to the presence of central airway obstruction and obviating pursuit of other considerations, such as pulmonary embolism. Treatment of respiratory failure due to atelectasis is directed toward the combined goals of adequate oxygenation and re-expansion of lung segments. Supplemental oxygen should be titrated to achieve an arterial oxyhemoglobin saturation of at least 90 percent. Refractory hypoxemia, severe respiratory distress, progressive hypercapnia, or inability of the patient to clear copious airway secretions should prompt immediate intubation and mechanical ventilatory support. This life-saving intervention permits more efficient delivery of oxygen, secures access for suctioning of the airways, and facilitates performance of bronchoscopy should it be necessary. Moreover, the positive pressure and large tidal volumes delivered by the ventilator are often effective in rapidly re-expanding collapsed lung segments. In less dire circumstances, noninvasive delivery of continuous positive airway pressure (CPAP) via a nasal or face mask may be equally effective. Fiberoptic bronchoscopy has a limited role in the treatment of serious postoperative atelectasis; its indiscriminate use should be avoided. The immediate use of fiberoptic bronchoscopy does not result in more rapid or complete resolution of acute lobar atelectasis when compared with standard chest physiotherapy consisting of deep breathing, coughing, suctioning of the intubated patient, aerosolized bronchodilator treatments, chest percussion, and postural drainage. Resolution of atelectasis appears to be dictated not by the treatment modality employed, but by radiographic evidence of central airway patency. In this regard, both chest physiotherapy and bronchoscopy are highly effective in the absence of an air bronchogram. In contrast, the presence of an air bronchogram, which indicates that the atelectasis is not due to proximal airway obstruction, is associated with minimal response to either modality. Therefore, simple and standard respiratory therapy techniques applied to either the spontaneously or mechanically ventilated patient form the mainstay of treatment for lobar atelectasis. Fiberoptic bronchoscopy should be reserved for those situations where chest physiotherapy is contraindicated (e.g., chest trauma, immobilized patient), poorly tolerated, or unsuccessful. In these circumstances, the decision to employ bronchoscopy should be tempered by the presence of an air bronchogram. A number of other measures are commonly employed in the treatment of atelectasis. Judicious use of analgesia is an essential adjunct, permitting the patient to breathe deeply, cough forcefully, and comfortably participate in chest physiotherapy maneuvers. Care must be taken to avoid excessive sedation which will offset the beneficial effects of pain control. In the setting of marked hypoxemia, attempts should be made to discontinue vasoactive drugs with the potential to influence the pulmonary vascular bed; examples include nitrates, nitroprusside, calcium channel blockers, angiotensin-

converting enzyme inhibitors, and hydralazine. Mucolytics, such as N-acetylcysteine, are commonly administered in an effort to promote clearance of tenacious secretions; however, their efficacy in this setting has not been well documented. Some clinicians and respiratory therapists advocate the use of nasotracheal suctioning of the nonintubated patient with a weak and ineffective cough. However, this technique is associated with considerable discomfort and, in the opinion of this author, is an inefficient and highly transient means of clearing secretions from the tracheobronchial tree. The important role of prophylactic maneuvers in reducing the incidence and magnitude of postoperative atelectasis in high-risk patients should not be overlooked. These techniques, intended to promote periodic full lung expansion, include intermittent positive pressure breathing (IPPB), cough and deep breathing exercises, and incentive spirometry. All three techniques have been shown to be equally efficacious and superior to no therapy in the prevention of postoperative pulmonary complications following abdominal surgery, although their efficacy following cardiac surgery has recently been called into question. IPPB has largely been abandoned due to its expense, need for specially trained personnel and close patient supervision, and tendency to produce abdominal distention. For maximal benefit, prophylactic measures should be taught and instituted prior to surgery and used hourly in the postoperative period. Early ambulation of the postsurgical patient has been found to be as effective as respiratory therapy maneuvers in the prevention of postoperative atelectasis and should be strongly encouraged.

Pneumonia Pneumonia is the second most common nosocomial infection and the most lethal, with an associated mortality rate of 20 to 50 percent. Pneumonia represents a principal cause of postoperative respiratory compromise and may precipitate acute respiratory failure, as well as complicate respiratory failure in the patient who is ventilator-dependent for other reasons. In epidemiological surveys, surgery has been identified as an independent risk factor for nosocomial pneumonia. In particular, the risk is greatest following standard thoracic and upper abdominal procedures, where an incidence of 15 to 20 percent has been documented. Lung transplant recipients represent an emerging population with a similarly high risk of postoperative pneumonia. In contrast, the risk of pneumonia is only 5 percent following lower abdominal surgery, and it is even less frequently encountered following procedures remote from the chest and abdomen. Overall, the incidence of nosocomial pneumonia is up to fivefold greater among patients in surgical ICUs than among patients in medical ICUs. Epidemiological studies have identified a number of other risk factors for nosocomial pneumonia, but these studies fail to fully distinguish those factors that are causally linked from those that are simply surrogate markers. Factors reflective of poor preoperative health, including a low serum albumin level, presence of COPD, extensive smoking history, advanced age, protracted preoperative hospital stay, and high

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status according to the American Society of Anesthesiologistsâ&#x20AC;&#x2122; (ASAs) preanesthesia classification, have been linked to an excessive risk of pneumonia. A direct relationship between duration of surgery and incidence of postoperative pneumonia has been demonstrated. Other identified risk factors include presence of a nasogastric tube, use of antacids or H2 -blockers for stress ulcer prophylaxis, immunosuppression, impaired consciousness, and witnessed aspiration. Perhaps the most important and consistently identified risk factor is the need for prolonged mechanical ventilatory support. Overall, mechanically ventilated patients have a 3- to 21-fold increased risk of pneumonia compared with nonventilated patients. Moreover, the risk of pneumonia is linked to the duration of ventilatory support, approximating 1 percent per day on the ventilator. The microbiological profile of nosocomial pneumonia is distinctly different from that of community-acquired infection. Gram-negative aerobic bacilli of the Enterobacteriaceae family prevail, collectively accounting for approximately one-third of all infections. Other highly virulent gram-negative rods which are commonly encountered are Pseudomonas aeruginosa and Acinetobacter species. Of the gram-positive organisms, Staphylococcus aureus predominates, while the pneumococcus, the most common bacterial respiratory pathogen in the community setting, plays an insignificant role. Often the pneumonia is polymicrobial; studies employing bronchoscopic culture techniques or postmortem cultures of lung tissue have identified more than one organism in up to 46 percent of cases. While organisms may reach the lower respiratory tract by several routes, microaspiration of oropharyngeal secretions appears to be the predominant mechanism in the pathogenesis of nosocomial pneumonia. A critical initiating event in this pathway is colonization of the oropharynx with gramnegative aerobic bacilli, a process that characteristically occurs in response to serious illness or surgical stress. Clinically occult aspiration of these virulent organisms is facilitated by a number of iatrogenic measures imposed upon the surgical patient. Paramount among these is the placement of an endotracheal tube, which impairs swallowing, stents open the glottis, and permit pooling of secretions above the tube cuff. The inflated cuff is an imperfect barrier and allows intermittent seepage of secretions into the lower airways. Prolonged intubation has also been associated with postextubation swallowing dysfunction. Depressed consciousness as a consequence of general anesthesia and postoperative analgesia further contributes to the risk of aspiration. Recent attention has focused on the stomach as an additional source of bacteria in the development of nosocomial pneumonia. While the acidic milieu of the stomach normally inhibits bacterial growth, the common use of H2 -blockers and antacids as stress ulcer prophylaxes overrides this natural barrier and promotes gastric colonization with gram-negative enteric organisms. Gastroesophageal reflux, a common feature of the critically ill patient, permits bacteria-laden gastric contents to enter the respiratory tract either directly or by first colonizing the oropharynx. This route of migration

Acute Respiratory Failure in the Surgical Patient

has been confirmed by recovery of technetium-99m (99m Tc)labeled gastric contents in endobronchial secretions and by the demonstration in some patients that organisms cultured from the airways first appeared in the stomach. Perhaps the most compelling, albeit circumstantial, evidence derives from several studies that have shown a higher incidence of nosocomial pneumonia in patients receiving H2 -blockers or antacids compared with those given sucralfate, a drug that does not result in alkalinization of gastric pH. However, conflicting data abound, and firm conclusions about the role of gastric colonization in the pathogenesis of nosocomial pneumonia await the outcome of larger and more methodologically rigorous studies. The fate of organisms introduced into the lower respiratory tract is dependent upon the integrity of mechanical and immunologic pulmonary defense mechanisms. Impairment of the mucociliary escalator (e.g., due to recent cigarette smoking or underlying COPD), weak and ineffective cough, and use of immunosuppressive medications (e.g., corticosteroids) favor the proliferation of organisms and the development of pneumonia. It is widely held that postoperative atelectasis predisposes to pneumonia by entrapping bacteria. However, studies demonstrating a lack of concordance between the degree of atelectasis and the subsequent risk of pneumonia challenge this contention. The constellation of fever, leukocytosis, purulent sputum, and radiographic infiltrates has traditionally defined the presence of pneumonia. While these diagnostic criteria are reasonably accurate in the previously healthy outpatient, they are notoriously nonspecific in the setting of recent surgery, particularly with prolonged use of mechanical ventilation. In one autopsy series, traditional clinical and radiographic criteria provided the correct antemortem diagnosis in only 70 percent of cases. Alternative etiologies of radiographic infiltrates include atelectasis, pulmonary edema, infarction or hemorrhage due to pulmonary emboli, pulmonary contusion, and chemical pneumonitis. Cultures of sputum and tracheal aspirates are poorly reflective of the bacterial flora of the distal airways, since these specimens are contaminated by colonizing organisms in the oropharynx and upper respiratory tract. In an attempt to enhance diagnostic certainty, bronchoscopic sampling of the distal airways using a sterile sheathed brush or bronchoalveolar lavage has been advocated. While the absence of a â&#x20AC;&#x153;gold standardâ&#x20AC;? for the diagnosis of pneumonia has complicated attempts to define the accuracy of these techniques, rates of false-positive and false-negative results have generally fallen in the range of 30 percent. It is questionable, therefore, whether the performance of bronchoscopy actually contributes significantly to a reduction in the degree of diagnostic uncertainty. These concerns, coupled with the need to perform the procedure prior to institution of antibiotics and to collect and process specimens in a fastidious and standardized fashion, have severely limited the use and acceptance of currently available bronchoscopic techniques. Despite all of the pitfalls, most clinicians continue to rely on conventional assessment strategies in establishing a diagnosis of pneumonia and in determining the need for therapy.

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Empiric treatment of nosocomial pneumonia is broad in spectrum and includes effective coverage of gram-negative organisms (including Pseudomonas) and S. aureus. The initial choice of antibiotics is influenced by the particular epidemiological profile and microbiologic susceptibility patterns at a given institution; many ICUs are currently plagued by highly resistant organisms, such as Acinetobacter and methicillinresistant Staphylococcus, which have unusual, but predictable, susceptibilities. Preventive strategies intended to diminish the risk of pneumonia are an important consideration in the care of the surgical patient. Prevention begins in the preoperative phase with emphasis on abstinence from cigarette smoking for a minimum of 8 wk prior to elective surgery. Following surgery, nasogastric and endotracheal tubes should be removed as soon as possible. Postoperative analgesia must be titrated to permit the patient to comfortably and vigorously cough, but excessive sedation impairing protection of the airway and enhancing the risk of aspiration must be avoided. For the high-risk, ventilator-dependent patient, maintenance of a semierect position has been shown to diminish the magnitude of clinically occult aspiration of gastric contents and the incidence of pneumonia. While the use of sucralfate has been associated with a lower incidence of gastric colonization and nosocomial pneumonia compared with agents that raise gastric pH, additional corroborating studies are required before a firm recommendation to preferentially employ sucralfate in stress ulcer prophylaxis can be made. An emerging approach to pneumonia prevention in the high-risk patient is selective digestive decontamination (SDD), intended to prevent or diminish the magnitude of gram-negative colonization of the aerodigestive tract. Regimens have varied among studies, but they typically consist of some combination of antibiotics applied topically to the oropharynx, instilled into the stomach as a slurry, and/or administered systemically. A recent meta-analysis of prospective, randomized trials concluded that SDD reduced the incidence of pneumonia and decreased overall mortality among critically ill surgical patients. Some studies have demonstrated emergence of resistant pathogens, while others have not. Despite the proven efficacy of this approach in high-risk surgical patients, SDD is not yet widely used.

Acute Lung Injury The hallmark of acute lung injury is the presence of noncardiogenic pulmonary edema resulting from widespread damage to the alveolar-capillary membrane. Referred to clinically as acute respiratory distress syndrome (ARDS), the syndrome is defined by the constellation of hypoxemic respiratory failure, diffuse pulmonary infiltrates, and a normal pulmonary artery occlusion pressure or absence of clinical evidence of elevated left atrial pressure. ARDS represents the end result of a variety of insults that either involve the lung directly (e.g., aspiration of gastric contents) or trigger pulmonary inflammation as part of a systemic process (e.g.,

Table 147-5 Incidence of ARDS by Risk Factor Risk Factor

Incidence of ARDS



Massive transfusions


Pulmonary contusion




Multiple fractures


Sourc: Data adapted from Hudson LD, et al. Clinical risks for development of the acute respiratory distress dyndrome. Am J Respir Crit Care Med 151:293â&#x20AC;&#x201C;301, 1995.

sepsis). Many of the risk factors associated with development of ARDS are commonly encountered in surgical patients (Table 147-5). In decreasing order of risk, these include sepsis, massive blood transfusion, pulmonary contusion, aspiration of gastric contents, and multiple fractures. Causes of acute lung injury of particular relevance to the surgical patient, and, in some cases, unique to this population, are described in greater detail below. Aspiration of Gastric Contents Aspiration of gastric contents can rapidly lead to widespread acute lung injury and is an important cause of ARDS in the surgical patient. It is the third leading cause of anesthesiarelated deaths, accounting for 10 to 30 percent of fatal outcomes. Aspiration typically occurs when the mechanisms of glottic closure and cough, which normally protect the airway, are compromised. In the surgical patient, the period of maximal vulnerability for aspiration spans from the induction of general anesthesia to full return of consciousness postoperatively. A number of factors combine to enhance the risk of aspiration during this period. Most important is the blunting of consciousness that accompanies induction and administration of general anesthesia. Insufflation of air into the stomach during induction may cause gastric distention and promote vomiting. Vomiting may also be provoked by noxious stimulation of the posterior oropharynx during intubation or extubation. Reflux of gastric contents is facilitated by medicationinduced relaxation of the lower esophageal sphincter, placement of the patient in a supine position, and manipulation of the bowel during abdominal procedures. At the completion of surgery, extubation is commonly performed at a time when the patient, while able to ventilate adequately, may not yet be capable of fully protecting the airway. Indeed, upperairway reflexes remain significantly impaired for up to 2 h after recovery from anesthesia, even at a time when mental alertness has returned. Moreover, translaryngeal intubation, even

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when brief, may cause residual glottic dysfunction for up to 8 hours following removal of the tube. While the risk of aspiration diminishes beyond the immediate perioperative period, it remains a concern in the patient receiving narcotic analgesia, which may not only induce vomiting, but also depress consciousness. The risk of aspiration during the immediate perioperative period was delineated in a survey of over 215,000 general anesthetic procedures performed at the Mayo Clinic. Aspiration was defined as the presence of bilious or particulate matter in the airways or the development of a new infiltrate on the immediate postoperative chest radiograph. The overall incidence of aspiration was only 0.03 percent, but the incidence was nearly fourfold higher (0.11 percent) in the setting of emergency surgery. In addition to the use of general anesthesia, other predisposing factors were present in over one-half of the patients who aspirated. These included gastrointestinal obstruction, swallowing dysfunction, altered sensorium, previous esophageal surgery, and a recent meal. The majority of events occurred during laryngoscopy (in preparation for insertion of the endotracheal tube) and during tracheal extubation. Twenty percent of patients who aspirated required postoperative mechanical ventilation in excess of 6 h; 5 percent died as a direct result of this complication. Acidic gastric content introduced into the airways is rapidly disseminated throughout the bronchial tree and lung parenchyma, producing an almost instantaneous chemical burn. In addition, acid aspiration triggers a more delayed inflammatory response, with release of inflammatory cytokines and recruitment of neutrophils into the lung. The result is injury to the alveolar-capillary membrane, with flooding of the interstitium and airspaces by proteinaceous edema fluid. Surfactant levels drop precipitously due to both direct acid denaturation and diminished production, leading to alveolar instability and atelectasis. The magnitude of lung injury is directly related to the pH and volume of aspirated material. Initial studies in animals suggested that a pH of less than 2.5 and a volume in excess of 0.4 ml/kg are critical threshold values for the induction of lung injury. While these values are now often quoted in the literature, their validity has been challenged by more recent studies demonstrating significant injury in association with lower volumes and higher pH. In particular, aspiration of bile is capable of inducing widespread injury even at a pH as high as 7.19. The presence of large food particles may further exacerbate the problem by causing airway obstruction and atelectasis. Notably, infection does not normally play a significant role in the initial lung injury from aspiration of acidic gastric contents, as the low pH serves to maintain relative sterility of the inoculum. However, gastric colonization with bacteria can occur in patients maintained on acid suppressive agents, those receiving enteral feeds, and those with gastroparesis or small bowel obstruction. The diagnosis of aspiration is most firmly established in the setting of witnessed vomiting or recovery of gastric contents from the airways. More often, the diagnosis is suspected circumstantially in a patient with risk factors and a compatible clinicoradiographic picture. Massive aspiration

Acute Respiratory Failure in the Surgical Patient

presents in a characteristic fashion, with the development of fever, tachypnea, and diffuse crackles within several hours of the event. Wheezing is appreciated in approximately onethird of patients and may be due either to obstruction of airways by particulate matter or, more commonly, to reflex bronchospasm. Hypoxemia is universally present with massive aspiration and is sufficiently severe in the majority of patients to mandate use of mechanical ventilation. The initial presence of apnea or shock is particularly ominous and portends a high risk of subsequent death. Initial radiographic patterns vary, depending upon the volume, causticity, and distribution of the aspirated material. However, three general patterns have been described: (1) extensive bilateral consolidation resembling diffuse pulmonary edema; (2) widespread, but discrete, patchy infiltrates involving dependent areas of the lung; and (3) focal consolidation, usually localized to one or both lung bases. The clinical course following massive aspiration is variable, but it typically diverges along one of several pathways. A minority of patients follow a fulminant course marked by refractory hypoxemia and shock that eventuates in death within several days. More commonly, patients demonstrate progressive radiographic and clinical improvement over the first several days. Although most of these patients will go on to full recovery, a subset demonstrates secondary deterioration due to the development of ARDS or nosocomial pneumonia. The overall mortality rate associated with massive aspiration is approximately 30 percent and exceeds 50 percent in those patients with initial shock or apnea, secondary pneumonia, or ARDS. Treatment of respiratory failure secondary to aspiration is supportive and includes mechanical ventilatory strategies generic to other forms of ARDS (detailed below). Bronchoscopy is indicated only when large-airway obstruction by particulate matter is suspected on the basis of a localized wheeze or lobar atelectasis. Because acid is disseminated and endogenously neutralized within seconds, large-volume bronchoalveolar lavage is ineffective in attenuating the degree of injury and is not recommended. Studies of the administration of systemic corticosteroids in the treatment of aspiration pneumonitis have been inconclusive and do not currently justify their use. Similarly, use of prophylactic antibiotics is generally discouraged in the absence of supportive data and because of fear that this practice will preferentially select more highly resistant organisms. Some authors do advocate use of empiric antibiotics for that subset of patients at risk for gastric colonization with bacteria, as described above. Additionally, up to 40 percent of patients will develop a superimposed bacterial pneumonia within several days of the aspiration event, often heralded by a new fever, new or progressive infiltrates, and purulent sputum. Broad-spectrum antibiotic therapy is indicated at that time. The high morbidity and mortality associated with aspiration and the lack of effective therapy once the event has occurred have focused attention on measures to prevent this complication. The most straightforward and widely used measure is the convention of overnight fasting prior to

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elective surgery. However, despite prolonged fasting, up to one-third of patients will maintain a gastric volume in excess of 0.4 ml/kg (approximately 25 to 30 ml in the average adult), and up to three-fourths will have a gastric pH below 2.5. Administration of H2 -blockers and proton-pump inhibitors can effectively raise the pH and reduce the volume of gastric contents, suggesting a potentially appealing strategy. Currently, prophylactic administration of antisecretory agents is recommended only for patients deemed to be at increased risk for aspiration. Unfortunately, there is generally insufficient time to allow these agents to act in the setting of emergency surgery, where the risk of aspiration is highest. In high-risk patients, rapid sequence induction of anesthesia should be employed to shorten the time between loss of consciousness and tracheal intubation. During induction, manual pressure should be applied to the cricoid cartilage (Sellick maneuver) and maintained until the endotracheal tube is in proper position and the cuff is inflated. Postoperatively, extubation should be performed only when consciousness and the gag reflex have returned to a level sufficient to permit adequate protection of the airway. Postpneumonectomy Pulmonary Edema Over the past 25 years, a number of published reports have documented the rapid development of pulmonary edema in the remaining lung of some patients following pneumonectomy. Initially attributed to overzealous fluid administration in the operating room, it has since been demonstrated that this complication occurs in the face of a normal pulmonary artery occlusion pressure. In addition, the edema fluid is protein-rich, arguing that the driving force behind edema formation is increased vascular permeability, rather than increased hydrostatic pressure. Postmortem studies confirm the universal presence of pathological features of acute lung injury. The exact mechanism responsible for lung injury after pneumonectomy remains obscure. One theory suggests that mechanical stress due to single lung ventilation in the operating room may cause ultrastructural damage to the alveolar epithelium, while diversion of the entire cardiac output through this remaining lung may similarly cause endothelial injury. Other factors that may contribute to edema formation include surgical trauma and disruption of lymphatic drainage. In a study employing stringent criteria for excluding patients with congestive heart failure (CHF) or known risk factors for ARDS, the incidence of postpneumonectomy pulmonary edema was 2.6 percent. Other studies employing variable criteria have documented an incidence of 1 to 7 percent. For unclear reasons, the complication is encountered more frequently following right pneumonectomy. The observed mortality rate associated with postpneumonectomy pulmonary edema is in the range of 50 to 100 percent. Cardiopulmonary Bypass ARDS has been documented to develop immediately following use of cardiopulmonary bypass in approximately 1

percent of cases. While factors unrelated to the use of CPB may be at play, there is compelling evidence from both animal models and clinical studies to suggest that CPB activates a number of inflammatory mechanisms that could lead to acute lung injury. It is well established, for example, that CPB results in neutrophil activation, likely through mechanical sheer stress and exposure to the artificial surfaces of the bypass circuit. Additionally, an increased expression of cell surface adhesion molecules has been demonstrated, which may promote neutrophil binding to pulmonary endothelium and release of proteolytic enzymes and reactive oxygen species. The central role played by neutrophils in causing acute lung injury following CPB is supported by several lines of evidence: (1) bronchoalveolar lavage fluid from patients undergoing CPB contains an increased number of neutrophils; (2) plasma levels of neutrophil elastase and myeloperoxidase are increased; and (3) inhibition of neutrophil activation with pentoxifylline as well as neutrophil depletion attenuate the degree of pulmonary dysfunction. A number of other inflammatory mediators are released in association with CPB, including complement, proinflammatory cytokines, and prostaglandins. Post-CPB ARDS is frequently accompanied by evidence of a systemic inflammatory response including fever, leukocytosis, and multi-organ system failure. Mortality associated with this complication is in the range of 60 to 90 percent. Amiodarone Amiodarone-induced pulmonary toxicity usually presents as a subacute illness characterized by cough, dyspnea, fever, and patchy pulmonary infiltrates. Less commonly, use of amiodarone has been linked to the development of ARDS immediately following cardiac and thoracic surgery. In most of the reported cardiac cases, amiodarone was administered preoperatively for varying periods of time for control of arrhythmias. The majority of patients had no evidence prior to surgery of the more indolent form of amiodarone pulmonary toxicity. More recently, development of ARDS has been described in patients whose only exposure to amiodarone occurred in the postoperative period, when the drug was initiated as prophylaxis or treatment for atrial arrhythmias following lung resection. In one report, postoperative ARDS developed in 11 percent of patients receiving amiodarone and in only 1.8 percent of untreated patients. The specific perioperative factors that act in concert with amiodarone to produce acute lung injury remain to be defined. Some authors have suggested that exposure to high levels of supplemental oxygen may be a contributing factor. The diagnosis rests on exclusion of other causes, rather than on specific diagnostic tests or histology. Transfusion-Related Acute Lung Injury The transfusion of blood and blood products has been linked to the development of ARDS in two ways. Epidemiologically, an association between massive blood transfusion (greater than 15 U/24 h) and ARDS has been noted, but it remains

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unclear whether this link is truly causal or is indirect and reflective only of the critically ill nature of the patient requiring such massive transfusion support. More clearly defined mechanistically is the induction of acute lung injury by leukoagglutinating antibodies, a process that has been termed “transfusion-related acute lung injury” (TRALI). These antibodies are typically contained in blood products derived from multiparous female donors, whose exposure to foreign human leukocyte antigen (HLA) or granulocyte antigens occurred during prior pregnancies. When transfused into a recipient with these same antigens, these antibodies result in leukoagglutination and activation of recipient granulocytes or monocytes within the pulmonary microvasculature, triggering increased capillary permeability and development of noncardiogenic pulmonary edema. Less commonly, TRALI can be caused by the interaction between leukoagglutinating antibodies from the recipient and donor-derived leukocytes. TRALI has rarely been associated with infusion of biologically active mediators derived from breakdown of the cellular component of stored blood products. The true incidence of TRALI is difficult to determine since this entity is underrecognized and frequently misdiagnosed. One study involving 36 cases over a 2-year period documented an incidence of 0.02 percent per unit and 0.16 percent per patient transfused. Most cases were detected in surgical patients in the immediate postoperative period, a fact that likely reflects the frequent need for transfusions in this setting and the close monitoring of cardiopulmonary function in the postanesthesia recovery area. Mild episodes of TRALI may present as dyspnea and fever. More severe cases are characterized by the abrupt onset of respiratory distress, hypoxemia, and diffuse pulmonary infiltrates within 2 to 4 h of transfusion. Accompanying features include fever, chills, and hypotension; urticaria is present in a minority of patients. Respiratory distress and hypoxemia are of sufficient magnitude to require mechanical ventilatory support in most patients. The differential diagnosis includes volume overload, CHF myocardial infarction, and aspiration. The reaction tends to be self-limited and is typically characterized by rapid clearing of infiltrates and improved oxygenation within several days. However, a more protracted course of greater than 1 wk can be seen in approximately 20 percent of patients; a mortality rate of 5 to 10 percent has been reported. When TRALI is suspected, the blood bank should be notified and all units that have been transfused should be assayed for the presence of leukoagglutinating antibodies. Any blood product containing plasma or plasma proteins is capable of inducing this reaction. Indeed, packed red blood cells, which contain only 60 to 100 ml of plasma, are one of the more common culprits. Ischemia-Reperfusion Injury The restoration of blood flow to previously ischemic tissue may, paradoxically, worsen tissue injury. This ischemiareperfusion effect involves a “two-hit” mechanism. Tissue is-

Acute Respiratory Failure in the Surgical Patient

chemia leads to formation of xanthine oxidase and its substrate, hypoxanthine, while reperfusion supplies molecular oxygen that fuels the reaction to produce oxygen free radicals injurious to cells. Neutrophils recruited to the site of ischemia-reperfusion serve as an additional source of oxygen free radicals, as well as proteolytic enzymes. Within the lung, ischemia-reperfusion produces diffuse injury to the alveolar epithelium and resultant noncardiogenic pulmonary edema. This mechanism underlies the development of acute lung injury in two important clinical settings: lung transplantation (Chapter 101) and pulmonary thromboendarterectomy. Noncardiogenic pulmonary edema is a nearly universal feature of the freshly implanted lung allograft, but it is usually mild and self-limited. In approximately 10 percent of cases, however, the allograft is severely injured, with widespread and persistent alveolar edema causing profound hypoxemia and low pulmonary compliance, necessitating mechanical ventilatory support beyond the immediate posttransplant period. This entity, termed primary graft dysfunction, is nonimmunologic in nature and is believed to represent a severe form of ischemia-reperfusion injury. Primary graft failure occurs despite acceptable ischemic times below the perceived safe threshold of 6 h. Injury is manifest exclusively in the allograft, sparing the native lung in cases of single lung transplantation. The presence of unilateral lung injury may create difficulties in postoperative ventilator management. This is particularly true in the presence of underlying COPD, when positive-pressure breaths and PEEP are preferentially applied to the highly compliant emphysematous lung, leading to progressive hyperinflation, mediastinal shift, and potentially catastrophic impairment in gas exchange and hemodynamics. This situation can be effectively addressed with insertion of a double-lumen endotracheal tube, enabling use of independent lung ventilation and selective application of PEEP to the edematous allograft, while ventilating the native lung using low-airway pressures and a prolonged expiratory phase to minimize hyperinflation. Pulmonary thromboendarterectomy is an established surgical technique for definitive treatment of chronic thromboembolic pulmonary hypertension (Chapter 82). Although operative mortality has decreased dramatically to less than 10 percent, reperfusion pulmonary edema remains a common postoperative complication. It is most often encountered within the initial 24 h after surgery, but its onset may occasionally be delayed for up to 72 h. A striking characteristic is the radiographic restriction of edema to those lung zones supplied by previously obstructed vessels. Exacerbating the degree of shunt and hypoxemia associated with this complication is the redistribution of blood from previously wellperfused segments to newly endarterectomized vessels supplying edematous areas of lung—a phenomenon referred to as “pulmonary artery steal.” Fortunately, the degree of reperfusion edema and attendant hypoxemia is mild in the majority of cases. In approximately 10 percent of cases, however, the presence of severe hypoxemia necessitates prolonged mechanical ventilatory support with high levels of oxygen and application of PEEP.

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Treatment and Outcome Detailed discussion of the management of ARDS is beyond the scope of this chapter but is covered elsewhere in this text (Chapter 145) and in recent reviews. However, several fundamental aspects of care should be underscored. First and foremost, clinical management remains supportive; specific therapies aimed at ameliorating lung injury or accelerating healing are presently lacking. Care largely centers on use of mechanical ventilation, adjusted to maintain adequate gas exchange, while minimizing potentially harmful effects of high concentrations of oxygen, high tidal volumes, and highairway pressures, all of which can induce further acute lung injury. To this end, efforts should be made to reduce the FIO2 to 0.6 or less, accepting an arterial saturation in excess of 90 percent and using PEEP to recruit atelectatic areas of the lung and improve oxygenation. A “low stretch” ventilatory pattern should be employed, using tidal volumes of less than or equal to 6 ml/kg and limiting maximum plateau airway pressures to less than or equal to 30 cm H2 O. This ventilatory strategy, to which clinicians should strictly adhere, has been shown to decrease mortality associated with ARDS. Inhaled nitric oxide preferentially vasodilates vessels supplying well-ventilated areas of the lung and has been shown to reduce shunt fraction and improve oxygenation in patients with severe ARDS. Unfortunately, these beneficial effects are typically short-lived, and multiple phase III clinical trials have failed to show a meaningful impact on duration of mechanical ventilation or mortality. Similarly, placing patients in the prone position can improve oxygenation but has not, to date, been shown to impact survival. Sedatives should be administered to maintain patient comfort and promote synchronous breathing with the ventilator. Paralysis of the patient is occasionally required in the acute situation of life-threatening hypoxemia or hypercapnia, but prolonged use of neuromuscular blocking agents is discouraged because of the risk of a debilitating myopathy. Despite aggressive support, the overall mortality from ARDS approximates 30 percent. The mortality rate is significantly higher in the elderly and in those with concurrent failure of other organ systems. On the other hand, patients with acute lung injury due to TRALI tend to have a more favorable prognosis.

Phrenic Nerve Injury and Diaphragmatic Dysfunction Phrenic nerve injury is a well-described complication of CABG. In the past, this complication arose chiefly from the use of iced saline slush placed in the pericardium for topical cooling of the heart. Thermal injury causes both demyelination and axonal degeneration of the nerve, with slowing of conduction and impaired activation of the diaphragm. The use of topical cooling techniques has fallen out of favor largely because of this potential complication. However, the phrenic nerves can also be injured by traction, ischemia, use of diathermy, or transection during sternal retraction and harvesting of the internal mammary arteries. Unilateral phrenic

nerve injury, typically involving the left phrenic nerve, has been reported in up to 10 percent of patients undergoing CABG. Bilateral phrenic nerve injury was reported to occur in 1 to 3 percent of cases in the era of widespread topical cardioplegia usage but is now a rare event. Phrenic nerve injury is not restricted to CABG; it is also seen in association with other cardiac procedures, thoracic surgery, neck surgery, and liver transplantation. Although typically inconsequential in the otherwise healthy patient, unilateral diaphragmatic paralysis can lead to significant respiratory compromise in patients with underlying chronic lung disease or those who are otherwise marginal. In patients with COPD, for example, the duration of postoperative mechanical ventilation and the rate of reintubation are higher for those with than those without unilateral phrenic nerve injury following CABG. Bilateral diaphragmatic paralysis results in marked impairment in pulmonary function and frequently leads to respiratory failure. In the proper setting, phrenic nerve injury should be suspected when attempts to wean a postoperative patient from mechanical ventilation result in progressive hypercapnia or atelectasis. The spontaneously breathing patient will often complain of orthopnea, which may be misinterpreted by the unsuspecting clinician as indicative of CHF. However, orthopnea is actually due to further impairment in diaphragmatic function resulting from loss of gravitational assistance in the supine position. The detection of inspiratory thoracoabdominal paradox—an inward movement of the abdominal wall with simultaneous expansion of the thorax—is an important bedside clue to the presence of bilateral diaphragmatic paralysis and is best evoked in the supine position. The chest radiograph may also hold important clues, demonstrating either unilateral or bilateral elevation of the diaphragms and accompanying basilar atelectasis. However, these findings are not specific for phrenic nerve injury and may also be due to splinting or abdominal distention. A reduced maximum inspiratory pressure recorded at the mouth is another sensitive but nonspecific indication of significant diaphragmatic dysfunction. Unilateral diaphragmatic paralysis can be readily diagnosed by fluoroscopic inspection, which reveals paradoxical upward movement of the affected hemidiaphragm with a maximal inspiratory effort (“sniff ”). The situation is more problematic with bilateral diaphragmatic dysfunction. In this setting, patients often assume an altered breathing pattern marked by active contraction of the abdominal muscles during expiration, forcing the flaccid hemidiaphragms upward. With subsequent inspiration, the abdominal muscles relax and the hemidiaphragms descend briefly, potentially creating the false impression that they are functional. Because of this, fluoroscopy may not be confirmatory in these patients. The “gold standard” for confirmation of phrenic nerve injury is electrophysiological testing, although even this methodology is occasionally flawed. The phrenic nerve is stimulated transcutaneously in the neck, and the diaphragmatic electromyogram (EMG) is recorded by surface

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electrodes placed in the seventh intercostal space at the costochondral junction. Demonstration of a prolonged latency between nerve stimulation and diaphragmatic action potential confirms a diagnosis of demyelinating injury. It is more difficult to interpret the significance of diminished amplitude or complete absence of the surface recording of the diaphragmatic EMG. This finding could represent either phrenic nerve injury or transection or failure to properly localize the diaphragm, which is typically shifted caudally in the postoperative patient and, therefore, away from the surface electrodes. Direct puncture of the diaphragm with a recording electrode may be employed to clarify this issue, but the technique requires a high level of expertise and carries a risk of pneumothorax. Nontraumatic causes of phrenic nerve injury and diaphragmatic dysfunction can also lead to prolonged respiratory failure and delayed weaning in the surgical patient. Phrenic neuropathy can be a component of a more generalized polyneuropathy of critical illness, commonly encountered in the wake of an episode of severe sepsis or systemic inflammatory response syndrome. A critical illness myopathy affecting the diaphragms and other muscles of respiration can be encountered under the same circumstances. Finally, diaphragmatic dysfunction can arise as a component of a myopathy induced by the concurrent use of high-dose systemic corticosteroids and neuromuscular blocking agents. Patients with diaphragmatic dysfunction are generally well-suited for noninvasive positive pressure ventilatory support if they are awake and able to effectively handle respiratory secretions. Tracheostomy is indicated for patients with ineffective cough and those who cannot be weaned from conventional mechanical ventilation. The prognosis for patients with thermal or traction injury of the phrenic nerve is favorable; recovery is typically complete, but often protracted. In symptomatic patients with unilateral diaphragmatic paralysis due to transection of the phrenic nerve, surgical plication of the flaccid hemidiaphragm usually results in improved pulmonary function and can lead to successful liberation from mechanical ventilation.

Pulmonary Embolism An increased risk of pulmonary embolism (PE) accompanies a number of surgical procedures, including upper abdominal, neurosurgical, cardiac, major urological, and lower extremity orthopedic procedures. Other, nonsurgical risk factors that predispose the patient to PE may also be present, including obesity, immobility, and underlying malignancy. While alterations in gas exchange typify pulmonary embolism, frank hypoxemic respiratory failure is relatively uncommon and suggests massive clot burden. Lesser degrees of clot burden may produce equally devastating physiological impairment in patients with underlying pulmonary disease. In the presence of severe hypoxemia, there is little remaining cardiopulmonary reserve. Failure to establish a correct diagnosis and to swiftly and appropriately intervene can prove lethal.

Acute Respiratory Failure in the Surgical Patient

Unfortunately, little information pointing specifically to a diagnosis of PE is easily gleaned at the bedside. The patient is often dyspneic, and tachypnea and tachycardia are observed on physical examination. However, these features are common in many postoperative patients because of pain and atelectasis. More informative, but infrequently detected, is evidence of acute cor pulmonale (e.g., distended neck veins, a parasternal heave, right-sided third heart sound, and accentuation of the pulmonic component of the second heart sound). An electrocardiogram may also demonstrate evidence of right heart strain, with an “S1Q3T3” pattern or new right bundle branch block. The chest radiograph is most suggestive of PE when it is normal in the face of severe hypoxemia. When abnormal, the greatest use of the chest radiograph is in identifying other causes of hypoxemia, such as pneumonia, pneumothorax, or ARDS. Echocardiography is commonly performed in the setting of hypotension; evidence of a dilated right ventricle in the face of a normal or underfilled left ventricle should raise suspicion for massive PE. The choice of diagnostic studies is dictated by the urgency of the situation. In the setting of life-threatening hypoxemia or hemodynamic instability, pulmonary angiography provides the most definitive and expeditious means of establishing the diagnosis. Pulmonary angiography also permits the immediate placement of an inferior vena cava filter or performance of catheter embolectomy or thrombus fragmentation, as needed. In more stable patients, CT angiography is emerging as the imaging procedure of choice. Until its performance characteristics in the ICU patient population are better defined, however, a negative CT angiogram in the setting of high clinical suspicion should not necessarily be viewed as definitively excluding PE. While anticoagulation with heparin forms the mainstay of therapy for the otherwise stable patient, the presence of life-threatening hypoxemia and/or hemodynamic instability should prompt consideration of alternative or additional interventions. Since additional clot burden could be fatal, insertion of an inferior vena cava filter is generally advised in this setting. Certainly this intervention is mandatory when anticoagulation is contraindicated. Thrombolytic therapy should also be considered in the critically ill patient, but its use in the postoperative period is limited by the risk of precipitating bleeding at the site of recent surgery. This risk appears to fall to an acceptable level beyond the seventh postoperative day; the exception is intracranial surgery, which contraindicates use of lytic agents for at least 2 months. Several interventional radiologic techniques—thrombus fragmentation, suction embolectomy, and intraembolic infusion of low-dose thrombolytics—as well as surgical embolectomy are alternative considerations in the deteriorating patient for whom systemic thrombolytics are either contraindicated or unsuccessful.

Obstructive Sleep Apnea Obstructive sleep apnea (OSA) is a common disorder affecting 2 to 4 percent of the adult population. It is characterized by

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repetitive upper-airway obstruction during sleep, resulting in periodic arterial desaturation, hypercapnia, and arrhythmias. Because of alterations in oropharyngeal anatomy that commonly accompany obesity and OSA, orotracheal intubation at the time of induction may be difficult. The immediate postoperative period is a particularly precarious time for patients with this disorder, as the use of volatile anesthetics, opioids, and sedatives diminish the activity of the upper-airway musculature and increase the frequency and duration of obstructive apneas. Failure to recognize and appropriately support patients with OSA in the perioperative period can lead to serious complications, including respiratory arrest, hypoxemia, confusion, and ventricular arrhythmias. Institution of nasal continuous positive airway pressure immediately after extubation permits safe administration of analgesic and sedative agents, without undue risk of precipitating life-threatening airway obstruction. It is estimated that as many as 80 percent of patients with OSA are undiagnosed; a high index of suspicion, therefore, is required in the surgical patient to intervene appropriately when upper-airway obstruction is anticipated or observed.

USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION For patients with respiratory failure refractory to conservative measures, endotracheal intubation is the standard means to facilitate mechanical ventilatory support. However, in recent years, a greater appreciation for the untoward effects of endotracheal intubation has emerged. In addition to airway trauma, these include an increased risk of nosocomial pneumonia and sinusitis and the frequent need for heavy sedation that, while addressing patient discomfort, often prolongs the process of weaning and extubation. The desire to avoid endotracheal intubation has prompted interest in the use of noninvasive positive pressure ventilation (NIPPV), employing a tight-fitting nasal or full-face mask as the interface between patient and ventilator. There is ample evidence supporting the benefits of NIPPV in the treatment of a variety of causes of respiratory failure in the medical patient, but only recently have data emerged confirming its safety and efficacy in the postoperative setting. The most compelling study randomized patients with hypoxic respiratory failure following lung resection surgery to standard therapy (supplemental oxygen, bronchodilators, chest physiotherapy) with or without NIPPV. Compared to the control group, the use of NIPPV was associated with a marked reduction in the need for endotracheal intubation (20.8 percent versus 50 percent) and in mortality at 3 months (12.5 percent versus 37.5 percent). While there has been concern about using NIPPV following esophageal or gastric surgery, recent experience suggests that this can be accomplished safely. In this setting, care must be taken to avoid gastric distention, using a nasogastric tube for decompression

if necessary, and the magnitude of positive pressure ventilation employed should be limited to less than 12 cm H2 O. Since NIPPV often requires a period of acclimation, it should not be used in unstable patients. Other contraindications to its use include depressed or agitated mental status, inability to protect the airway, and compromised airway clearance due to copious secretions or weak cough.

SUGGESTED READING Al-Ruzzeh S, Ambler G, Asimakopoulos G, et al: Off-pump coronary artery bypass surgery reduces risk-stratified morbidity and mortality: A United Kingdom multi-center comparative analysis of early clinical outcome. Circulation 108(Suppl II):II-1–II-8, 2003. Arozullah AM, Daley J, Henderson WG, et al: Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 232:242– 253, 2000. Asimakopoulos G, Smith PLC, Ratnatunga CP, et al: Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 68:1107–1115, 1999. Auriant I, Jallot A, Herve P, et al: Noninvasive ventilation reduces mortality in acute respiratory failure following lung resection. Am J Respir Crit Care Med 164:1231–1235, 2001. Bolliger CT, Jordan P, Soler M, et al: Exercise capacity as a predictor of postoperative complications in lung resection candidates. Am J Respir Crit Care Med 151:1472–1480, 1995. Canver CC, Chanda J: Intraoperative and postoperative risk factors for respiratory failure after coronary bypass. Ann Thorac Surg 75:853–858, 2003. Cashman JN, Dolin SJ: Respiratory and haemodynamic effects of acute postoperative pain management: Evidence from published data. Br J Anaesth 93:212–23, 2004. Cohen AJ, Katz MG, Katz R, et al: Phrenic nerve injury after coronary artery grafting: Is it always benign? Ann Thorac Surg 64:148–53, 1997. Dureuil B, Cantineau JP, Desmonts JM: Effects of upper or lower abdominal surgery on diaphragmatic function. Br J Anaesth 59:1230–1235, 1987. Hudson LD, Milberg JA, Anardi D, et al: Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 151:293–301, 1995. Jaber S, Delay JM, Chanques G, et al: Outcomes of patients with acute respiratory failure after abdominal surgery treated with noninvasive positive pressure ventilation. Chest 128:2688–2695, 2005. Jayr C, Matthay MA, Goldstone J, et al: Preoperative and intraoperative factors associated with prolonged mechanical ventilation: A study in patients following major abdominal vascular surgery. Chest 103:1231–1236, 1993.

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Jordan S, Mitchell JA, Quinlan GJ, et al: The pathogenesis of lung injury following pulmonary resection. Eur Respir J 15:790–799, 2000. Linden PA, Bueno R, Colson YL, et al: Lung resection in patients with preoperative FEV1 <35% predicted. Chest 127:1984–1990, 2005. Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665–671, 2001. Marini JJ, Pierson DJ, Hudson LD: Acute lobar atelectasis: A prospective comparison of fiberoptic bronchoscopy and respiratory therapy. Am Rev Respir Dis 119:971–978, 1979. Markos J, Mullan BP, Hillman DR, et al: Preoperative assessment as a predictor of mortality and morbidity after lung resection. Am Rev Respir Dis 139:902–910, 1989. Money SR, Rice K, Crockett D, et al: Risk of respiratory failure after repair of thoracoabdominal aortic aneurysms. Am J Surg 168:152–155, 1994. Nakahara K, Ohno K, Hashimoto J, et al: Prediction of postoperative respiratory failure in patients undergoing lung

Acute Respiratory Failure in the Surgical Patient

resection for lung cancer. Ann Thorac Surg 46:549–552, 1988. Pedersen T, Eliasen K, Henriksen E: A prospective study of risk factors and cardiopulmonary complications associated with anaesthesia and surgery: Risk indicators of cardiopulmonary morbidity. Acta Anaesthesiol Scand 34:144– 155, 1990. Strandberg A, Tokics L, Brismar B, et al: Atelectasis during anaesthesia and in the postoperative period. Acta Anaesthesiol Scand 30:154–158, 1986. Van Mieghem W, Coolen L, Malysse I, et al: Amiodarone and the development of ARDS after lung surgery. Chest 105:1642–1645, 1994. Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342:1334–1349, 2000. Warner MA, Warner ME, Weber JG: Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology 78:56–62, 1993. Wilcox P, Baile EM, Hards J, et al: Phrenic nerve function and its relationship to atelectasis after coronary artery bypass surgery. Chest 93:693–698, 1988.

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Respiratory Pump Failure


Pump Failure: The Pathogenesis of Hypercapnic Respiratory Failure in Patients with Lung and Chest Wall Disease Steven G. Kelsen

Nathaniel Marchetti

I. COMPENSATORY/ADAPTIVE MECHANISMS Respiratory Chemosensitivity Responses to Heightened Respiratory Load Integrated Motor Responses Changes in Respiratory Structure II. DECOMPENSATING/MALADAPTIVE RESPONSES Respiratory Muscle Fatigue Rapid, Shallow Breathing Undernutrition III. SPECIFIC DISEASES Chronic Obstructive Pulmonary Disease Asthma Neuromuscular Diseases

The ventilatory pump accomplishes bulk transfer of air to and from the alveoli. Accordingly, diseases that perturb the mechanical properties of any component of the ventilatory pump (i.e., the bony rib cage, the extra- and intrathoracic

Obesity Kyph oscoliosis Obesity IV. ASSESSMENT OF PATIENTS WITH ABNORMALITIES OF THE VENTILATORY PUMP Symptoms Physical Findings Maximum Static Inspiratory Pressure V. TREATMENT Abnormalities in Chemosensitivity Respiratory Muscle Weakness or Fatigue Chronic Ventilatory Support/Nasal Positive-Pressure Ventilation

conducting airways, and the respiratory muscles) may interfere with CO2 elimination and O2 uptake. If disturbances in the function of the ventilatory pump are sufficiently severe, alveolar hypoventilation and respiratory acidosis may ensue.

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Hypercapnic respiratory failure is defined as a steady-state Paco2 while awake at more than 45 mmHg, the upper limit of normal. This definition is somewhat arbitrary but has proved clinically useful. Conceptually, diseases that cause hypercapnic respiratory failure do so by deranging respiratory mechanics and lung dead-space volume (e.g., chronic obstructive pulmonary disease [COPD], asthma, or kyphoscoliosis) or by impairing the contractile properties of the respiratory muscles (e.g., neuromuscular disease). Diseases that impair respiratory mechanics increase the elastic or resistive load against which the respiratory muscles must contract. On the other hand, neuromuscular diseases impair the strength or endurance properties of the respiratory muscles and impair their ability to generate swings in intrathoracic pressure sufficient to maintain ventilation. A variety of compensatory neural mechanisms that sense alterations in blood gas tensions or ventilatory performance elicit increases in the neuromuscular drive to breathe—which, in turn, helps preserve alveolar ventilation. In fact, in most patients, rather marked abnormalities in ventilatory pump performance are required before hypercapnic respiratory failure ensues. Conceptually, the susceptibility to develop CO2 retention in the setting of lung, chest wall, or respiratory muscle dysfunction, therefore, depends on the balance between the severity of the derangement in ventilatory pump function and the intensity of the respiratory neuromuscular drive to breathe. This chapter deals with the pathogenic mechanisms at work in the development of CO2 retention in lung and chest wall diseases. The compensatory/adaptive mechanisms that help preserve ventilation (e.g., respiratory chemosensitivity, motor responses to alterations in the mechanics of breathing, and intrinsic changes in respiratory muscle strength and endurance) and the decompensating/maladaptive responses that predispose to CO2 retention (e.g., respiratory muscle wasting and fatigue and a rapid, shallow pattern of breathing) will be discussed.

COMPENSATORY/ADAPTIVE MECHANISMS Respiratory Chemosensitivity Overview---Regulation of Ventilation Hypoxia and hypercapnia stimulate chemoreceptors in the arterial circulation (peripheral chemoreceptors) and ventrolateral medulla (central chemoreceptors) that reflexively increase motor activity to the respiratory skeletal muscles of the chest wall and upper airway. Contraction of the muscles of the chest wall (e.g., diaphragm, intercostals, abdominals, and neck muscles) deforms the ventilatory pump and moves air. Contraction of the muscles of the upper airway (genioglossus, alae nasae, posterior arytenoids, pharyngeal dilators, sternohyoid, etc.) increases the caliber of the upper

airway and diminishes its susceptibility to collapse during inspiration. Chemoreceptor-induced increases in inspiratory and expiratory muscle activity are proportional to the severity of abnormalities in blood gas tensions and represent a feedback control loop that restores blood gas tensions toward normal by enhancing alveolar ventilation. The magnitude of the swings in intrathoracic pressure and resistance and compliance of the upper airway are determined by these changes in respiratory motor activity. The maintenance of blood gas tensions within a relatively narrow, normal range from neonatal life to senescence attests to the power of this homeostatic mechanism. Hypoxic and hypercapnic chemical drives to breathe exert the following stereotypic effects on the activity of chest wall and upper-airway muscles. Peak respiratory muscle electrical activity and its rate of rise are increased. For the inspiratory muscles, these changes in muscle electrical activity increase the rate of change and peak inspiratory intrathoracic pressure, inspiratory airflow, and tidal volume. For the expiratory muscles, increased electrical activity enhances the rate of expiratory airflow. For the upper-airway muscles, the resistance to inspiratory airflow decreases. Chemosensitivity-induced increases in respiratory activity also affect the timing of respiratory motor activity as reflected in the duration of inspiration (Ti ) and expiration (Te ). Hypoxia and hypercapnia lead to decreased Ti and Te , allowing the frequency of breathing to increase. Reductions in Te are generally out of proportion to Ti , thereby increasing the fraction of the respiratory cycle spent in inspiration. This partitioning of the respiratory cycle is reflected in the Ti /Tt ratio, where Tt is the total breath cycle duration (i.e., the sum of Ti and Te ). Hypoxia and hypercapnia differ in their effects on the activity of the inspiratory muscles after the cessation of inspiratory airflow, the so-called postinspiratory inspiratory activity (PIIA). Hypoxia increases PIIA in both chest wall inspiratory muscles and muscles that constrict the laryngeal aperture. Accordingly, hypoxia has a braking effect on the rate of expiratory airflow. As Te decreases with increasing hypoxic drive, end-expiratory lung volume increases. PIIAinduced increases in lung volume increase the caliber of the intrathoracic airways and the O2 content of the lung. Hypoxiainduced PIIA affects the load on the respiratory muscles in complex fashion; that is, PIIA reduces inspiratory resistive work of breathing but increases the inspiratory elastic and expiratory resistive work of breathing. It has been suggested, however, that the net effect of hypoxia-induced PIIA is a reduction in overall energy expenditure during breathing. In contrast, hypercapnia diminishes the duration of PIIA. Indices of Respiratory Motor Output

Ventilation is a well-accepted index of respiratory motor output. Traditionally, ventilation was viewed as the product of tidal volume (Vt ) and respiratory rate (which is equal to 60/Tt ). More recently, ventilation has been viewed as the product of separate “drive” and “timing” components. The

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average rate of inspiratory airflow, Vt /Ti —which reflects the rate of rise of inspiratory muscle activity and intrathoracic pressure—is increased when blood gas tensions are deranged. Accordingly, Vt /Ti has been taken as a reflection of the activity of mechanisms that regulate the drive to breathe. Of note, Vt /Ti may also be increased by excitatory inputs arising from respiratory mechanoreceptor afferents (e.g., vagal irritant receptors) and higher central nervous system (CNS) structures engaged in thermoregulation and emotion (i.e., hypothalamic and limbic areas). Conversely, the Ti /Tt ratio has been taken as a reflection of the activity of mechanisms that regulate respiratory timing. The Ti /Tt ratio is strongly affected by afferent input from mechanoreceptors in the lungs, airways, and respiratory muscles, as well as increasing chemical drive. For example, Ti /Tt increases in anesthetized animals when vagal stretch receptors are stimulated by increases in lung volume and is decreased by bronchoconstrictioninduced activation of vagal irritant receptors. In subjects with normal lung function, Vt /Ti and ventilation are accurate reflections of inspiratory muscle electrical activity and the rate of rise of intrathoracic pressure. On the other hand, diseases that adversely affect the mechanical properties of the ventilatory pump (e.g., obstructive lung disease, kyphoscoliosis) interfere with the translation of changes in intrathoracic pressure into ventilation and airflow. Conversely, conditions that impair respiratory muscle contractility (e.g., neuromuscular diseases, respiratory muscle fatigue) interfere with the translation of inspiratory muscle electrical activity into intrathoracic pressure changes. Accordingly, Vt /Ti reflects the intensity of motor outflow to the inspiratory muscles produced by increasing chemical drive only when the mechanical properties of the ventilatory pump and inspiratory muscle strength are normal. When the ventilatory pump function is abnormal, respiratory motor outflow is best assessed from respiratory muscle electrical activity (i.e., diaphragm electromyography [EMG] activity), a complicated measurement largely confined to the research laboratory. A simpler, clinically useful measurement that reflects the neuromuscular drive to breathe and the driving pressure to inspiratory airflow is the airway occlusion pressure. The occlusion pressure is the pressure generated at the airway opening 100 ms after the onset of an occluded inspiratory effort (i.e., P100 or P0.1 ) initiated at end-expiratory lung volume. Since the airway is occluded, the inspiratory muscles contract quasi-isometrically, a condition in which muscle force correlates closely with muscle electrical activity. Measurements are made early in inspiration (100 ms) to prevent behavioral responses elicited in response to airway occlusion from altering the shape/trajectory of the pressure waveform. The lack of flow or volume change during the measurement means that the occlusion pressure is unaffected by abnormalities in the flow-resistive or compliance properties of the ventilatory pump. The occlusion pressure, therefore, has been used to assess the drive to breathe in patients with lung diseases (e.g., COPD and asthma) and chest wall diseases (e.g., kyphoscoliosis) during resting and chemically stimulated breathing. On

the other hand, the occlusion pressure depends on the ability of the inspiratory muscles to convert neural activity into force and pressure. Accordingly, like ventilation, occlusion pressure may not reflect respiratory motor-neuron activity when the inspiratory muscles are weak (e.g., neuromuscular disease) or fatigued. Hypoxic Response Under isocapnic conditions, ventilation (or occlusion pressure) increases in curvilinear fashion as Po2 falls. However, hypoxic responses depend importantly on the prevailing level of Paco2 (i.e., the O2 –CO2 interaction). When Paco2 is in the hypocapnic range, arterial Po2 must fall considerably (to approximately 55 to 60 mmHg or less) before respiratory activity increases. Hypercapnia profoundly increases the response to hypoxia by shifting the threshold of the response toward higher levels of Po2 and augmenting the change in ventilation elicited for a given reduction in Po2 . Although the physiological stimulus for the hypoxic response is the Pao2 of the blood perfusing the peripheral chemoreceptors, for convenience the oxyhemoglobin saturation assessed with a pulse oximeter has been taken as a reflection of the stimulus. Use of the oxyhemoglobin saturation linearizes the relationship between the hypoxic stimulus, ventilation, and occlusion pressure. The intensity of the hypoxic response has been assessed from the slope of the change in ventilation (or occlusion pressure) relative to the change in O2 saturation (i.e., # Ve /# % O2 sat) and from the intercept of the relationship (e.g., ventilation at O2 saturation of 85 percent). Hypercapnic Response In contrast to the response to hypoxia, the ventilatory and occlusion pressure responses to hypercapnia under iso-oxic conditions are linear over a relatively wide range of Paco2 above and below the resting level of 40 mmHg. The intensity of the ventilatory and occlusion pressure response to CO2 has been assessed from the slope of the relationship of Ve to Paco2 (i.e., # Ve/# Paco2 ) and from the intercept of the relationship (i.e., Ve at Paco2 50 mmHg). The ventilatory response to hypercapnia is strongly affected by the prevailing level of Pao2 and is heightened as Pao2 decreases. In fact, hypoxemic and hypercapnic stimuli interact multiplicatively to enhance inspiratory and expiratory motor activity. Worsening hypoxemia enhances the ventilatory response to hypercapnia in accordance with the O2 –CO2 interaction. The strength of a subject’s chemosensitivity to O2 and CO2 and, in particular, to the O2 –CO2 interaction is a powerful feedback mechanism opposing the tendency to retain CO2 in patients with ventilatory pump dysfunction. Consequently, treatment of the hypercapnic, hypoxemic patient with supplemental O2 may decrease Vt /Ti and Ti /Tt and, hence, worsen hypercapnia in accordance with O2 –CO2 interaction. Increases in Pao2 in hypoxic, hypercapnic subjects move the O2 response to the right (less stimulus)

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Figure 148-1 Theoretical effects of supplemental O2 on the ventilatory response to CO2 and steady-state arterial PCO 2 in subjects with COPD in hypercapnic respiratory failure. Increasing PaO 2 decreases alveolar ventilation and increases PaCO 2 as dictated by effects of O2 on the CO2 ventilatory response. The two straight lines represent hypercapnic ventilatory response curves at PaO 2 of 40 and 60 mmHg. As may be seen, increasing PaO 2 produces a downward, rightward shift of the ventilatory response. In contrast, the hyperbolic line intersecting the ventilatory response lines is the metabolic CO2 –ventilation curve, which represents the effect of increasing alveolar ventilation (independent variable) on PaCO 2 (the dependent variable) when CO2 production is normal (∼200 ml/min). Steady-state alveolar ventilation and PaCO 2 at rest are dictated by intersection of the ventilatory response curves with the metabolic curve (points 1 and 2). Note the increase in PaCO 2 as the ventilatory response with PaO 2 60 mmHg intersects at a lower alveolar ventilation and higher PaCO 2 (point 2) compared to the higher ventilatory response when PaO 2 was 40 mmHg (point 1).

and decrease the slope and shift the intercept of the ventilatory response to hypercapnia to the right (Fig. 148-1). Shifts in the CO2 response with increases in the prevailing Pao2 mean that a higher CO2 stimulus is required to maintain ventilation at the baseline level. Accordingly, ventilation falls and Paco2 rises. The magnitude of the rise in Paco2 in patients with COPD in acute respiratory failure produced by supplemental O2 varies widely among subjects as determined by their chemosensitivity. Of note, hypercapnia induced by supplemental O2 in patients with COPD is multifactorial and reflects increases in lung dead-space volume as well as reductions in alveolar ventilation. Hypoxemia causes bronchoconstriction via increases in parasympathetic outflow to airway smooth muscle. Accordingly, relief of hypoxemia causes bronchodilation and increased dead-space volume. Role of Blunted Chemosensitivity in Development of Respiratory Failure Chemosensitivities to hypoxemia and hypercapnia are hereditofamilial and ethnic traits that vary widely interindividually

Figure 148-2 Variability of the slopes of the ventilatory responses to progressive hypercapnia (i.e., VE /PCO 2 ) in a normal population. Shown is the frequency distribution histogram of the slopes in 126 normal South African medical students. Note the considerable interindividual variation in CO2 responsiveness. In some healthy subjects, the ventilatory response is blunted to less than 1 L/min/mmHg PCO 2 . (Based on data from Irsigler GB: Carbon dioxide response lines in young adults: The limits of the normal response. Am Rev Respir Dis 114:529–536, 1976, with permission.)

(Fig. 148-2). In a given subject, responses to hypoxemia and hypercapnia correlate weakly, so that subjects with strong responses to hypercapnia also tend to have strong responses to hypoxia. Respiratory chemosensitivity to both hypoxemia and hypercapnia declines with age. The decline in chemosensitivity with aging may explain why elderly subjects with lung disease (e.g., COPD) or chest wall disease (e.g., kyphoscoliosis) develop hypercapnic respiratory failure more frequently than young adults. When chemosensitivity is low, subjects with diseases of the ventilatory pump are predisposed to develop hypercapnic respiratory failure. In patients with advanced COPD, the severity of airway obstruction required to cause CO2 retention varies widely from subject to subject (Fig. 148-3). Subjects with the greatest respiratory effort responses to changes in Paco2 —as measured by diaphragm EMG, respiratory work of breathing, or occlusion pressure—have arterial Paco2 values closer to normal than subjects with blunted responses to CO2 but the same severity of lung dysfunction. Accordingly, when chemosensitivity is low, subjects with diseases of the ventilatory pump are predisposed to develop hypercapnic respiratory failure. However, since CO2 retention per se may blunt the response to acute hypercapnia, studies in patients in respiratory failure have not been able to determine whether blunted CO2 responses are a cause or consequence of respiratory failure. The tendency for chemosensitivity to be inherited has been used in a number of subsequent studies to assess the role of hypoxic and hypercapnic responses in the pathogenesis of CO2 retention in the setting of obstructive lung disease. Study of relatives with normal lung function and blood gases has been employed to circumvent the effects of CO2 retention on respiratory chemosensitivity in patients with COPD. In general, normal relatives of hypercapnic patients with COPD have lower ventilatory responses to hypoxia and hypercapnia than relatives of eucapnic patients with COPD

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Figure 148-3 Results of repeated measurements of arterial PCO 2 and FEV1 (liters) in five patients with advanced COPD. Free-hand curves of the data are shown plotted together in the lower right graph. Note that cases 1, 11, and 13 show marked increases in PCO 2 , with relatively small changes in FEV1 , whereas cases 4 and 5 do not. (Based on data from Lane DJ, Howell JBL, Giblin B: Relation between airways obstruction and CO2 tension in obstructive airways disease. Br Med J 3:707â&#x20AC;&#x201C;709, 1968, with permission.)

(Fig. 148-4). Among the offspring of patients with COPD with equally severe airway obstruction, the slopes of the ventilatory responses to isocapnic hypoxemia and hyperoxic hypercapnia are 30 to 40 percent lower in the offspring of hypercapnic patients than in offspring of eucapnic patients. Similarly, the slopes of the ventilatory and airway occlusion pressure responses to isocapnic hypoxia in the offspring of hypercapnic patients are approximately 40 percent of the values obtained in the offspring of normocapnic patients. In one study, the Pao2 of COPD patients while in a stable state and the Pao2 and Paco2 during COPD exacerbations correlated with the

hypoxic ventilatory response of their sons. It appears that blunted chemosensitivities to hypoxia and hypercapnia are likely to be premorbid characteristics of hypercapnic patients with COPD, which contribute to the development of respiratory failure. A number of reports describe patients with asthma and respiratory failure who had blunted ventilatory responses to hypoxia and hypercapnia and whose healthy immediate family members also showed blunted hypoxic and hypercapnic responses. Respiratory responses to hypoxia and hypercapnia in patients with asthma who have near-fatal attacks differ from those of asthmatics who did not have near-fatal attacks and age-matched, normal subjects. The slopes of the ventilatory and occlusion pressure responses to hypoxia in the patients with a history of near-fatal asthma are approximately 33 percent of the responses of the asthmatics without nearfatal attacks or normals, which are similar. Hypercapnic responses tend to be lower in the near-fatal asthmatic groups than in the other two groups, but the differences are smaller in magnitude.

Responses to Heightened Respiratory Load

Figure 148-4 Mean isocapnic hypoxia and hyperoxic hypercapnic ventilatory response curves of 12 offspring of hypoventilating patients with COPD (solid line) and 10 offspring of eucapnic COPD patients (dashed line). Ventilatory responses to hypoxia and hypercapnia are significantly lower in the offspring of hypercapnic COPD than in the offspring of eucapnic COPD patients. (Based on data from Mountain R, Zwillich CW, Weil JV: Hypoventilation in obstructive lung disease: The role of familial factors. N Engl J Med 297:521â&#x20AC;&#x201C;525, 1978, with permission.)

A complex array of mechano- and proprioceptors whose afferents project to respiratory neurons in the brain stem and higher CNS structures provides the respiratory controller with information about the mechanics of breathing and performance of the ventilatory pump. The sensory receptors providing this afferent feedback and the CNS structures that integrate this feedback into a coordinated respiratory response (see below) are not perfectly understood. However, mechanoreceptors in the intercostal muscles that sense muscle tension and length (Golgi tendon receptors and spindle

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organs, respectively) and pressure and flow sensors in the lower (vagal irritant receptors) and upper airway (larynx and mouth) clearly play a role in shaping the neuromuscular response to alterations in the mechanics of breathing. Diseases of the airways (COPD and asthma) or chest wall (kyphoscoliosis) change the resistance and compliance properties of the ventilatory pump and, hence, stimulate mechanoreceptors in the ventilatory pump. In normal subjects and those with COPD, mechanoreceptor afferent inputs increase inspiratory neuromuscular output as reflected in airway occlusion pressure in response to bronchoconstriction or external resistances or elastance. Changes in ventilation during acute increases in airway resistance are inversely related to changes in occlusion pressure. Thus, the magnitude of the motor response to increases in respiratory load determines the ventilatory response. External ventilatory loads that can be consciously detected and alter the intensity of the sensations associated with breathing elicit increases in respiratory effort as reflected by the diaphragm EMG and occlusion pressure. Increases in effort occur abruptly within the first loaded breath and in feedforward fashion; that is, the experience of the previous breath elicits a response in anticipation that the load will still be present. These responses are eliminated by general anesthesia and dulled if not absent in stages III and IV and REM sleep. The afferent input to the CNS elicited by external ventilatory loads probably arises from spindle and tendon organs in the respiratory muscles that project to the sensorimotor cortex and medullary respiratory neurons. The motor response to external ventilatory loads is thought to be behavioral. The magnitude of the respiratory motor response to external loads varies widely from subject to subject and may be a hereditofamilial trait. Of considerable importance, some subjects with COPD demonstrate lesser occlusion pressure responses to acutely applied external resistive loads than agematched normal subjects. It has been suggested that the blunted respiratory motor response to external loads may be a form of sensory adaptation to chronic increases in respiratory resistance. The fact that occlusion pressure responses of patients with COPD to external elastic loads and patients with asthma to external resistive loads are normal supports this concept. Of interest, the blunted motor response to external loads in some patients with COPD may reflect an increase in endogenous opiates within the CNS, since naloxone administration immediately enhances the response. In subjects with COPD, bronchoconstriction increases airway occlusion pressure in proportion to increases in airway resistance and to a greater extent than with external flowresistive loads. Bronchoconstriction increases the activity of vagal â&#x20AC;&#x153;irritantâ&#x20AC;? receptors in the airway, which exert an inspiratory augmenting effect on breathing. Irritant receptors may also be excited chemically by inflammatory mediators (e.g., histamine, prostaglandin F2Îą) and, in contrast to external loads, elicit simple monosynaptic reflexes not abolished by sleep or anesthesia. Mechanoreceptor inputs modify the respiratory motor responses to chemical stimuli to breathing. Increases in the elastic or resistive load to inspiration augment inspira-

tory muscle electrical activity and the airway occlusion pressures to hypoxia and hypercapnia. Subjects with asthma show heightened occlusion pressure responses to hypoxia and hypercapnia for this reason. Increases in the inspiratory neuromuscular drive to breathe allow ventilation to be maintained in the face of abnormalities in respiratory mechanics. Respiratory motor activity (i.e., occlusion pressure) also tends to be increased when the respiratory muscles are weak. In all likelihood, this reflects the fact that the maintenance of force output by a weakened muscle requires an increase in activation by the CNS. Increased ventilatory loads also alter the pattern of breathing in load-dependent fashion. Subjects breathing against resistive loads breathe slowly and deeply, with an increase in tidal volume and prolongation of Ti and Te . In contrast, subjects breathing against elastic loads tend to breathe with smaller tidal volumes and a reduced Ti and Te ; that is, they demonstrate a rapid and shallow pattern of breathing. Slow, deep breathing during resistive loading and rapid, shallow breathing during elastic loading diminish the resistive and elastic work of breathing, respectively. Alterations in breathing pattern when the mechanics of breathing are deranged are believed to be attempts to minimize the work of breathing, muscle tension, or energy expended.

Integrated Motor Responses Respiratory motor responses to heightened chemical or mechanoreceptor drives to breathe elicit highly coordinated patterns of muscle activity that optimize the mechanical output of the respiratory musculature contracting in concert. These responses may take the following forms: (1) simple reflex-mediated recruitment of additional agonists, which exert similar mechanical effects on the chest wall; (2) sequential activation of inspiratory and expiratory muscles, which exert opposing effects on chest wall structures; and (3) complex behavioral acts that use nonrespiratory muscles to effect changes in body posture and expiratory airflow, minimizing dyspnea. For example, hypercapnia and hypoxia recruit the external intercostal and parasternal muscles during inspiration in a stereotypic rostral-to-caudal direction, and the internal intercostals and triangularis sterni during expiration in the opposite direction. Preferential activation of the inspiratory external intercostal and parasternal muscles in the rostralmost interspaces decreases the impedance of the rib cage to rostral movement and, hence, facilitates thoracic expansion. Conversely, recruitment of the expiratory internal intercostals and triangularis sterni in the most caudal interspaces decreases the impedance to caudal movement and facilitates thoracic deflation. In addition, recruitment of the parasternal intercostal muscles facilitates inspiratory pressure as tidal volume increases. The parasternal intercostal muscle fiber length, which is optimum for tension development, is shorter than that of the diaphragm and occurs at higher lung volume. Accordingly, the parasternal muscles become mechanically more effective than the diaphragm as lung volume increases above functional residual capacity (FRC).

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Moreover, hypercapnia and hypoxia increase phasic and tonic inspiratory activity in the dilator muscles of the upper airway (e.g., posterior arytenoid, alae nasae, genioglossus). Increases in activity of the dilator muscles of the upper airway decrease the load on the chest wall pumping muscles by decreasing the resistance to inspiratory airflow through the upper airway. Increased activity of these muscles also diminishes the susceptibility of the upper airway to collapse as inspiratory efforts become greater and subpharyngeal pressure becomes more subatmospheric. In addition, phasic increases in abdominal expiratory muscle electrical activity during expiratory airflow accelerate lung emptying, thereby allowing the time of expiration to decrease. When sufficiently intense, activation of the abdominal muscles reduces end-expiratory lung volume and improves the ability of the diaphragm to generate pressure by favorably affecting its precontraction length, radius of curvature, and alignment with the rib cage. Reductions in end-expiratory lung volume achieved by the expiratory muscles also allow elastic work to be stored in the passive recoil of the chest wall and released suddenly at the onset of inspiration. Sudden release of the recoil pressure of the chest wall thereby “assists” the inspiratory muscles by contributing to the driving pressure to inspiratory airflow. A portion of the inspiratory load is thus assumed by the expiratory muscles. Finally, hyperinflated, dyspneic patients with COPD often assume a stereotypic body posture that improves diaphragm, neck accessory, and pectoral girdle muscle mechanical advantage. This posture is forward flexion of the trunk, extension of the head and neck, bracing of the pectoral girdle by rounding of the shoulders, and grasping of the thighs with the arms. The effect of this posture is to increase abdominal pressure (thus increasing diaphragm precontraction length and radius of curvature); provide more favorable alignment of the scalenes and sternomastoid with the upper rib cage; and anchor the pectoral girdle muscles, allowing them to apply an inspiratory action on the rib cage. In this posture, transdiaphragmatic pressure is increased and diaphragm and sternomastoid muscle EMG activity is decreased. Patients with advanced COPD also spontaneously adopt pursed-lip breathing to slow expiratory airflow, thus minimizing dynamic airway compression. Effects of Sleep Responses to chemical stimuli to breathing are powerfully influenced by CNS state (e.g., sleep vs. waking). Slow-wave and REM sleep depress O2 and CO2 chemosensitivity, with greatest depression occurring in REM sleep. While the subject is awake, apnea does not occur in the presence of even marked hypocapnia, and ventilation is largely independent of changes in Pco2 . Rather, ventilation persists even when Paco2 is less than about 30 to 35 mmHg. Persistence of ventilation in the setting of hypocapnia (the so-called wakefulness drive to breathe) probably represents the effects on medullary neurons of inputs activated by auditory, visual, and tactile stimuli. In contrast, in the sleeping or anesthetized state, the ventilatory response to CO2 extrapolates to zero ventilation

in the hypocapnic range. In fact, apnea occurs when Pco2 falls only 4 to 6 mmHg below waking eucapnic levels. Sleeprelated changes in chemosensitivity, therefore, underlie the recurrent periods of apnea and hyperpnea and exaggerated hypercapnia that occur in some patients with diseases of the lung and chest wall. The increase in respiratory motor activity induced by derangements in respiratory mechanics is also statedependent; that is, heightened activity in awake subjects is absent in sleeping or anesthetized subjects. REM sleep, in particular, impairs the “load” response and causes collapse of the upper rib cage during inspiration, which adversely affects the level of ventilation as well as its distribution. Descending inhibitory drives to spinal α– and spindle γ– motor neurons in REM sleep cause atonia of all the respiratory muscles except the diaphragm. Muscle spindle γ-efferent activity determines spindle sensitivity by progressively contracting the intrafusal fiber. Accordingly, reductions in muscle spindle γ-efferent activity diminish spindle organ sensitivity and interfere with a mechanism for augmenting respiratory muscle spinal α– motor neuron activity. The diminished or absent load response during sleep and anesthesia probably explains the exaggerated increases in Paco2 that occur during these periods in patients with lung and chest wall disease. In fact, REM sleep is the period in which Paco2 is highest and Pao2 lowest in patients with stable COPD (Fig. 148-5).

Changes in Respiratory Structure Respiratory Muscles The respiratory muscles are highly plastic and undergo changes in structure, biochemistry, and contractile properties in response to chronic increases in load or changes in precontraction length. Chronic increases in inspiratory muscle activity enhance their strength and endurance. In animal models, chronic increases in inspiratory load produced by emphysema or inspiratory resistive loading increase diaphragm endurance and the content of oxidant enzymes (e.g., succinic dehydrogenase and citrate synthase) essential for high-energy phosphate synthesis. In patients with chronic asthma, inspiratory and expiratory muscle endurance assessed from the time course of the fall in maximum static pressure is about 40 percent greater than in normal controls. The effect of COPD per se on inspiratory muscle endurance has not been assessed. In subjects with COPD, however, daily training with inspiratory resistive ventilatory loads increases inspiratory muscle strength by about 40 percent as reflected by maximum static inspiratory pressure (Pimax ) over an 8- to 10-week period. Hyperinflation impairs the force- and pressuregenerating ability of the inspiratory muscles by decreasing muscle precontraction length and unfavorably changing muscle alignment with the chest wall. In particular, severe hyperinflation alters diaphragm shape (i.e., flattening) and decreases the zone of apposition with the rib cage. Flattening of the diaphragm displaces the vector of contraction force from a rostral-caudal direction to a medial-lateral direction and diminishes the ability of the diaphragm to increase abdominal

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Figure 148-6 Active (upper trace) and passive (lower trace) length-tension (L-T) relationship of costal diaphragm of emphysematous (open circles) and normal hamsters (solid circles), assessed in vitro during electrical stimulation. Note that in emphysematous animals, the L-T curve is displaced toward shorter fiber lengths. This adaptive change in emphysematous animals allows the diaphragm to generate maximal tension (force) at shorter fiber lengths and helps preserve diaphragm contractile performance in the face of considerable hyperinflation. (From Supinski GS, Kelsen SG: Effect of elastase-induced emphysema on the forcegenerating ability of the diaphragm. J Clin Invest 70:978–988, 1982, with permission.) Figure 148-5 Changes in steady-state arterial PCO 2 during sleep in eight patients with stable COPD. Note that arterial PCO 2 increases and arterial PO 2 decreases during sleep. Greatest changes occur during REM sleep. For PaCO 2 , average increase is 10 mmHg. (Based on data from Koo KW, Sax DS, Snider GL: Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease. Am J Med 58:663–670, 1975, with permission.)

pressure. Reductions in the zone of apposition diminish the inflationary effects on the lower rib cage produced by increases in abdominal pressure induced by the diaphragm. In extreme cases of hyperinflation, the diaphragm may exert an expiratory action on the lower rib cage and retract the lower rib cage on inspiration (Hoover’s sign). In part, hyperinflation-induced impairment in the action of the diaphragm is compensated for by adaptive changes in the intrinsic muscle length–tension characteristic. In emphysematous animals, the active and passive length–tension curve of the costal diaphragm is displaced toward shorter lengths, thereby allowing maximum tension to be developed at significantly shorter lengths and higher lung volumes (Fig. 148-6). The shift in the length–tension curve appears to be the reverse of normal growth, in which muscle length is increased by addition of sarcomeres in series. A similar adaptation in the diaphragm seems to occur in chronically hyperinflated, stable outpatients with COPD. Chest Wall Anatomy Chronic hyperinflation elicits adaptive changes in the pressure-volume (P-V) characteristic of the passive chest wall. In animal models of emphysema, the static deflation, chest

wall P-V curve is shifted up and to the left, so there is a decrease in elastic recoil at any given lung volume. Shifts in the passive P-V curve are accomplished by a structural remodeling of the rigid structures in the chest wall. The length of the sternum and the lengths of the ribs in anteroposterior and transverse dimensions are increased. This displacement of the chest wall P-V curve diminishes the inspiratory elastic work of breathing during hyperinflation and preserves the zone of apposition of the diaphragm. An increase in the zone of apposition of the diaphragm in hyperinflation preserves the appositional force exerted by the diaphragm on the lower rib cage by virtue of changes in abdominal pressure. If present in patients with COPD, the process is reversible, since recent observations of the thorax after volume reduction surgery or lung transplantation for COPD indicate that the shape of the chest wall can quickly revert to normal.

DECOMPENSATING/MALADAPTIVE RESPONSES Respiratory Muscle Fatigue Overview/Definition Studies in the laboratory and in the clinic indicate that the respiratory skeletal muscles, like muscles in the limbs, fatigue under conditions of intense activity, leading to respiratory failure. Conditions that increase the level of phasic inspiratory muscle activity, or the duty cycle of breathing, or that decrease the maximal pressure-generating capacity of

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the muscle, make fatigue more likely. For example, derangements in the mechanical properties of the lung or chest wall or increases in ventilatory drive increase inspiratory muscle contractile activity. Of note, increases in ventilatory drive increase both the peak inspiratory pressure and Ti /Tt ratio, the latter by causing greater reductions in the duration of expiration than in that of inspiration. Decreases in inspiratory muscle strength caused by aging, protein-calorie malnutrition, or electrolyte imbalances predispose to fatigue at any given level of inspiratory impedance or ventilation by decreasing Pimax . Finally, on the basis of data from animal models, reductions in diaphragm blood flow are likely to decrease the level of muscle activity that leads to fatigue. Respiratory muscle fatigue has been defined as a loss in muscle capacity to develop force or shorten, resulting from muscle fiber activity under load; it is reversible by rest. In contrast, respiratory muscle weakness has been defined as impairment in the capacity of a fully rested muscle to generate force. Fatigue is viewed as developing when the muscle is highly active and generating appreciable levels of force. Recovery from fatigue is generally observed over a short time (e.g., minutes to hours). On the other hand, muscle weakness is commonly caused by muscle fiber atrophy, metabolic derangements that impair the ability of actomyosin crossbridges to generate force (e.g., acidosis or electrolyte abnormalities that affect intracellular calcium flux), or chronic reductions in muscle precontraction length that impose a mechanical disadvantage (e.g., hyperinflation of the thorax and its effects on the inspiratory muscles). Implied in the definition of weakness is the idea that alterations in muscle function are secondary to alterations in muscle structure or lung volume and hence induce changes in muscle function that are more slowly reversible than fatigue (e.g., days to weeks). In the clinical setting, however, the distinction between muscle weakness and fatigue is difficult and not easily accomplished. Moreover, a close association exists between respiratory muscle weakness and respiratory muscle fatigue. In fact, weak muscles are predisposed to fatigue (see below). Fatigue produces complex effects on muscle mechanical output. Fatigue prolongs contraction and relaxation time and depresses the force generated at a given stimulus frequency and fiber length, and reduces the velocity of shortening against a given load. Depending on the cause of the fatigue, depression of force output can occur at primarily subtetanizing frequencies of muscle stimulation (e.g., less than 15 to 20 Hz), a condition called low-frequency fatigue, or at frequencies above 50 Hz, a condition called high-frequency fatigue (Table 148-1, Fig. 148-7). The biochemical and biophysical processes that underlie low-frequency and high-frequency fatigue differ. Muscle force responses to tetanizing frequencies of stimulation (i.e., above 50 Hz) are primarily determined by the processes of neuromuscular transmission and muscle excitation. In contrast, muscle mechanical output at subte-

Table 148-1 Classification of Respiratory Muscle Fatigue Central Refers to decreases in phrenic motor output mediated by spinal or supraspinal mechanisms Peripheral Refers to fatigue occurring at the level of the muscle itself Transmission Failure of mechanisms operative in muscle excitation (“high-frequency” fatigue) Contractile Failure of mechanisms involved in excitationcontraction coupling or contractile protein function (“low-frequency” fatigue)

tanizing frequencies is determined primarily by the processes of excitation-contraction coupling (e.g., calcium release from the sarcoplasmic reticulum, calcium-troponin interactions), perhaps caused, in part, by O2 free radical–induced injury. Of interest, recovery from high-frequency fatigue is more rapid (minutes) than recovery from low-frequency fatigue (hours) (Fig. 148-8). Moreover, the two forms of fatigue have different physiological consequences. High-frequency fatigue impairs muscle force output under conditions in which the muscle is maximally driven by the CNS (i.e., when muscle strength is being evaluated). Low-frequency fatigue, on the other hand, impairs force generation during resting breathing, when phrenic motor unit discharge rates are typically about 15 Hz. Since low- and high-frequency fatigue reflect impairments occurring at the level of the muscle, they have been termed peripheral fatigue. Performance of strenuous ventilatory tasks may also elicit an additional, qualitatively different response—i.e., a reduction in central motor output and failure of the CNS to fully activate the respiratory muscles. That is, the diaphragm EMG or phrenic neurogram may decrease late in the performance of strenuous respiratory efforts before the point of exhaustion. This reduction in motor activity may limit task performance. The failure of CNS mechanisms to fully activate the muscle near the point of exhaustion has been termed central fatigue. The mechanisms underlying central fatigue are poorly understood. It is not clear whether central fatigue represents a behavioral response elicited by the unpleasant sensations present during ventilatory loading or is mediated reflexively or by changes in brain neurotransmitter levels. Detection of Respiratory Muscle Fatigue Diaphragm muscle fatigue has been diagnosed in humans from changes in the response of the muscle to electrical stimulation (i.e., the force-frequency relationship), the power

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Figure 148-7 Force-frequency relationship of the human diaphragm during electrophrenic stimulation showing rate of recovery from high- and low-frequency fatigue. Data obtained in four subjects before and after a period of inspiratory resistive loading to exhaustion. At the point of exhaustion, the subject was unable to generate targeted values of transdiaphragmatic pressure (Pdi). Note the decrease in Pdi in response to low (20 Hz) and high (50 Hz) electrical stimulation immediately after loading, indicating the presence of both high- and low-frequency fatigue. Note also that high-frequency fatigue disappears within 14 to 17 min. In contrast, low-frequency fatigue persists beyond the period of observation (>30 min). (Based on data from Aubier M, Farkas A, De Troyer RT, et al: Detection of diaphragmatic fatigue in man by phrenic stimulation. J Appl Physiol 50:538â&#x20AC;&#x201C;544, 1981, with permission.)

spectral content of the EMG, and Pimax . As will be seen, the force-frequency relationship and EMG power spectrum analyses are complex and require sophisticated electronics and instrumentation. Consequently, their use has been confined to the research laboratory. On the other hand, Pimax is convenient and easily performed at the bedside but suffers from relative nonspecificity.

Electrical Stimulation

The force-frequency relationship represents a way of assessing muscle mechanical output over a wide range of stimulus intensities. Since fatigue shifts the force-frequency curve downward (and possibly to the left), the magnitude of the shift in the force-frequency relationship can be used to assess the severity of low- and high-frequency fatigue and the time course of recovery. Electrical stimulation of the muscle of interest has several advantages. It allows the muscle to be activated in response to a standard stimulus without the cooperation of the

subject. Hence, neurological deficits, decreased effort, and central fatigue, which may diminish muscle activation, are circumvented and peripheral fatigue can be detected.

EMG Power Spectrum

Fatigue alters the power-EMG spectral content of the raw EMG of the respiratory muscles analyzed by fast Fourier transform (Fig. 148-8). In the fresh diaphragm, the power (or voltage) contained in the EMG waveform reaches a maximum between approximately 85 and 105 Hz, and thereafter declines. (Maximum power in the EMG of the diaphragm, parasternal intercostal, and sternocleidomastoid occurs at somewhat different frequencies, however.) Fatigue-inducing contractions cause a leftward shift of the power spectral density, so that more of the power in the EMG is contained in a lower-frequency domain. The power-spectral density of the contracting diaphragm changes almost immediately with fatiguing contractions and considerably before the mechanical output of the muscle fails. The diaphragmatic EMG power

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under standard conditions as well as during volitional contractions. Muscle Activity

Figure 148-8 Schematic representation of the power-spectral density of a respiratory muscle EMG determined by fast Fourier transform. Note the concave appearance of the relationship. Note that fatigue (dashed line) decreases and increases power in the high- and low-frequency domains, respectively, thereby shifting the relationship toward the left. (Based on data from Moxham J, Edwards RHT, Aubier M, et al: Changes in EMG power spectrum (highto-low ratio) with force fatigue in humans. J Appl Physiol 53:1094– 1099, 1982, with permission.)

spectrum can be obtained from the raw EMG of the muscle, recorded from surface electrodes on the chest wall or within the esophagus. It is, therefore, relatively noninvasive and well tolerated. Moreover, the EMG power spectrum, unlike maximal static pressure, can be measured continuously— i.e., breath by breath—and does not require subject cooperation. Accordingly, the EMG power spectrum has proved to be a useful tool to study the pathophysiological mechanisms of human respiratory muscle fatigue. A significant caveat in the use of the power spectrum is the suggestion that it may be unable to detect low-frequency fatigue. Pathogenesis of Respiratory Muscle Fatigue Studies designed to examine the pathogenetic mechanisms that lead to respiratory muscle fatigue have largely focused on the diaphragm. The diaphragm has been the primary focus of attention for several reasons. First, it is the major respiratory muscle. Second, anatomic considerations allow the mechanical output of the diaphragm (i.e., transdiaphragmatic pressure) and its EMG, an index of phrenic motor outflow and fatigue state, to be assessed relatively easily. Finally, the cervical phrenic nerves can be electrically stimulated, thereby allowing the mechanical output of the muscle to be assessed

In seminal studies, Roussos and Macklem observed that the time of onset of diaphragm fatigue was not related to the magnitude of the phasic inspiratory swings in Pdi during loading alone or to Pdimax alone. Rather, the time of onset of mechanical failure of the diaphragm was a unique curvilinear function of the ratio of Pdi generated on each breath over Pdimax (Pdi/Pdimax ) (Fig. 148-9). Values of Pdi/Pdimax less than 40 to 50 percent could be maintained indefinitely; values greater than this threshold were associated with progressively more rapid exhaustion. These results made several important points. First, diaphragm fatigue depended on the relative intensity of contraction (i.e., muscle force output as a percentage of its strength). Second, contractions below some critical threshold could be sustained indefinitely and did not lead to fatigue. Subsequent studies demonstrated that the timing as well as the intensity of diaphragmatic contractions determined the time of onset of mechanical failure of that muscle. Increases in the ratio of the Ti over the Tt increased the rapidity of onset of fatigue at any given Pdi/Pdimax ratio. That is, increasing the duration of diaphragm contraction relative to the period during which the diaphragm is relaxed, the duty cycle of breathing, predisposes to fatigue. In fact, diaphragm fatigue appears to be largely a function of the product of Pdi/Pdimax × Ti /Tt , which has been termed the diaphragm tension–time index (TTI) (Fig. 148-10). The TTI is, in essence, the integrated area under the pressure waveform over time. The TTI is usually expressed not in absolute terms of pressure per unit of time but, rather, in relative terms as a dimensionless value (i.e., as a percentage of the maximum) to reflect the importance of relative changes in pressure and timing of contraction. The TTI determines muscle energy use as reflected in the O2 consumption. A threshold for the onset of fatigue occurs at a TTI of approximately 15 to 20 percent of maximum (Fig. 148-10). The greater the TTI above this value, the more rapidly fatigue ensues. Subsequent studies in normal subjects demonstrated that mechanical failure of the inspiratory muscles as pressure generators can be accelerated at a given TTI by increasing the Vt /Ti . Increases in Vt /Ti reflect an increase in the velocity of inspiratory muscle shortening. Since the greater the velocity of shortening and the more rapid actomyosin cross-bridge cycling, the greater the rate of adenosine triphosphate splitting, this is not surprising. Also of interest, respiratory maneuvers associated with high levels of ventilation appear to selectively fatigue the diaphragm, whereas maneuvers that produce high levels of pressure primarily fatigue the intercostal and neck muscles. Muscle Blood Flow

Diaphragm fatigue may relate, in part, to a compromise of muscle blood flow during intense contractions. The

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Figure 148-9 Relationship between the intensity of diaphragm contractile activity reflected in the diaphragm tension-time index (TTdi)–-i.e., the product of Pdi/Pdimax × TI /TT and the time of onset of mechanical failure of the diaphragm, Tlim. The two scales are logarithmic. Data obtained in normal subjects during strenuous volitional contractions during inspiratory resistive ventilatory loading. Note that above approximately 15 percent TTdi, Tlim decreases progressively with increasing TTdi. These data indicate that a fatigue threshold exists for the human diaphragm above TTdi 15 to 20 percent and that above this threshold, diaphragm endurance is a unique function of the TTdi. (Based on data from Bellemare F, Grassino A: Evaluation of human diaphragm fatigue. J Appl Physiol 53:1196–1206, 1982, with permission.)

relationship of diaphragm blood flow to muscle contractile activity is complex and depends, like fatigue itself, on both the intensity and timing of contractions. The level and pattern of diaphragm activation, therefore, determine not only muscle energy use but also the availability of metabolic fuel (i.e., glucose, free fatty acids, and other nutrients). Contractions of low intensity increase blood flow. In contrast, contractions in excess of 20 to 30 percent of Pdimax mechanically compromise blood flow and cause postcontraction hyperemia. When the diaphragm contracts rhythmically, the Ti /Tt also affects diaphragm blood flow. At Pdi/Pdimax values that compromise blood flow during contraction (i.e., above 20 to 30 percent), blood flow occurs solely during the phase of muscle relaxation. Consequently, increases in the Ti /Tt ratio decrease overall blood flow by encroaching on relaxation time. Diaphragm blood flow is, therefore, a function of the TTI rather than Pdi/Pdimax or the Ti /Tt alone. Blood flow increases up to a TTI of 20 to 30 percent and thereafter falls progressively with further increases in TTI. Compromise of diaphragm blood flow when TTI is greater than 20 to 30 percent of maximum may lead to a condition in which the metabolic needs of the muscle outstrip the availability of energy supply. Alternatively, the importance of blood flow may lie in washing out toxic metabolites (e.g., hydrogen and

phosphate ions) from the muscle. The diaphragmatic TTI associated with limitation of blood flow is also a complex function of the level of systemic arterial pressure. Reductions in arterial pressure produced in animal models by bleeding decrease blood flow at any given level of TTI and reduce the Pdi value at which blood flow is mechanically impeded. Of considerable importance, diaphragm blood flow may also be a determinant of steady-state diaphragm contractile function in COPD patients in acute respiratory failure. In small numbers of COPD patients, 30 to 50 percent increases in diaphragm blood flow with intravenous dopamine (8 µg/kg/min) caused rapid, approximately 40 percent increases in Pdi during electrophrenic twitch contractions. These findings require confirmation before vasodilator therapy to improve diaphragm function can be advocated. However, they suggest the possibility that diaphragm blood flow may be compromised by intense contractile activity in patients with severe lung disease.

Rapid, Shallow Breathing Patients with abnormalities in ventilatory pump function breathe rapidly and shallowly in respiratory failure. Respiratory rate is increased and tidal volume is decreased.

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Figure 148-10 Effect of increasing Pdi/Pdimax (i.e., the ratio of peak inspiratory Pdi) during resistance breathing over maximum static Pdi (ordinate) at the time of onset of mechanical failure of the diaphragm, Tlim (abscissa). Data from three normal subjects (shown as separate symbols). Note that progressive increases in Pdi/Pdimax are associated with more rapid onset of diaphragm fatigue. Note also the curvilinear nature of the relationship, with apparent asymptote between 40 and 50 percent Pdi/Pdimax , which represents a fatigue threshold. (Based on data from Roussos CS, Macklem PT: Inspiratory muscle fatigue, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 511â&#x20AC;&#x201C;527, with permission.)

Reductions in Ti are out of proportion to reductions in Te , so the duty cycle of breathing (Ti /Tt ) is reduced to less than normal values (below 40 percent). Average inspiratory airflow (Vt / Ti ) tends to be normal, despite abnormalities in mechanics, because of increases in the neuromuscular drive to breathe as reflected in the airway occlusion pressure. Reductions in Ti have the effect of increasing the dead-spaceto-tidal-volume ratio (Vd /Vt ) and predisposing to alveolar hypoventilation. A rapid, shallow pattern of breathing with an abnormally low Ti /Tt ratio and reduced tidal volume is extremely common in patients with COPD during acute exacerbations and tends to get better with improvements in clinical condition. Rapid, shallow breathing appears to cause CO2 retention rather than result from it. It can be produced in patients with COPD by histamine-induced bronchoconstriction and reversed by topical airway anesthesia. Patients with neuromuscular disease in whom the ability to generate inspiratory pressure is impaired require more intense motor outflow to the respiratory muscles to maintain tidal volume. Patients with respiratory muscle weakness also tend to breathe rapidly and shallowly. The pattern of breathing has been quantified in adults receiving ventilatory support for acute respiratory failure from the ratio of respiratory rate (breaths per minute) divided by tidal volume (liters). This useful parameter has been termed the rapid shallow breathing index (RSBI). It has proved to be an extremely powerful way of assessing weanability in

adults with a variety of medical and surgical conditions. The greater the value, the more rapid and shallow is the pattern of breathing. Values for the RSBI exceeding 100 are associated with a high probability of failure to wean from mechanical ventilation. The RSBI lends itself to a more general use in patients with disorders of the ventilatory pump not requiring mechanical ventilation. Rapid, shallow breathing leading to CO2 retention exerts a number of deleterious effects. First, CO2 retention decreases Pao2 and arterial pH. Decreases in Pao2 result in accordance with the alveolar air equation. In general, a 1 mmHg increase in Pco2 causes a 1.25 mmHg reduction in Pao2 (assuming a respiratory quotient of 0.8; larger respiratory quotient values are associated with smaller changes in Pao2 ). Second, renal compensation for hypercapnia-induced respiratory acidosis stimulates bicarbonate resorption. Increases in body fluid bicarbonate restore pH toward normal values but blunt the ventilatory response to further increases in CO2 . Third, hypercapnia depresses diaphragm contractility; that is, Pdi is decreased at a given level of diaphragm electrical activity in proportion to the increase in Pco2 . However, rapid, shallow breathing may also confer beneficial effects to subjects with severe ventilatory pump dysfunction. First, CO2 retention increases the CO2 partial-pressure gradient between the alveolus and atmosphere. Accordingly, during hypercapnia the same volume of metabolically produced CO2 can be excreted at a lower level

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of alveolar and minute ventilation and O2 cost of breathing than during eucapnia. As such, CO2 retention affords a mechanism to diminish the activity level of the inspiratory muscles and their propensity to fatigue. Normal humans and animal models fatigued by inspiratory resistive loads in the laboratory spontaneously minimize the diaphragm TTI after fatigue by adopting a shallow, rapid pattern of breathing. In fact, a large study of stable outpatients with advanced COPD indicates that the inspiratory muscle TTI is below the fatigue threshold even in markedly hypercapnic (above 60 mmHg) subjects (see below). Second, rapid, shallow breathing minimizes the magnitude of dynamic hyperinflation in patients with severe COPD who breathe on the envelope of the maximum expiratory flow-volume loop; that is, reductions in tidal volume and decreases in the Ti /Tt ratio diminish the volume to be exhaled and prolong the expiratory time available to reach FRC. The balance between the beneficial and deleterious effects of CO2 retention is difficult to define with precision; however, the balance probably is determined by the magnitude and rapidity of the changes in Paco2 and pH and their effect on the cardiovascular and central nervous systems. Relatively small (5 to 15 mmHg) changes in Paco2 , produced gradually over days to weeks and leaving pH at levels of 7.25 to 7.30, are likely to be well tolerated and, on balance, beneficial. On the other hand, Paco2 changes that occur rapidly and reduce pH to less than 7.25 are likely to exert net negative effects. In fact, respiratory acidosis to pH values under 7.25 is life-threatening and generally considered an indication for intubation and mechanical ventilation. Cardiac function and sympathetic regulation of peripheral vascular resistance are impaired at this level of pH. Patients become encephalopathic (i.e., somnolent and unable to care for themselves and control their airway secretions). Obviously, hypercapnia of such magnitude is to be avoided. Pathogenesis of Rapid, Shallow Breathing The neurophysiological mechanisms driving the altered pattern of breathing are obscure. Moreover, whether changes in breathing pattern in animal models and humans are reflexively induced or behaviorally mediated, or reflect changes in brain neurotransmitter levels (e.g., endorphins), is unclear. However, chemosensitivity-induced alterations in respiratory activity do not appear to be the explanation. Hypoxia- and hypercapnia-induced reductions in Te are disproportionately greater than reductions in Ti , so the Ti /Tt ratio increases. Moreover, Vt / Ti and the tidal volume increase rather than decrease. Reflexes originating from mechanoreceptors in the contracting rib cage muscles and diaphragm (i.e., Golgi tendon organs, spindle organs, and type III and type IV endings) probably play a role in shaping the rapid, shallow pattern of breathing. In deeply anesthetized animals, stretch of the intercostal muscles or an increase in diaphragm tension may abruptly terminate inspiration. Activation of vagal irritant receptors in the airway may also produce rapid, shallow breath-

ing. In animal models, rapid, shallow breathing produced acutely by inhalation of allergen or inflammatory mediators (e.g., histamine, bradykinin) can be prevented by vagal blockade. These observations suggest that rapid, shallow breathing in bronchoconstriction may be mediated by vagal sensory endings in the airways. Finally, changes in the pattern of breathing may represent a behavioral response to minimize the sense of dyspnea. The sense of dyspnea is a complex perceptual construct that is not fully understood but is probably multifactorial. In fact, an important determinant of the sense of dyspnea is the magnitude of the CNS motor command to the inspiratory muscles as reflected in the peak inspiratory intrathoracic pressure. Studies indicate that the sense of breathlessness increases for any set of respiratory mechanical conditions with increases in peak inspiratory pressure, the duration of inspiration, or respiratory rate. In particular, the magnitude of the sense of dyspnea depends on inspiratory pressure (P) swings as a percent of maximum (P/Pmax ), the duration of inspiration relative to the total breath cycle (Ti /Tt ), and the respiratory rate (freq). However, the relative importance of these three terms is quite different. The peak inspiratory pressure has a far greater effect than the duration of inspiration, which in turn has a greater effect than breathing frequency. The sensation of dyspnea can be expressed quantitatively by each of these parameters raised to a power: Dyspnea = P1.3 × Ti /Tt 1.14 × freq–0.97 Increases in intrathoracic pressure required to maintain airflow and tidal volume in patients with abnormalities in ventilatory pump function increase the sense of dyspnea. Given the greater exponential value for P than for the timing variables, it can be seen that the magnitude of the swing in inspiratory pressure is the predominant determinant of dyspnea. Thus, at a given level of minute ventilation and set of respiratory mechanics, the pattern of breathing determines the intensity of breathlessness. When the mechanics of breathing are deranged by COPD or kyphoscoliosis, diminishing peak inspiratory intrathoracic pressure (i.e., tidal volume) and increasing respiratory rate (i.e., a rapid, shallow pattern of breathing) tend to minimize the sense of breathlessness. At equivalent levels of airway resistance and inspiratory effort, the sense of dyspnea is greater during bronchoconstriction than during external resistive loading, probably because of the activation of vagal irritant receptors. Differences in the intensity of dyspnea at any given level of airway obstruction, therefore, may depend on the site of airway obstruction (i.e., intra- vs. extrathoracic). Also, the sense of dyspnea at a given level of peak intrathoracic pressure, Ti /Tt ratio, and frequency of breathing are increased in the setting of inspiratory muscle fatigue, probably because a greater motor command is required to generate a given level of intrathoracic pressure. Finally, it should be apparent from the above equation that the sense of dyspnea depends on the same variables that determine respiratory muscle fatigability. However, respiratory muscle fatigue, in contrast to dyspnea, does not

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Figure 148-11 Severity of dyspnea experienced during breathing against external resistive ventilatory loads in normal subjects, patients with asthma but no near-fatal attacks, and patients with near-fatal asthma. Y axis indicates the intensity of dyspnea (i.e., Borg score). Increasing numerical values on the Borg score indicate increasing dyspnea. Note that at any given level of external resistance, dyspnea was significantly less in patients with near-fatal asthma than in the normal group. (Based on data from Kikuchi Y, Okabe S, Tamura G, et al: Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 330:1229–1234, 1994, with permission.)

appear to depend on the pattern in which TTI is developed; that is, whether a given TTI is arrived at by a higher P/Pmax or a higher Ti /Tt is irrelevant in the development of fatigue, but it is important in the generation of respiratory sensations. Perceptual acuity of the respiratory sensations elicited when the mechanical properties of the ventilatory pump are deranged is a major determinant of the pattern of breathing and tendency to develop CO2 retention in subjects with COPD. For example, when airway resistance is increased experimentally, patients with COPD who retain CO2 are those with the greatest perceptual acuity for changes in intrathoracic pressure. That is, spontaneous tidal volume and Ti are smallest in patients with COPD who have the highest perceptual acuity for changes in intrathoracic pressure. On the other hand, when airway resistance was increased experimentally by external resistive loads, asthmatics with near-fatal attacks experienced less dyspnea at any level of resistance than normal subjects (Fig. 148-11). Accordingly, in patients with COPD the acuity of respiratory perception plays an important role in the pathogenesis of respiratory failure. The mechanism by which respiratory perception contributes to respiratory failure awaits clarification.

Undernutrition Undernutrition, defined as a body weight less than 90 percent of the ideal, is extremely common in patients with COPD, occurring in about 25 percent of stable outpatients and about 40 percent of hospitalized patients. Undernutrition is an independent risk factor for mortality. For a given level of lung function, undernourished patients with COPD have a greater

5-year mortality than normally nourished subjects. The respiratory muscles, like skeletal muscles in other parts of the body, atrophy under conditions of chronic protein-calorie deficiency. In patients without lung disease, Pimax is significantly smaller in those who are undernourished than in those who are well-nourished. In those with COPD at autopsy, the mass (i.e., weight and thickness) of the diaphragm is diminished in undernourished compared to well-nourished subjects. Both slow and fast fibers in respiratory muscles (e.g., the diaphragm and intercostals) atrophy in subjects with advanced COPD. In patients with COPD, resting Paco2 is inversely related to Pimax . The weaker the subject, the greater the Paco2 . Reductions in Pimax predispose to inspiratory muscle fatigue by increasing the Pdi/Pdimax ratio and, hence, the TTI during breathing against a given set of lung mechanics. Of practical importance, aggressive nutritional repletion, which increases body weight, augments Pimax and Pdimax . Thus, respiratory muscle wasting and atrophy are reversible in undernourished patients with COPD. The pathogenesis of body wasting in subjects with chronic diseases like COPD is unclear. However, increases in the work of breathing and respiratory muscle activity increase resting energy expenditure by as much as 50 to 100 percent above normal. In normal subjects in whom basal energy requirements are similarly increased by heavy physical labor (e.g., lumberjacks), caloric intake is increased appropriately to meet metabolic demands and body weight is preserved. Accordingly, the root of the problem in undernourished patients with COPD may be “relative anorexia,” so that increases in basal caloric requirements are not accompanied by adequate caloric intake. Undernourished patients with COPD have higher blood levels of the cachexia factor tumor necrosis factor-α than well-nourished COPD subjects.

SPECIFIC DISEASES Chronic Obstructive Pulmonary Disease Patients with advanced COPD develop CO2 retention because of abnormalities in the gas exchange and mechanical properties of the lung. The relationship between the severity of COPD as reflected by the forced expiratory volume in 1 s (FEV1 ) and steady-state resting Pco2 is curvilinear (Fig. 148-12). In general, Paco2 does not increase above normal until the FEV1 decreases to about 20 to 25 percent of predicted normal values. The effects of COPD on lung gas exchange are complex. Simply put, increases in lung dead space and abnormalities in ventilation/perfusion relationships impair CO2 elimination and O2 uptake. Increases in physiological dead space require greater than normal levels of ventilation and tidal volume to maintain eucapnia. Maintenance of “normal tidal volume” in the setting of increased dead space predisposes to CO2 retention because of an unfavorable Vd /Vt . Normally, during resting breathing, ventilation is 4 to 5 L/min, of which alveolar ventilation is approximately 70 to 80 percent.

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Figure 148-12 Relationship between the severity of airway obstruction reflected in the FEV1 and steady-state arterial PCO 2 in COPD and asthma. Shaded area represents normal range of arterial PCO 2 . The relationship is curvilinear, so CO2 retention occurs only after FEV1 is considerably reduced. The asthmatic curve (dashed line) lies below and to the left of the curve for COPD, indicating that much greater levels of obstruction are necessary before arterial PCO 2 rises. (From Fishman AP: Pulmonary Diseases and Disorders. New York, McGraw-Hill, 1980, vol 1, p 426, with permission.)

In COPD, abnormalities in lung gas exchange for O2 and CO2 (i.e., increased dead-space volume and alveolar-arterial O2 gradient) require greater than normal levels of ventilation to maintain eucapnia and euoxia. Consequently, in subjects with advanced COPD, minute ventilation is typically two to three times the normal value (i.e., 10 to 15 L/min). Minute ventilation is increased still further in hypoxemia. Increases in ventilation require increases in airflow, tidal volume, and the duty cycle of breathing. Hyperinflation and heightened airway resistance are common in patients with advanced COPD. Hyperinflation and increases in FRC in patients with COPD are multifactorial. First, emphysema decreases lung (and possibly chest wall) elastic recoil pressure. Second, tonic activation of chest wall inspiratory muscles throughout the respiratory cycle enhances transpulmonary pressure. Third, activation of laryngeal constrictor muscles and pursed-lip breathing during expiration slow the rate of expiratory airflow. Fourth, severely obstructed patients breathing on the envelope of the maximum expiratory flow-volume curve may have insufficient time during expiration to exhale to passively determined FRC. In advanced COPD, increases in airway resistance and hyperinflation require greater than normal swings in intrathoracic pressure to generate normal levels of airflow and tidal volume. In consequence, the respiratory neuromuscular drive to breathe, peak inspiratory intrathoracic pressure, and the TTI of the inspiratory muscles are increased considerably. Normally, at rest, respiratory muscle O2 consumption is less than 2 percent of total body O2 consumption (i.e., about 5 ml/min or less). In contrast, patients with advanced cardiopulmonary disease may have levels of respiratory muscle O2 uptake greater than 50 percent of total body O2 uptake (i.e., in excess of 125 ml/min).

Figure 148-13 Inspiratory muscle strength as reflected in the maximum static inspiratory pressure (PImax ) at functional residual capacity (FRC) in subjects with advanced COPD and agematched normal subjects. Each symbol represents a single subject. Note that in COPD subjects, because of hyperinflation and muscle wasting, PImax is reduced to approximately 40 percent of the value in normal subjects. Note the tendency for hypercapnic subjects to have even lower values of PImax than eucapnic COPD subjects. (Based on data from Sharp JT, van Lith P, Nuchprayoon C, et al: The thorax in chronic obstructive lung disease. Am J Med 44:39â&#x20AC;&#x201C; 46, 1968, with permission.)

In subjects with severe COPD, hyperinflation reduces inspiratory muscle mechanical advantage, which decreases the capacity of the inspiratory muscles to generate pressure (Pmax ). Pmax values in patients with COPD may be as low as one-third to one-half that of age-matched normal subjects (Fig. 148-13). Moreover, aging- and malnutrition-associated changes in the diaphragm may further impair Pdimax in subjects with COPD. COPD typically becomes disabling in the sixth and seventh decades of life, a period of life at which Pdi normally falls. For example, Pdimax is about 25 percent less in healthy men over 65 years of age than in healthy men under 35 years of age. Respiratory Muscle Fatigue in COPD Severe COPD is arguably the clinical condition most likely to cause inspiratory muscle fatigue. The combined effects of increases in inspiratory muscle activity and decreases in

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Figure 148-14 Diaphragmatic tension-time index (TTdi) in 20 stable outpatients with COPD breathing room air at rest. Each symbol represents a separate COPD subject. Shaded area represents the fatigue threshold in normal subjects. Most COPD subjects breathe well below the fatigue threshold and cluster around 0.05 TTdi. (Based on data from Bellemare F, BiglandRitchie B: Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation. J Appl Physiol 62:1307â&#x20AC;&#x201C;1316, 1987, with permission.)

muscle strength in severe COPD increase the diaphragm TTI during resting breathing in elderly COPD patients considerably above the normal value of 1 to 2 percent. The TTI may, in fact, approach the fatigue threshold (i.e., 15 to 20 percent) in patients with COPD (Fig. 148-14). These and similar data indicate that diaphragm activity is increased in patients with advanced COPD, and that the diaphragm is highly susceptible to fatigue when breathing is increased above spontaneous levels by minor increases in tidal volume or Ti /Tt . The diaphragm TTI is higher in hypercapnic than in eucapnic COPD subjects, but even in hypercapnic subjects it does not exceed the fatigue threshold. Mean TTI, even for hypercapnic subjects, is approximately 10 percent. Therefore, hypercapnia per se does not indicate the presence of diaphragm fatigue even in patients with severe COPD. Rather, hypercapnia may be a manifestation of a breathing strategy (i.e., rapid, shallow breathing) that minimizes inspiratory muscle activity and, hence, prevents fatigue. On the other hand, inspiratory muscle fatigue may be a relatively common occurrence during the hyperpnea of exercise and could contribute to exercise limitation in COPD subjects. A high percentage (about 50 percent) of subjects with moderate to severe COPD demonstrate EMG evidence of scalene or diaphragm (or both) fatigue during exercise. Of interest, improvement in exercise performance and elimination of the EMG signs of fatigue can be achieved following inspiratory resistance training.

Subjects with COPD in acute respiratory failure requiring mechanical ventilation are more likely to show evidence of inspiratory muscle fatigue. During weaning from mechanical ventilation, diaphragm EMG changes indicative of fatigue precede the increases in Paco2 . These findings suggest that diaphragm fatigue contributes to ventilator dependence after the onset of hypercapnic respiratory failure in at least some critically ill subjects. In COPD patients being weaned from mechanical ventilation during a bout of acute respiratory failure, the tracheal occlusion pressure is usually greater than 6 cm H2 O and EMG evidence of diaphragm fatigue is present during spontaneous breathing. Patients with persistently elevated tracheal occlusion pressure values (above 6 cm H2 O) and EMG evidence of diaphragm fatigue generally cannot be successfully weaned from mechanical ventilation. In contrast, sternomastoid muscle fatigue is evident in fewer than 10 percent of COPD patients hospitalized for worsening respiratory distress. In summary, most subjects with stable COPD adopt a pattern of breathing that minimizes the diaphragm TTI and prevents inspiratory muscle fatigue. Behavioral mechanisms may be operative in an attempt to minimize the sensation of dyspnea. On the other hand, inspiratory muscle fatigue contributes to the morbidity of a subgroup of patients with COPD by preventing weaning from mechanical ventilation, and possibly by impairing exercise performance. The reported number of COPD subjects with respiratory muscle fatigue is small, however, and may represent a highly select population. Further studies are needed to define the extent of this problem.

Asthma The pathophysiology of CO2 retention appears to be generally similar in patients with asthma and COPD, but the likelihood of developing CO2 retention is less in asthma than in COPD. That is, the level of expiratory airway obstruction required to produce CO2 retention in subjects with acute asthma is greater than that required in subjects with COPD (Fig. 148-14). Several possibilities may explain this tendency. First, it appears that inspiratory drive is higher in patients with asthma than in those with COPD. The airway occlusion pressure is considerably higher at any given level of Paco2 in patients with asthma than in normal subjects or patients with COPD. The heightened inspiratory drive in patients with asthma may in part arise from irritant receptors within the airway, which have an augmenting effect on inspiratory motor neuron activity. Furthermore, the inspiratory muscles are stronger, and ventilatory responses to CO2 and hypoxia are greater, in the younger asthmatic than in COPD subjects. These differences are not simply due to age, as the endurance of the inspiratory and expiratory muscles is greater in asthmatic than in age-matched normal subjects. The increased respiratory muscle endurance in subjects with asthma may be a response to chronic increases in inspiratory muscle load. Finally, greater lung elastic recoil in asthma than in COPD tends to preserve maximal expiratory airflow.

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Neuromuscular Disease Subjects with neuromuscular disease and weak inspiratory muscles tend to breathe rapidly and shallowly. Despite this breathing pattern, these subjects tend to have hypocapnia at rest, and hyperventilate at any given level of CO2 during progressive hypercapnia. Increases in ventilation are associated with increases in airway occlusion pressure. Heightened occlusion pressure in the setting of weak inspiratory muscles suggests that the drive to the inspiratory muscles early in inspiration is greater than normal. The pathogenesis of hypercapnic respiratory failure is very different in patients with neuromuscular disease than in patients with COPD. Patients with neuromuscular disease demonstrate an impaired ability to sigh (i.e., a greater than twofold increase in the tidal volume) because of inspiratory muscle weakness. Inability to sigh decreases lung compliance by interfering with the redistribution of surfactant within the alveolar space. Progressive stiffening of the lung leads to microatelectasis and ultimately lobar atelectasis. Breathing high concentrations of O2 accelerates this process. In addition, expiratory muscle weakness impairs the cough mechanism and causes retention of secretions. The best indicators of a tendency to develop CO2 retention in patients with neuromuscular disease are reductions in inspiratory muscle strength (Pimax ) and forced vital capacity (FVC). Reductions in Pimax and FVC to less than 30 and 25 percent of predicted, respectively, are associated with CO2 retention. Suffice it to say, hypercapnia is a late manifestation of neuromuscular disease and requires marked impairment in inspiratory and expiratory muscle function. With diaphragm dysfunction, hypercapnia may occur during sleep (especially REM sleep) even when the subject is eucapnic while awake.

Obesity Obesity imposes a stress on the respiratory system both by altering lung mechanics and the work of breathing (see Chapter 92). The mass loads applied to the thorax and abdomen by excess fatty tissue decrease chest wall compliance and endexpiratory lung volume resulting in increases in the elastic and resistive work of breathing. Furthermore, by diminishing airway caliber, obesity predisposes to premature airway closure and even atelectasis. The resultant low ventilation-perfusion ratios of these lung regions increase alveolar-arterial O2 gradient and cause arterial hypoxemia. In fact, hypoxemia is the most common respiratory abnormality in the morbidly obese. In addition, the excessive body mass results in increased CO2 production and O2 consumption. Increases in metabolism may be two to three times normal in morbidly obese subjects. These metabolic changes require significant increases in minute and alveolar ventilation in order to maintain eucapnia and hence, increasing ventilatory demands. For example, a doubling in CO2 production requires a doubling in alveolar ventilation to maintain eucapnia. Finally, arterial hypoxemia, which is common, induces a further increase in ventilation.

Given these stresses, the maintenance of normal blood gas tensions requires a considerable increase in respiratory motor output and the work of breathing. Increased work of breathing appears to explain the common occurrence of dyspnea in the morbidly obese person. Not all morbidly obese subjects develop hypercapnic respiratory failure, however. Although body weight alone does not predict the development of hypercapnia, approximately 30 percent of severely obese subjects with a body mass index (BMI) of more than 35 kg/m2 and almost 50 percent with a BMI of 50 kg/m2 or greater have unexplained daytime hypercapnia. Observations of eucapnic and hypercapnic obese subjects demonstrate that eucapnic subjects have greater increases in diaphragm electrical activity with increases in CO2 than hypercapnic subjects. Obese subjects with hypercapnic respiratory failure may have impaired chemosensitivity to hypercapnia and hypoxemia. A subset of obese subjects with hypercapnia also have daytime hypersomnolence, polycythemia, pulmonary hypertension, and cor pulmonale. This constellation of signs and symptoms has been termed the obesity hypoventilation syndrome (see Chapter 92.) Of interest, leptin may be involved in the pathogenesis of hypercapnic respiratory failure in obese individuals. Leptin stimulates ventilation and a deficiency of leptin has been associated with hypoventilation. Clearly excessive body weight is the primary pathogenetic factor, since weight reduction into the normal range, however difficult this may be to accomplish, corrects the problem.

Kyphoscoliosis Kyphoscoliosis decreases chest wall and lung compliance, presumably as a result of atelectasis and deformation of the lungs (see Chapter 92). The elastic work of breathing is markedly increased. In addition, the mechanical action of the respiratory muscles may be impaired by changes in configuration of the bony structures on which the respiratory muscles insert. Ventilation-perfusion mismatch and increase in the alveolararterial O2 gradient are common. As expected in patients with diminished respiratory compliance, subjects with kyphoscoliosis breathe rapidly and shallowly. The tendency to develop CO2 retention is a function of the severity of the restrictive process in kyphoscoliosis, as reflected in the Cobb angles, and is predicted separately for the magnitude of scoliosis and kyphosis. Hypercapnic respiratory failure tends to develop late in life, even if the severity of the spinal deformity has not changed since childhood; that is, stability of the Cobb angles of kyphosis and scoliosis does not preclude development of hypercapnic respiratory failure. It is not clear why respiratory failure ensues late in life. However, several possibilities exist. Aging adversely affects compliance of the chest wall, leading to an increase in the elastic work of breathing. In addition, aging diminishes respiratory muscle strength. Finally, chemosensitivity to O2 and CO2 declines with advancing age, and it seems likely that the subjectâ&#x20AC;&#x2122;s ability to compensate

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for derangements in blood gas tensions is progressively impaired.

ASSESSMENT OF PATIENTS WITH ABNORMALITIES OF THE VENTILATORY PUMP Symptoms Dyspnea appears to be an early manifestation of respiratory muscle impairment in neuromuscular disease and typically occurs before the development of CO2 retention. Breathlessness in the supine position is characteristic of isolated diaphragm dysfunction. In the supine position, the increased hydrostatic pressure imposed by the abdominal viscera represents an increased inertial load on the diaphragm.

Physical Findings Physical signs of ventilatory pump dysfunction revolve around evidence of accessory respiratory muscle recruitment, abnormal thoracoabdominal movement, and rapid, shallow breathing. Use of Accessory Muscles Inspection and palpation demonstrate accessory respiratory muscle use. Intense respiratory efforts are associated with visible activation of the neck accessory muscles, interosseous intercostals, and abdominal expiratory muscles and flaring of the alae nasae. Abnormal Thoracoabdominal Movement Normally, in the supine position, the anterior abdominal wall displays a prominent outward movement during inspiration. With impaired diaphragm function, as occurs in diaphragm weakness or fatigue, the abdominal wall may move inward on inspiration. This is called abdominal paradox. Abdominal paradox reflects cephalad movement of the contracting diaphragm in response to the negative intrathoracic pressure generated by the inspiratory action of the neck and intercostal muscles. Abdominal paradox may also be present in patients with marked derangements in lung mechanics, in whom inspiratory intrathoracic pressure swings exceed 30 percent of maximum. Abdominal paradox, therefore, is not specific for diaphragm weakness or fatigue. Abdominal paradox, resulting from ineffectual contractions of the diaphragm, should be distinguished from pseudo-abdominal paradox, resulting from strong contractions of the expiratory muscles during expiration, with rapid relaxation during early inspiration. For example, intense contraction of the transverse abdominis muscles causes inward movement of the lateral abdominal wall and outward movement of the anterior abdominal wall during expiration. Subsequent relaxation of the abdominal muscles with the onset of inspiration causes outward movement of the lateral

abdominal wall and inward movement of the anterior abdominal wall. Tenseness of the lateral abdominal wall during expiration easily distinguishes pseudo- from true abdominal paradox.

Maximum Static Inspiratory Pressure Perhaps the most practical method of assessing the function of the inspiratory muscles contracting in aggregate is from the pressure generated during maximal volitional contractions against an occluded airway at FRC. This parameter is discussed in greater detail in Chapter 93. In brief, however, reductions in Pimax indicate inspiratory muscle weakness or high-frequency fatigue. Improvements in Pimax occurring over several hours to several days in a patient with COPD suggest that lung volume is improving toward normal and that the mechanical disadvantage imposed on the inspiratory muscles is disappearing. More rapid improvements (occurring over hours) may indicate resolution of high-frequency fatigue or elimination of the metabolic disturbances (e.g., hypercapnia or hypophosphatemia) that depress inspiratory muscle function. Of note, Pimax is not affected by low-frequency fatigue. Pimax depends on patient cooperation and motivation. With training, however, patients can provide reproducible values. Performance of the maneuver at FRC, where respiratory system recoil is zero, is preferred; that is, at FRC, changes in airway pressure during inspiratory efforts equal the pressure generated by the inspiratory muscles (Pmus ). Maximum static expiratory pressure at FRC (Pemax ) has been used in the laboratory setting to assess the endurance properties of the expiratory muscles. The Pemax has not been used extensively in the clinical setting, however, because of the perception that it is more difficult to obtain consistent values than Pimax with breathless subjects.

TREATMENT Abnormalities in respiratory mechanics and gas exchange are the most important pathogenetic factors in the development of respiratory failure. Accordingly, therapy should be directed toward achieving maximum improvement in airway, lung, and respiratory muscle function. For example, in patients with COPD or asthma, an intensive regimen of bronchodilators (e.g., β2 -adrenergic agonists, anticholinergics, and theophylline) and anti-inflammatory therapy (e.g., corticosteroids) can correct respiratory failure by diminishing airway resistance, FRC, lung dead-space volume, the alveolar-arterial O2 partial-pressure gradient, and the work of breathing. Improvements in lung function in certain patients with advanced COPD and emphysema may also be accomplished by lung-volume reduction surgery (volumereduction pneumectomy) or lung transplantation. Lungvolume reduction surgery removes 20 to 30 percent of the most emphysematous regions of lung and appears to improve

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FRC, FEV1 , ventilatory capacity, inspiratory muscle function, and elastic recoil pressure of the lung. In patients with myasthenia gravis, cholinesterase inhibitors can improve inspiratory muscle strength and vital capacity and reverse atelectasis, which causes hypercapnia. Additionally, noninvasive positive-pressure ventilation (NIPPV) has become one of the most important modalities for treating hypercapnic respiratory failure (see below).

Abnormalities in Chemosensitivity Respiratory failure caused by impaired chemosensitivity is difficult to treat, since drug treatments to improve chemosensitivity to hypoxia or hypercapnia are not very effective. Since it was observed that women exhibit alveolar hypoventilation during pregnancy and the luteal phase of the menstrual cycle, progestational agents have been used for many years to treat idiopathic hypoventilation syndromes. In some subjects, medroxyprogesterone acetate, given orally in a dose of 20 mg three times a day, acts centrally to augment the ventilatory responses to hypercapnia and hypoxemia and can improve resting arterial blood gas tensions. Medroxyprogesterone is generally well tolerated in women but may produce feminizing side effects in men. The onset of action of the drug is slow. Several weeks may be required before a response is observed. Theophylline, in doses that produce blood levels in the therapeutic range (10 to 15 Âľg/ml), also has weak respiratory stimulatory effects, which may contribute to a reduction in Paco2 in patients with COPD. Theophylline also produces modest improvements (about 10 to 20 percent) in diaphragm contractile function in this population. Finally, in some patients with hypercapnia, elimination of medications having CNS respiratory depressant effects (e.g., opiate analgesics, benzodiazepine anxiolytics) can lead to improvements in Paco2 . Hypoxemia leading to pulmonary artery hypertension and cor pulmonale may be the most serious complication of chronic hypercapnic respiratory failure. Supplemental O2 is usually indicated in patients with chronic hypercapnic respiratory failure. Supplemental O2 may produce exaggerated increases in Paco2 in patients with disorders of ventilatory control in whom the ventilatory response to CO2 is blunted but the O2 response is preserved. Accordingly, blood gas tensions should be monitored closely when O2 is applied initially. During sleep, patients with disorders of the control of breathing typically display exaggerated increases in Paco2 (e.g., 15 to greater than 30 mmHg) with hypoxemia and severe respiratory acidosis. In these subjects, mechanically assisted ventilation (typically with nasal positive-pressure ventilation), with or without O2 , may be required during the sleeping period. Nasal positive-pressure ventilation is an effective way of improving blood gas tensions during sleep. In fact, improvements in blood gas tensions achieved by nocturnal mechanical ventilation may carry over to the waking period in these patients, perhaps by preventing nocturnal increases in serum bicarbonate or hypoxic depression of CNS function.

Table 148-2 Principles of Therapy for Respiratory Muscle Fatigue Decrease inspiratory swings in transdiaphragmatic pressure (Pdi) Improve the mechanics of breathing (i.e., decrease airway resistance, improve thoracic compliance and static lung volume) Decrease ventilatory drive (i.e., relieve hypoxemia, hypercapnia, metabolic acidosis, fever, pulmonary congestion/inflammation, acute respiratory distress syndrome Increase Pdimax Correct hyperinflation Correct muscle atrophy induced by protein-calorie deficiency Correct electrolyte and blood gas abnormalities (i.e., hypoxemia, hypercapnia, hypophosphatemia, hypokalemia, hypocalcemia, hypomagnesemia) Optimize muscle blood flow and substrate availability Correct low cardiac output state (e.g., cardiogenic shock, hypovolemic shock). Correct hypoxemia, anemia, hypoglycemia

Respiratory Muscle Weakness or Fatigue The treatment of respiratory muscle weakness depends on pathogenic mechanisms. For example, inspiratory muscle weakness related to the hyperinflation of COPD is best treated by aggressive improvement of airway function. On the other hand, decreases in muscle strength caused by electrolyte abnormalities (e.g., hypophosphatemia) or proteincalorie malnutrition are best dealt with by repletion of the deficits. The treatment of respiratory muscle fatigue has not been systematically studied. However, several approaches based on theoretical considerations appear to be applicable (Table 148-2). It is clear that diaphragm fatigue is a result of muscle overactivity (i.e., a TTI greater than 20 percent). Accordingly, attempts should be made to decrease the TTI of the inspiratory muscles to values below the fatigue threshold by improving lung mechanics or reducing ventilatory drive. In patients with abnormalities in airway resistance and hyperinflation secondary to severe COPD, this can best be accomplished with bronchodilators and corticosteroids. Reductions in ventilatory drive in hypoxic or febrile patients can be accomplished by administration of O2 or antipyretics. Unloading the inspiratory muscles by reducing the TTI may be sufficient to prevent or reverse fatigue and allow the muscle to recover. In some cases, however, respiratory muscle fatigue may be sufficiently advanced so that the muscle must

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Pump Failure: The Pathogenesis of Hypercapnic Respiratory Failure in Patients with Lung and Chest Wall Disease

be placed at complete rest. Mechanical ventilation and ventilatory muscle rest are certainly indicated when the pH is less than 7.25 or the patient appears unable to maintain ventilation and stable blood gas tensions. The precise duration of mechanical ventilation to rest the inspiratory muscles in patients with respiratory muscle fatigue is unclear. However, no attempts at weaning should be made until the conditions that initiated fatigue are reversed. Since low-frequency fatigue persists for 24 h or more, it may not be advisable to wean patients with respiratory muscle fatigue from mechanical ventilation for at least 24 h, even if the factors that caused fatigue have been corrected.

Chronic Ventilatory Support/Nasal Positive-Pressure Ventilation Mechanically assisted ventilation, especially at night, may be helpful in reducing arterial Pco2 and increasing Po2 in the chronically hypercapnic subject. Nasal positive-pressure ventilation (NPPV) affords an effective, practical approach to treat selected subjects with chronic hypercapnia secondary to either impaired chemosensitivity or abnormalities in respiratory mechanics. In particular, selected subjects with the obesity hypoventilation syndrome, kyphoscoliosis, or neuromuscular disease have been successfully maintained on NPPV for prolonged periods. NPPV is particularly effective in hypercapnic respiratory failure. NPPV obviates the need for airway intubation, provides considerable patient comfort, and is easy to use. Many different types of masks exist. The most commonly used are oral or oronasal masks with a soft rubber seal. An oronasal mask may be more comfortable for mouth breathing patients. By setting the magnitude of the inspiratory positive airway (IPAP) and expiratory pressures (EPAP), tidal volume is determined. Small, portable, simple-to-operate bilevel ventilators (BiPAP) that deliver phasic pressure changes are available. Many bilevel machines allow manipulation of the pressure rise time during inhalation so that exhalation time and patient comfort can be maximized. No ideal pressure settings effective for all patients exist. Settings should be adjusted to maximize patient comfort and ventilation. The effectiveness of a given setting can be assessed by observing the degree of chest expansion and measuring the Paco2 . Disadvantages of NPPV include aerophagia and air leaks secondary to poorly fitting masks. The use of NPPV during acute hypercapnic respiratory failure secondary to COPD has been demonstrated repeatedly to reduce mortality, reduce the need for airway intubation, and rapidly improve respiratory rate, Paco2 , and pH. Recently NPPV has been successfully used over a prolonged period for the treatment of the obesity hypoventilation syndrome. In morbidly obese patients (mean BMI 44 kg/m2 ), NPPV decreased the Paco2 by an average of 17 mmHg and increased the Pao2 by 24 mmHg after an average of 50 months. NPPV is also used in neuromuscular disease, particularly for nocturnal hypoventilation or progressive hypercapnic respiratory failure (see Chapters 93 and 94). NPPV

prolongs and improves the quality of life in amyotrophic lateral sclerosis. Its use in this disorder is discussed in detail in Chapter 94. Unfortunately, the majority of the neuromuscular disorders are progressive and many patients develop bulbar symptoms and thus have difficulty controlling their secretions.

SUGGESTED READING Altose MD, McCauley WC, Kelsen SG, et al: Effects of hypercapnia and inspiratory flow-resistive loading on respiratory activity in chronic airways obstruction. J Clin Invest 59:500–507, 1977. Bark H, Supinski G, Kelsen SG: Relationship of changes in diaphragmatic muscle blood flow to muscle contractile activity. J Appl Physiol 62:291–299, 1987. Bellemare F, Grassino A: Evaluation of human diaphragm fatigue. J Appl Physiol 53:1196–1206, 1982. Cherniack NS, Altose, MD: Respiratory responses to ventilatory loading, in Hornbein TF (ed), Lung Biology in Health and Disease, vol 17: Regulation of Breathing, part II. New York, Dekker, 1981, pp 905–987. Coleridge HM, Coleridge JCG: Reflexes evoked from tracheobronchial tree and lungs, in Cherniack NS, Widdicombe JG (eds), Handbook of Physiology, section 3: The Respiratory System, vol II: Control of Breathing, part 1. Bethesda, MD, American Physiological Society, 1986, pp 395– 429. Cunningham DJC, Robbins PA, Wolff CB: Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH, in Cherniack NS, Widdicombe JG (eds), Handbook of Physiology, section 3: The Respiratory System, vol II: Control of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 475–528. De Troyer A, Loring SH: Action of the respiratory muscles, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 443–461. Grassino AE, Goldman MD: Respiratory muscle coordination, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 463–509. Hussain SNA, Roussos C, Magder S: Effects of tension, duty cycle, and arterial pressure on diaphragmatic blood flow in dogs. J Appl Physiol 66:968–976, 1989. Irsigler GB: Carbon dioxide response lines in young adults: The limits of the normal response. Am Rev Respir Dis 114:529–536, 1976. Kelsen SG, Cherniack NS, Jammes Y: Control of motor activity to the respiratory muscles, in Roussos C, Macklem PT (eds), The Thorax, Part A: Physiology. New York, Dekker, 1985, pp 493–529.

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Kikuchi Y, Okabe S, Tamura G, et al: Chemosensitivity and perception of dyspnea in patients with a history of nearfatal asthma. N Engl J Med 330:1229–1234, 1994. Killian KJ, Summers E, Basalygo M, et al: Effect of frequency on perceived magnitude of added loads to breathing. J Appl Physiol 58:1616–1621, 1985. Manning HL, Schwartzstein RM: Pathophysiology of dyspnea. N Engl J Med 333:1547–1553, 1995. Mehta S, Hill N: Noninvsive ventilation. Am J Resp Crit Care Med 163:540–577, 2001. Milic-Emili J, Whitelaw WA, Grassino AE: Measurement and testing of respiratory drive, in Hornbein TF (ed), Lung Biology in Health and Disease, vol 17: Regulation of Breathing, part II. New York, Dekker, 1981, pp 675–743. Moxham J, Edwards RHT, Aubier M, et al: Changes in EMG power spectrum (high-to-low ratio) with force fatigue in humans. J Appl Physiol 53:1094–1099, 1982. Oliven A, Supinski GS, Kelsen SG: Functional adaptation of diaphragm to chronic hyperinflation in emphysematous hamsters. J Appl Physiol 60:225–231, 1986. Olsen AL, Zwillich C: The obesity hypoventilation syndrome. Am J Med 118:948–956, 2005.

Perrin C, Unterborn JN, D’Ambrosio C, et al: Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 29:5–27, 2004. Rebuck AS, Slutsky AS: Measurement of ventilatory response to hypercapnia and hypoxia, in Hornbein TF (ed), Lung Biology in Health and Disease, vol 17: Regulation of Breathing, part II. New York, Dekker, 1981, pp 745– 904. Roussos CS, Macklem PT: Inspiratory muscle fatigue, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 511–527. Shannon R: Reflexes from respiratory muscle and costovertebral joints, in Cherniack NS, Widdicombe JG (eds), Handbook of Physiology, section 3: The Respiratory System, vol II: Control of Breathing, part 1. Bethesda, MD, American Physiological Society, 1986, pp 431–447. Tolep K, Higgins N, Muza S, et al: Comparison of diaphragm strength between healthy adult elderly and young men. Am J Respir Crit Care Med 152:677–682, 1995.


Management and Therapeutic Interventions


Oxygen Therapy and Pulmonary Oxygen Toxicity Michael F. Beers

I. TISSUE OXYGENATION Oxygen Delivery and Utilization Mechanisms of Hypoxia II. RECOGNITION AND ASSESSMENT OF TISSUE HYPOXIA Clinical Manifestations Laboratory and Other Objective Assessments III. INDICATIONS FOR OXYGEN THERAPY Sh ort-Term Oxygen Therapy Long-Term Oxygen Therapy IV. TECHNIQUES OF OXYGEN ADMINISTRATION Oxygen Delivery Systems in the Acute Setting Long-Term Oxygen Delivery Systems

Mechanisms of Pulmonary Cellular Toxicity Cellular Antioxidant Defenses VI. PATHOPHYSIOLOGY OF OXYGEN TOXICITY Primary Morphologic and Cellular Changes Secondary Changes VII. CLINICAL SYNDROMES OF OXYGEN TOXICITY Acute Toxicity: Tracheobronchitis and Acute Respiratory Distress Syndrome (ARDS) Chronic Pulmonary Syndromes Potentiation of Oxygen Toxicity Prevention and Therapy VIII. SUMMARY

V. PULMONARY OXYGEN TOXICITY Molecular and Cellular Mechanisms of Oxygen Toxicity

Following Joseph Priestley’s discovery of molecular oxygen and Lavoisier’s subsequent demonstration of respiratory gas exchange, use of inhaled oxygen in treatment of a variety of clinical disorders accelerated rapidly during the late eighteenth century. However, a backlash of criticism developed as studies demonstrated that, under ambient conditions, the

oxygen-carrying capacity of arterial blood was nearly maximal, and that further increases in the fraction of inspired O2 produced no appreciable additional physiological benefit. Furthermore, in 1899, Lorrain-Smith confirmed the early suspicions of Priestley, Lavoisier, and others regarding the potential toxicity of inhaled oxygen, describing the pulmonary

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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pathological alterations associated with excessive oxygen exposure. As a result of these observations, by the start of the twentieth century, use of oxygen as a therapeutic modality fell into disrepute. However, in the early 1920s supplemental oxygen breathing was rigorously reevaluated. Through pioneering efforts by Meakins, Baruch, and others, the concept of a therapeutic window for oxygen inhalation was established. Many investigators independently demonstrated that a reduction in oxygen availability had serious physiological consequences, and that in pathological states, the detrimental consequences of hypoxia could often be circumvented by administration of oxygen. Thus, use of inhaled oxygen again became mainstream therapy, but as adjuvant treatment for cardiac and pulmonary diseases specifically accompanied by hypoxemia and hypoxia. Over the past 80 years, with the advent of improved oxygen delivery systems, mechanical ventilation, the modern intensive care unit, and long-term home oxygen administration, oxygen has become widely available and frequently prescribed. Nevertheless, despite a large clinical experience, many persistent uncertainties inhibit rational use of supplemental oxygen. As with any drug, indications for, and contraindications to, its use exist. Consensus conferences and numerous studies have resulted in establishment of guidelines defining clinical criteria for proper use of supplemental oxygen. Unfortunately, in current practice, oxygen therapy is often prescribed without careful evaluation of its potential benefits and side effects and without adequate supervision. In a retrospective study of 90 consecutive hospitalized patients, oxygen therapy was prescribed inappropriately in 21 percent; monitoring was inadequate in 85 percent; and documentation of physiological criteria for termination of therapy was lacking in 88 percent of all patients. Prospective collected data have also indicated that less than 50 percent of hospitalized patients receiving supplemental oxygen do so at the prescribed dosage and flow. This chapter provides the basis for the rational use of inhaled oxygen therapy. A review of the physiology of tissue oxygenation is followed by a discussion of the current indications and guidelines for acute oxygen therapy, the role of long-term oxygen therapy, and the pathophysiological basis for pulmonary oxygen toxicity. Because prescribed oxygen is administered typically under normobaric conditions, oxygen therapy and its toxic consequences are considered in this setting (i.e., at one atmosphere of pressure).

TISSUE OXYGENATION The physiological basis for oxygen therapy has been well documented for over 40 years. While treatment and prevention of arterial hypoxemia are the most common indications for oxygen therapy, the ultimate goal in its use is correction or avoidance of tissue hypoxia. In 1965, Chance first demon-

strated that a partial pressure of oxygen (Po2 ) in mitochondria of 18 mmHg or more is required to generate the high-energy phosphate bonds (as adenosine triphosphate) essential for all major cellular biochemical functions. At rest, the average adult man consumes about 225 to 250 ml of oxygen per min; this rate of consumption may increase as much as 10fold during exercise. Ongoing oxygen utilization in peripheral tissues dictates a very small oxygen reserve which is consumed quickly (within 4 to 6 min of cessation of spontaneous ventilation). A complete understanding of the concepts of oxygen delivery and utilization is required for careful assessment of the hypoxic patient and implementation of proper therapy.

Oxygen Delivery and Utilization Transport of oxygen from atmospheric air to tissue mitochondria (the ultimate sites of oxygen utilization) requires the integrated function of the pulmonary, cardiovascular, and hematologic systems. Under normal conditions, a pronounced drop in Po2 between ambient atmosphere and tissues is observed (Fig. 149-1). The measured basal tissue Po2 (i.e., mixed venous Po2 or v¯ o2 ) is only marginally greater than the threshold value for mitochondrial anaerobic metabolism measured in vitro (as illustrated in Fig. 149-1 by the dashed line at a Po2 of 20 mmHg). The consequence of such a steep oxygen concentration gradient and a marginal tissue reserve is that a variety of environmental and pathological factors can significantly impact on tissue oxygenation by altering Po2 at one of these intermediary stages. Hence, tissue hypoxia develops whenever oxygen delivery is inadequate to meet metabolic demands. Oxygen delivery to the periphery is determined by two major factors: (1) oxygen content of arterial blood and (2) blood flow (i.e., cardiac output). Oxygen delivery is calculated as the product of cardiac output and arterial oxygen content. Total oxygen delivery is calculated as: Do2 = CO × Cao2 × 10


where Do2 = oxygen delivery, ml/min CO = cardiac output, L/min Cao2 = O2 content of arterial blood, ml/dl The oxygen content of arterial blood is determined by the hemoglobin concentration, its degree of saturation with molecular oxygen, and the fractional amount of oxygen physically dissolved in solution. The amounts of both bound and dissolved oxygen are related directly to the oxygen tension in arterial blood (Pao2 ), while the percentage of hemoglobin saturated with oxygen is a function of Pao2 , as described by the oxyhemoglobin dissociation curve (see Chapter 13). In turn, the amount of oxygen dissolved in solution is a function of the solubility coefficient of oxygen and the Pao2 . Hence, total arterial oxygen content is calculated as: Cao2 = ([Hgb] × 1.34 × Sao2 ) + (Pao2 × 0.0031) (2)

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Oxygen Therapy and Pulmonary Oxygen Toxicity

Figure 149-1 Graphical representation of sequential steps in the drop in oxygen tension (PO 2 ) at various stages of oxygen transport from atmosphere to peripheral tissues. Values depicted are calculated using the alveolar gas equation and data from Chance (J Gen Physiol 49:163–195, 1965). Dashed line represents the approximate intracellular anaerobic threshold.

where [Hgb] = hemoglobin concentration, g/dl 1.34 = O2 carrying capacity of hemoglobin at 37◦ C, ml/g hemoglobin Sao2 = measured %O2 saturation of hemoglobin 0.0031 = solubility coefficient for oxygen

Mechanisms of Hypoxia Aerobic metabolism requires a balance between oxygen deliv˙ 2 ). A biphasic relationery (Do2 ) and oxygen utilization (Vo ˙ 2 has been observed (Fig. 149-2). ship between Do2 and Vo During normal aerobic metabolism, oxygen transport and oxygen utilization are independent variables. Whereas the

amount of oxygen delivered to tissues per unit time defines the upper limit of oxygen availability for the body’s total metabolic needs, delivery of oxygen under normal circumstances always exceeds peripheral oxygen utilization. In this “supply-independent” region of the graph, oxygen consumption is commensurate with the rate of adenosine 5′ triphosphate (ATP) production and represents a measure of tissue cellular energy requirements. If oxygen delivery falls below a critical threshold (Do2 critical), or if utilization exceeds delivery (e.g., during strenuous exercise), tissues must shift from aerobic to anaerobic metabolism to supply adequate energy for total metabolic needs. When an imbalance arises, excessive lactic acid production ensues, resulting in progressive acidosis, disrupted cellular metabolism, and, potentially, cell death.

Figure 149-2 Relationship between oxygen consumption (V˙ O 2 ) and oxygen transport (DO 2 ). The critical DO 2 , indicative of the transition from supplydependent to supply-independent conditions, is denoted by the arrow. Anaerobic metabolism exists under supply-dependent conditions and ensues when oxygen consumption exceeds oxygen supply.

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Table 149-1 Causes of Tissue Hypoxia Categroy

Clinical Correlate



Cardiac Output


See Table 149-2

↔ or ↓

↓ or ↑ or ↔

Hypovolemia; heart failure Sepsis; arterial insufficiency Inherited abnormal hemoglobins Acquired abnormal hemoglobin (Carbon monoxide poisoning) Anemia

↔ ↓ or ↔

↓ ↔ or ↓

↓ ↑ or ↔

↔ or ↓

↑ or ↓

Impaired delivery Circulatory (forward flow) Distributive Defective Blood-O2 Transport

Table 149-1 lists the major causes of tissue hypoxia, which are mechanistically divided into three broad categories: (1) arterial hypoxemia, (2) reduced oxygen delivery, and (3) excessive or dysfunctional tissue utilization. Maintenance of tissue oxygenation depends on the proper integration of three separate components: (1) the cardiovascular system, which determines cardiac output and blood flow distribution; (2) the blood, which determines hemoglobin concentration; and (3) the respiratory system, which determines Pao2 . Although causes of hypoxemia primarily reflect failure of proper oxygen loading of the blood (low Pao2 ) due to abnormal function of the respiratory system, defects in oxygen transport may result from either dysfunction of the cardiovascular system or hematologic issues. Finally, “misuse” of delivered oxygen, resulting from either defects in cellular metabolism or excessive demand, represents another class of disorders character-

ized by hypoxia. Each of these three categories is discussed below. Arterial Hypoxemia Hypoxemia may be defined as a validated deficiency of oxygen tension in the arterial blood. A Po2 below the range of normal for age-matched subjects establishes the presence of arterial hypoxemia. Table 149-2 summarizes the major causes of hypoxemia. Since the driving force for oxygen transport across the alveolar barrier into the blood depends on both the concentration of oxygen in the alveolus (Pao2 ) and overall respiratory function, arterial hypoxemia results only from reduction of the inspired oxygen tension or respiratory dysfunction. The most common pathophysiological causes of hypoxemia in lung disease include ventilation-perfusion mismatch, true shunt, or a diffusion barrier. In some

Table 149-2 Causes of Arterial Hypoxemia and Response to Oxygen Therapy Cause

Clinical Examples

Effect of Oxygen Therapy

Decreased oxygen intake


Rapid increase in Pao2

Ventilation-perfusion imbalance

Chronic obstructive pulmonary disese

Moderately rapid increase in Pao2


Atrial septal defect Pulmonary arteriovenous fistula

Rapid but variable increase in Pao2 depending on size of shunt

Diffusion defect

Interstitial pneumonitis

Moderately rapid increase in Pao2

Alveolar hypoventilation

Chronic obstructive pulmonary disease

Initial response: Increase in Pao2 Late response: Variable depending upon whether supplemental O2 depresses minute ventilation

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nonpulmonary disorders, a low mixed-venous oxygen tension is responsible (Chapters 11 and 12). Alveolar hypoventilation, which also results in hypoxemia, acts indirectly through mechanisms that increase alveolar Pco2 and secondarily decrease alveolar Po2 . To a varying degree, most causes of arterial hypoxemia (with shunt physiology as the exception) can be improved by administration of supplemental oxygen. However, the magnitude of the response differs, based on the etiology. Reduced Oxygen Delivery In the setting of a normal Pao2 , tissue hypoxia may result from abnormalities in any of the determinants of oxygen delivery, including circulatory causes, abnormal blood oxygen transport, or maldistribution of blood flow. Circulatory hypoxia results when fully oxygenated blood is delivered to tissues in insufficient quantity or at an inadequate level to support tissue metabolic needs. Usual etiologies include low cardiac output states, systemic hypovolemia, and arterial insufficiency of peripheral tissues. Compensation is partially effected at the tissue level initially by increased oxygen extraction from blood, resulting in lowering of mixed-venous oxygen tension (vo2 ). Thus, a low vo2 is the hallmark of circulatory hypoxia. Because Pao2 may be normal and the hemoglobin normally saturated, oxygen administration is unlikely to be of great help in the majority of these disorders. Tissue hypoxia may also result from abnormal bloodoxygen transport, in which the oxygen-carrying capacity of the blood is reduced, as manifested primarily by a decrease in the total hemoglobin content (i.e., anemia), or secondarily as a consequence of abnormal hemoglobin-O2 affinity. States of abnormal hemoglobin-O2 affinity are characterized by an inability to bind oxygen (e.g., hemoglobinopathies) or to release oxygen to tissues (e.g., low levels of 2,3diphosphoglycerate). Acquired defects result typically from binding of a ligand with stronger affinity for hemoglobin than oxygen (e.g., carbon monoxide) or a toxic alteration in hemoglobin structure (e.g., methemoglobin). Under these circumstances, cardiac output is increased as an adaptive response, and vo2 is normal or decreased. Although not a primary therapy, oxygen administration may play an adjunctive role. In certain situations, including carbon monoxide poisoning, hyperbaric oxygen therapy (Chapter 62) may be helpful. Finally, tissue hypoxia may result from maldistribution of a normal or supranormal cardiac output. Examples include microvascular perfusion defects observed in classical septic shock or in the more recently recognized systemic inflammatory response syndrome (SIRS) (Chapter 146). Maldistribution of perfusion leading to tissue hypoxia has also been described in other situations, such as experimental interleukin-2 therapy. The hallmark of a maldistributive hypoxia is the development of precapillary shunting in peripheral tissues. Thus, cardiac output is normal or increased, and vo2 is usually low. Because of the presence of peripheral shunt-

Oxygen Therapy and Pulmonary Oxygen Toxicity

ing, supplemental oxygen is usually not effective in increasing local cellular oxygen tension. Cellular Causes of Hypoxia Hypoxia may also arise from misuse of oxygen at the tissue level. Cellular hypoxia results from inhibition of either intracellular enzymes or oxygen-carrying molecules involved in intermediary metabolism and energy generation. In hydrogen cyanide poisoning, Pao2 , hemoglobin concentration, percentage of hemoglobin saturation, and tissue perfusion are normal. However, peripheral utilization of oxygen is impaired as cyanide binds to cytochrome oxidase and inhibits intramitochondrial transport of electrons to molecular oxygen. This event blocks production of ATP via oxidative phosphorylation, resulting in lactic acidosis as anaerobic metabolism is triggered. In addition, oxygen extraction is often impaired, leading to a normal or increased vo2 . Although oxygen therapy is usually not effective, 100 percent oxygen is often administered while the patient is treated with specific antidotes. “Demand hypoxia” results when tissue oxygen utilization is supernormal and exceeds the rate of oxygen delivery. Common causes include maximal exercise and hypermetabolic states, such as thyrotoxicosis. As in circulatory hypoxia, vo2 is decreased, but in contrast, cardiac output is normal or, more likely, increased. Because oxygen-carrying capacity is normal, oxygen administration is often ineffective, and definitive treatment requires control of the underlying disorder.

RECOGNITION AND ASSESSMENT OF TISSUE HYPOXIA The correct use of oxygen therapy requires clinical recognition of tissue hypoxia, careful evaluation of the pathophysiological basis for the hypoxia, understanding of factors that predict those hypoxic patients likely to receive benefit, and continued assessment of the optimal dosage. The benefit must be balanced against potential toxicity. In most circumstances, tissue hypoxia is not directly measurable, and detection is usually accomplished through a combination of clinical and laboratory parameters. In cases of isolated arterial hypoxemia, awareness of tissue hypoxia is enhanced through inference of abnormal measurements of arterial oxygen saturation.

Clinical Manifestations Clinical manifestations of hypoxia are highly variable and nonspecific and depend on both duration of the hypoxia (acute or chronic) and the individual’s fitness. Symptoms and signs associated with acute hypoxia, outlined in Table 149-3, include changes in mental status, dyspnea, tachypnea, respiratory distress, and cardiac arrhythmias. Alterations in mental status range from impaired judgment to confusion or coma. Cyanosis, often considered a hallmark of hypoxia, occurs only when the concentration of reduced hemoglobin

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Table 149-3 Signs and Symptoms of Acute Hypoxia System

Signs and Symptoms


Tachypnea, breathlessness, dyspnea, cyanosis


Increased cardiac output, palpitations, tachycardia, arrhythmias, hypotension, angina, vasodilatation, diaphoresis, and shock

Central nervous

Headache, impaired judgment, inappropriate behavior, confusion, euphoria, delierium, restlessness, papilledema, seizures, obtundation, coma


Weakness, tremor, asterixis, hyper-reflexia, incoordination


Sodium and water retention, lactic acidosis

in the blood is 1.5 g/dl or greater. However, this is not a reliable sign, as it is absent in anemia and during periods of poor peripheral perfusion.

patients who are chronically hypoxemic and who have developed compensatory mechanisms. In addition, assumptions about the adequacy of tissue oxygenation may not be warranted in clinical settings in which factors other than arterial hypoxemia are responsible for the development of hypoxia (Table 149-1).

INDICATIONS FOR OXYGEN THERAPY In every sense, oxygen must be thought of as a drug having a therapeutic window based on the dose and duration of administration. In addition, the cost of both short-term oxygen therapy for hospitalized patients and long-term therapy for patients with chronic lung disease dictates a rational understanding regarding its administration. For example, in the United States, using data from the Health Care Financing Administration, total annual Medicare expenditures for therapy and equipment range from $1.3 to $1.8 billion. Thus, indications for use of supplemental oxygen must be clear. Oxygen should be administered in precise amounts, and patients should be monitored for both efficacy and toxicity of treatment. Despite the facts that the scientific foundation underlying these principles is incomplete and that all-inclusive guidelines have been difficult to develop, the economic implications and requirements for laboratory monitoring have prompted development of recommendations for oxygen therapy. These recommendations allow the physician flexibility in exercising appropriate clinical judgment in prescribing oxygen in a cost-effective manner, in both acute and chronic settings.

Laboratory and Other Objective Assessments Because of the variability of presentation and nonspecificity of the symptoms and signs of hypoxia, the laboratory assessment of the state of tissue oxygenation is desirable. Unfortunately, the current state of the art remains imprecise. Quantification of the degree of oxygenation of individual tissues is difficult. The vo2 represents an approximation of mean tissue Po2 , and a level of less than 30 mmHg indicates overall tissue hypoxia. However, measurements of vo2 require pulmonary artery catheterization and, therefore, are limited to intensive care settings. In most clinical situations, direct determinations of Pao2 , arterial hemoglobin oxygen saturation, and serum lactate levels are surrogate markers for tissue hypoxia. Pao2 determinations are made invasively with blood samples obtained from arterial puncture or indwelling arterial catheters, while noninvasive assessment of percent saturation of blood hemoglobin is routinely available by infrared pulse oximetry. Both are useful in excluding arterial hypoxemia; neither directly measures tissue Po2 . Inadequate tissue oxygen delivery is inferred from moderate decreases in Pao2 , and the inference is usually warranted in acutely ill patients whose Pao2 is less than 50 mmHg or in whom blood lactate levels are elevated. However, this judgment may be unsubstantiated in

Short-Term Oxygen Therapy Recommendations for administration of supplemental oxygen, based upon guidelines of the American College of Chest Physicians, the National Heart, Lung and Blood Institute, and other organizations, are summarized in Table 149-4. Tissue Hypoxia Associated with Arterial Hypoxemia In the acute setting, the most common indication for supplemental oxygen, regardless of the underlying etiology, is arterial hypoxemia. For a normal, middle-aged adult, the usual level of hypoxemia at which oxygen therapy is instituted is a Pao2 of less than 60 mmHg. Based on the oxyhemoglobin dissociation curve, this value for Pao2 results in a hemoglobin saturation of about 90 percent. Because of the sigmoidal shape of the curve at this Pao2 , a further decrease in oxygen tension results in a considerable drop in oxygen saturation. Ventilation-perfusion mismatch is the most common pathophysiological cause of arterial hypoxemia (see Chapter 11). The magnitude of the response to administration of supplemental oxygen depends upon the range and degree of ventilation-perfusion mismatch within individual lung regions. Therefore, repeated measurements of Pao2 or Sao2

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Table 149-4 Guidelines for the Use of Acute Oxygen Therapy Accepted Indications Acute hypoxemia (Pao2 < 60 mmHg; Sao2 < 90%) Cardiac and respiratory arrest Hypotension (systolic blood pressure < 100 mmHg) Low cardiac output and metabolic acidosis (bicarbonate < 18 mmol/L) Respiratory distress (respiratory rate > 24/min) Questionable Indications Uncomplicated myocardial infarction Dyspnea without hypoxemia Sickle cell crisis Angina ∗ Data

from Fulmer JD, Snider GL: Chest 86:234–247, 1984.

should be performed to document an effective response to a particular Fio2 . Hypoxemia secondary to right-to-left shunting is often less responsive to administration of supplemental oxygen. Mixing of shunted and unshunted blood results in a large fall in Pao2 . When the shunt fraction is greater than 20 to 25 percent, hypoxemia may persist, despite an Fio2 of 1.0. Finally, alveolar hypoventilation is often easily corrected with supplemental oxygen. However, recognition and correction of the underlying cause and immediate restoration of ventilation are the primary aims of treatment. Although a Pao2 of 60 mmHg is a reasonable goal in the initial treatment of arterial hypoxemia, in certain clinical situations the acceptable threshold level may be adjusted upward or downward. For example, in patients with low oxygen-carrying capacity (e.g., severe anemia), or in flowlimited states (e.g., acute angina pectoris), increases in Pao2 beyond 60 mmHg (yielding increases in Sao2 from 90 to 100 percent) may result in marginal, but potentially important, increases in tissue oxygen delivery. Conversely, the “acceptable” Pao2 may have to be set at a lower level in patients with abnormal control of respiration, such as those with an acquired reduced hypoxic ventilatory drive due to chronic carbon dioxide (CO2 ) retention. Tissue Hypoxia with Normal PaO2 The efficacy of supplemental oxygen in diseases that cause arterial hypoxemia is well-established. However, in cases where tissue hypoxia may exist without concomitant arterial hypoxemia, treatment should be directed ultimately to correcting the underlying cause. In these cases, Pao2 is an inadequate index of the need for, or the potential to benefit from, oxygen therapy. When available, alternative indices of tissue oxygena-

Oxygen Therapy and Pulmonary Oxygen Toxicity

tion should be used; oxygen therapy should be initiated and modified, based on the indices. Nevertheless, in some disorders, oxygen therapy has often been used even if Pao2 is not at a substantially depressed level. There is not always a consensus about the proper uses of oxygen in these circumstances. Acute Myocardial Infarction Hypoxemia is extremely common in acute myocardial infarction. In such patients, oxygen administration is of unquestioned benefit. Data supporting use of oxygen therapy in nonhypoxemic patients with acute myocardial infarction is controversial. Double-blinded studies of the value of oxygen in uncomplicated myocardial infarction demonstrate no significant effects on morbidity or mortality. Inadequate Cardiac Output (Low-Flow States) Oxygen has been recommended for temporary treatment of inadequate systemic perfusion resulting from cardiac failure. Although this practice seems reasonable, no clinical studies to date have proved the value of oxygen therapy in this setting. Oxygen therapy is used in conjunction with inotropic agents and other devices to assist cardiac output as definitive treatment is undertaken. Trauma and Hypovolemic Shock Oxygen has been advocated as adjunctive therapy in the setting of acute trauma. The low-flow state induced by acute hemorrhage is best treated by increasing the supply of circulating hemoglobin. However, supplemental oxygen as supportive therapy seems warranted until red blood cells become available for transfusion. Carbon Monoxide Intoxication In carbon monoxide poisoning, the Pao2 is a poor guide to the need for oxygen therapy. Despite a normal or “supranormal” Pao2 , a state of significant tissue hypoxia exists, as often indicated by a severe metabolic acidosis. Because of the high concentration of carbon monoxide–bound hemoglobin (carboxyhemoglobin), administration of supplemental oxygen does not increase tissue oxygen delivery. However, administration of pure oxygen markedly shortens the half-life of circulating carbon monoxide (80 min vs. 320 min on room air). Thus, oxygen administration for carbon monoxide poisoning constitutes an accepted therapy. Hyperbaric oxygen administration represents the current standard of care for those patients with high carboxyhemoglobin levels and evidence of end-organ ischemia-reperfusion damage (Chapter 62). Miscellaneous Disorders Use of supplemental oxygen as adjuvant therapy in sickle cell crisis, in accelerating resorption of air in pneumothorax, and for relief of dyspnea without hypoxemia remains controversial.

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Long-Term Oxygen Therapy In recent years, use of long-term oxygen therapy in the chronically ill patient has increased. In the United States, over 800,000 patients currently receive long-term oxygen therapy; most are patients with arterial hypoxemia. Patients with chronic obstructive pulmonary disease (COPD) represent the largest group of patients, and most of the data regarding clinical efficacy of supplemental oxygen come from studies of these patients. Early studies of oxygen therapy in COPD showed that continuous supplemental oxygen administered for 4 to 8 weeks decreased the hematocrit, improved exercise tolerance, and lowered pulmonary vascular pressures. In the early 1980s, two well-controlled studies demonstrated the value of longterm oxygen administration in patients with chronic hypoxemia due to COPD. Both the Nocturnal Oxygen Therapy Trial (NOTT) and the British Medical Research Council Domiciliary (BMRCD) study documented a significant reduction in mortality in patients receiving supplemental oxygen compared with controls who received no supplemental oxygen. Although the treatment groups in the two studies are not directly comparable (patients in NOTT received either continuous or nocturnal oxygen, whereas those in BMRCD received nocturnal oxygen or no supplementation), nocturnal oxygen (greater than 15 h/day) is better than no oxygen; continuous supplemental oxygen imparts the most benefit. The greatest efficacy is seen in patients with polycythemia, pulmonary hypertension, or hypercapnia. Although similar studies in other groups of patients with chronic hypoxemia are not available, extension of the concept of long-term oxygen therapy for patients with resting hypoxemia from a variety of cardiopulmonary diseases, including restrictive lung disease, cystic fibrosis, and chronic cardiac disease, has become widely accepted in clinical practice. Table 149-5 lists the currently accepted indications for long-term oxygen therapy. In addition to chronic arterial hypoxemia at rest, continuous-flow oxygen therapy is indicated for patients with exercise-induced hypoxemia (i.e., exercisedinduced arterial desaturation). Current data suggest that supplemental oxygen improves exercise endurance, as measured by either treadmill walking or bicycle ergometry. However, since ventilatory, rather than circulatory, factors often limit exercise in patients with airflow obstruction, increasing oxygen saturation is not a reliable predictor of improved exercise performance in all patients. A third group of patients who benefit from chronic oxygen administration are those who develop significant decreases in arterial oxygen during sleep. Included are patients with primary sleep-disordered breathing (e.g., obstructive sleep apnea and obesity hypoventilation syndrome) and patients with primary lung disease who exhibit nocturnal desaturation. For the first part of this group, oxygen therapy may need to be coupled with invasive or noninvasive ventilatory support for treatment of hypercarbia; the latter part of the group can often make use of low-flow oxygen to blunt arterial desaturation.

Table 149-5 Indications for Long-Term Oxygen Therapy Continuous Oxygen 1. Resting Pao2 < 55 mmHg or oxygen saturation < 88% 2. Resting Pao2 of 56–59 mmHg or oxygen saturation of 89% in the presence of any of the following indicative of cor pulmonale: a. Dependent edema suggesting congestive heart failure b. P pulmonale on the electrocardiogram (P wave > 3 min in standard leads II, III, or aVF) 3. Polycythemia (hematocrit > 56%) 4. Resting Pao2 > 59 mmHg or oxygen saturation > 89% reimbursable only with additional documentation justifying the oxygen prescription and a summary of more conservative therapy that has failed. Noncontinuous Oxygen∗ 1. During exercise: Pao2 < 55 mmHg or oxygen saturation < 88% with a low level of exertion 2. During sleep Pao2 < 55 mmHg or oxygen saturation 88% with associated complications, such as pulmonary hypertension, daytime sommolence, and cardiac arrhythmias ∗ Oxygen

flow rate and number of h-day must be specified.

In all patients, the need for additional supplemental oxygen should be based on measurements of arterial saturation. Certificates of medical necessity can then be completed appropriately. Most data support the notion that strategies for delivery of long-term oxygen should include early followup for assessing efficacy, followed by routine reevaluation at fixed intervals.

TECHNIQUES OF OXYGEN ADMINISTRATION In either the acute or chronic setting, once the need for supplemental oxygen is established, one of several types of delivery devices can be used to supply the patient with O2 -enriched gas. The choice of delivery system is based upon a variety of criteria, including: (1) the degree of hypoxemia, (2) the requirement for precision of delivery, (3) patient comfort, and (4) cost. The devices discussed below are reserved primarily for conscious patients who are capable of protecting their airways. Not included in the discussion are details on the use of endotracheal intubation (Chapter 151) or mechanical ventilation (Chapter 153).

2621 Chapter 149

Oxygen Therapy and Pulmonary Oxygen Toxicity

Figure 149-3 Commonly used classes of oxygen delivery systems. See text for complete descriptions.

Oxygen Delivery Systems in the Acute Setting A variety of delivery systems are available for short-term oxygen administration. The systems vary in complexity, expense, efficiency, and precision of oxygen delivery. Other than anesthesia breathing circuits, virtually all oxygen delivery systems are non-rebreathing (full or partial). In non-rebreathing circuits, the inspiratory gas is not made up of any portion of the exhaled volume, and the only inhaled CO2 is that which is entrained from ambient room air. Rebreathing is avoided through use of one-way valves to sequester expired from inspired gases. In addition, in all these systems, inspired gas mixtures must be presented in sufficient volume and at flows to allow compensation for the high-flow demands often exhibited by critically ill patients. The major types of oxygen delivery systems are outlined in Fig. 149-3. They can be divided into low-flow and highflow varieties, each of which can deliver humidified, inspired gases. Each has advantages and drawbacks. Low-Flow Oxygen Devices Low-flow oxygen delivery systems provide a fraction of the patientâ&#x20AC;&#x2122;s minute ventilatory requirement as pure oxygen; the remainder of the ventilatory requirement is fulfilled by addition of another gas, usually entrained room air. Flows supplied through these devices are low (less than 6 L/min), and they cannot deliver constant inspired oxygen concentrations, since small fluctuations in each tidal volume lead to variations in the amount of entrained room air. Consequently, in patients with an abnormal or variable ventilation pattern, marked variation

in the fraction of inspired oxygen may exist. Patient-related factors that affect the fractional concentration of inspired oxygen include: (1) shallow breathing, which results in entraining less room air and, therefore, a higher concentration of inspired oxygen; (2) deep, hyperpneic breathing, which enhances entraining of more room air; and (3) changes in respiratory frequency, which affect exhalation time, thereby producing variable filling of the deviceâ&#x20AC;&#x2122;s inspiratory reservoir. When the delivery of a constant Fio2 is required (e.g., in patients with chronic CO2 retention), low-flow systems should not be used. Nasal Cannulae

Nasal catheters and cannulae are the most widely used devices for delivering low-flow oxygen. They are simple, inexpensive, easy to use, and well-tolerated. As for all low-flow systems, the Fio2 may vary greatly, depending on the oxygen flow, inspiratory flow, and minute ventilation. With low-flow nasal cannulae set to deliver oxygen to the nasopharynx at flows between 1 and 6 L/min, the Fio2 ranges between 0.24 and 0.44 (Table 149-6). Flows above 6 L/min do not significantly increase Fio2 above 44 percent; these higher flows may result in drying of mucous membranes. Oxygen Masks

Simple plastic oxygen masks which cover the nose and mouth are capable of delivering concentrations of oxygen up to 50 to 60 percent. Depending on mask size, these devices provide a self-contained reservoir of 100 to 200 ml of additional gas,

2622 Part XVII

Acute Respiratory Failure Masks with Reservoir Bags

Table 149-6 Approximate Fraction of Inspired Oxygen with Low- and High-Flow Oxygen Devices 100% O2 Flow Rate (L/min) Low-Flow Systems Nasal cannula 1 2 3 4 5 6 Transtracheal catheter 0.5–4 Oxygen mask 5–6 6–7 7–8 Mask with reservoir bag 6 7 8 9 10 Non-rebreathing 4–10 High-Flow System Venturi mask∗ 3 (80) 6 (68) 9 (50) 12 (50) 15 (41)

FI o2 (%)

24 28 32 36 40 44 24–40 40 50 60 60 70 80 90 >99 0.60–1.00

0.24 0.28 0.35 0.40 0.50

To deliver an Fio2 of greater than 0.6 to patients who do not have artificial airways, a reservoir bag (600 to 1000 cc) can be attached to a simple face mask (Fig. 149-4). A source of continuous oxygen at flow rates of 5 to 8 L/min is needed to ensure adequate distention of the bag and to flush out CO2 from the mask. If there are no one-way valves on the reservoir bag, the apparatus is referred to as a partial non-rebreathing mask (Fig. 149-4A). Partial non-rebreathing masks can deliver oxygen in concentrations of 80 to 85 percent. The true non-rebreathing mask makes use of a one-way valve between the mask and the bag so that the patient can only inhale from the reservoir bag and exhale through separate valves on either side of the mask (Fig. 149-4B). A very high Fio2 can be achieved when these masks fit tightly against the patient’s face. However, tight-fitting molded masks, including those used to deliver continuous positive airway pressure (CPAP), are often uncomfortable and are not suitable for use for more than a few hours. High-Flow Oxygen Delivery Devices High-flow oxygen delivery systems maintain the selected Fio2 by incorporating a reservoir whose volume exceeds the patient’s anatomic dead space or by delivering oxygen at a very high flow. In quantitative terms, the flow of all high-flow systems exceeds four times the patient’s actual minute volume; otherwise, entrainment of room air at peak inspiration arises. Common clinical indications for use of a high-flow oxygen delivery system are: (1) treatment of hypoxic patients who depend on their hypoxic drive to breathe but who require controlled increments in Fio2 , and (2) young, vigorous patients with hypoxemia who have an abnormal ventilatory pattern and whose ventilatory requirements may exceed the delivery capabilities of low-flow systems. When a clinical indication exists for a tightly controlled, high Fio2 , or when high flows are necessary, a high-flow delivery system should be used. Jet-Mixing Venturi Masks

∗ Numbers

in parentheses indicate total flow of entrained room air in the Venturi mixture.

thereby facilitating increases in the achievable fraction of inspired oxygen above 0.44. Simple face masks require a flow of inspired oxygen of 5 to 6 L/min to avoid accumulation of CO2 within the mask. Conventional oxygen masks suffer from the limitations of all face masks. They interfere with drinking, eating, and expectorating, and they can become displaced, particularly at night as the patient sleeps. In addition, use of face masks increases the risk of aspiration by concealment of vomitus or containment of regurgitant materials. Therefore, when using these devices, the risk-benefit ratio should be considered. As with nasal cannulae, respiratory mucous membrane drying from the inspired gas mixture is possible. Humidification of inspired gas reduces the magnitude of the problem.

Another high-flow oxygen delivery device is the Venturi mask, the operation of which is based on the Venturi modification of the Bernoulli principle of fluid physics for gaseous jet-mixing (Fig. 149-5). As forward flow of inspired gas increases, the lateral pressure adjacent and perpendicular to the vector of flow decreases, resulting in entrainment of gas. In a Venturi mask, a jet of 100 percent oxygen flows through a fixed constrictive orifice, past open side ports, thereby entraining room air. The flow of jetting gas passing through, and then out of, the central orifice of the mask increases in velocity, and the resultant pressure drop along the sides of the jet draws room air into the face mask via the side ports. The amount of air entrained and, therefore, the resultant Fio2 , depend on the size of the side ports and flow of oxygen. Since both of these parameters are fixed, the resultant oxygen-room air mixing ratio is held steady, resulting in a well-controlled, constant Fio2 . Exhalation occurs through valved exhalation ports. The range of Fio2 obtainable through adjustments in the amount

2623 Chapter 149


Expired Gas

Expired Gas

Inspired Gas

Inspired Gas 100% Oxygen

Oxygen Therapy and Pulmonary Oxygen Toxicity

NONREBREATHING Expired Gas One Way Valve

Expired Gas One Way Valve

Inspired Gas One Way Valve

100% Oxygen

Mixed Inspired and Expired Gas

Reservoir Bag



Reservoir Bag

Figure 149-4 Mask-reservoir bag systems, illustrating airflows with partial rebreathing ( A) and nonrebreathing (B ) masks. Arrows indicate direction of airflow. See text for details.

of entrained room air and oxygen flow (i.e., the â&#x20AC;&#x153;entrainment ratioâ&#x20AC;?) is broad (Table 149-6). Masks currently in use deliver inspired gas with an Fio2 between 0.24 and 0.50. Since the Venturi mask reliably provides an accurate Fio2 up to 0.50, it is an ideal device for use in treatment of hypoxemia in patients with COPD and chronic respiratory failure characterized by a blunted hypercarbic respiratory drive. Although the Fio2 usually can be regulated precisely, technical factors can alter the value. For example, water drops may clog the oxygen injector device, resulting in changes in gas flow. In addition, development of back pressure by occluded exhalation ports may lead to decreases in the volume of entrained room air and a resultant increase in Fio2 .

Expired Gas

Other High-Flow Systems

Reservoir nebulizers and humidifiers are used to provide supplemental oxygen or highly humidified gas (including room air). Provision of high humidification is often important as adjuvant management of increased airway secretions. Usually, this delivery system is combined with endotracheal tubes or tracheostomy collars, and, therefore, its use is limited to patients with artificial airways. However, such delivery systems have also been used in combination with aerosol masks, face tents, and CPAP masks. If high-flow rates (in excess of 40 L/min) are supplied, they can usually provide a constant and predictable Fio2 . Air-oxygen blenders consist of precision metering devices that convert high-pressure wall sources of compressed air and oxygen (at 50 to 70 psi) to usable, predictable flows of up to 100 L/min at an Fio2 ranging from 0.21 to 1.0. These devices also require pressure-reduction valves and an inlet pressure monitor to ensure consistency of Fio2 against minor fluctuations in wall pressure. Although they provide a predictable Fio2 , the devices have some disadvantages. They are noisy and require specialized personnel to set up and monitor the instrumentation.

Long-Term Oxygen Delivery Systems Room Air

Room Air

100% Oxygen

Figure 149-5 Venturi mask. Arrows denote direction of airflow. See text for details.

A variety of modes of oxygen delivery and oxygen administration devices are available for use in the home and other chronic care settings. Gas supplies for long-term oxygen therapy include oxygen concentrators and compressed gas or liquid oxygen sources. Most patients requiring a stationary source of supplemental oxygen use oxygen concentrators.

2624 Part XVII

Acute Respiratory Failure

Because the concentrators weigh about 35 lb and require wall current, their use is limited as a fixed source of oxygen. Unless patients are immobile or confined to bed, both stationary and mobile oxygen delivery systems should be employed. Both compressed gas and liquid oxygen portable systems are available, but the liquid system containers are easier to refill than high-pressure cylinders. The major disadvantages of liquid oxygen are higher cost and the requirement for pressure-relief venting. The delivery devices for long-term oxygen therapy include most of the low-flow devices described previously. Most patients who receive chronic oxygen use nasal cannulae and oxygen flow rates of 2 to 4 L/min. To improve the efficiency of oxygen delivery and to limit both the need for repetitive home delivery and cost, a number of devices have been designed to “conserve” home oxygen. These include reservoir nasal cannulae, electronic conserving devices, and transtracheal catheters. The reservoir nasal cannulae have a pouch that stores 20 ml of extra oxygen during expiration and delivers the oxygen as a bolus at the onset of the next inspiration. Electronic demand devices, triggered by the onset of inspiration, deliver a pulse of oxygen early in the breath. Oxygen conservers include those that deliver a fixed volume per breath (pulse devices) and those that deliver a variable volume, which is commensurate with the length of inspiration (demand devices). Pulse-type devices deliver fixed volumes for each flow setting each time a pulse is triggered and do not deliver any more or less volume as the length of the patient’s inspiration time varies. Some pulse devices deliver with every breath, others with alternate breaths. By comparison, demand devices vary the amount of oxygen delivered during each and every breath, consistent with the duration of inhalation. Following the initial gas bolus, demand devices deliver (at an equivalent flow) a continuous flow for the remainder of the inspiration. These devices provide a variable volume at each flow setting, depending on the length of inspiration, and they have lower levels of savings at low breath rates. In addition, demand devices tend to deliver volumes equal to or greater than those achieved using continuous flow therapy in most settings; in the event of conserver malfunction, they revert automatically to continuous flow without patient interaction. Transtracheal catheters improve oxygen delivery by bypassing the anatomic dead space of the upper airway, effectively using the upper airway as an oxygen reservoir during inspiration and expiration. Transtracheal oxygen is delivered directly into the trachea via a hollow catheter implanted surgically under local anesthesia, or inserted percutaneously using the Seldinger technique. In numerous studies, transtracheal catheters have been shown to effect reductions in total oxygen usage of 50 to 75 percent. Other advantages of transtracheal oxygen systems include their inconspicuousness, lack of nasal or facial irritation due to oxygen flow, and infrequency of catheter displacement during sleep. Disadvantages include an increased incidence of infection, development of potentially fatal “mucus balls,” and catheter breakage which necessitates replacement.

PULMONARY OXYGEN TOXICITY Potential adverse effects of exposure to increased oxygen tensions at one atmosphere include alterations of normal physiological functions and oxygen-mediated tissue damage. Physiological changes to high concentrations of oxygen involve perturbations of both pulmonary and extrapulmonary homeostasis; they are easily correctable, if recognized promptly. Extrapulmonary physiological effects of hyperoxia include suppression of erythropoiesis, systemic vasoconstriction, and depression of cardiac output. These effects are usually clinically insignificant. In contrast, pulmonary physiological effects of hyperoxia include depression of hypoxic ventilatory drive, pulmonary vasodilation, and absorption atelectasis. Each is clinically relevant. In addition to producing adverse physiological effects, oxygen in high concentrations is cytotoxic. Whereas all respiring cells are potentially susceptible to the toxicity derived of hyperoxia, the major clinical adverse effects are related to lung damage.

Molecular and Cellular Mechanisms of Oxygen Toxicity The molecular and cellular bases for tissue injury in oxygen toxicity are thought to be mediated biochemically by reactive free radicals, the formation of which directly depends on the oxygen concentration. Since oxygen concentration is directly proportional to partial pressure, breathing 100 percent O2 at an altitude of 5000 feet (0.8 ata), 80 percent O2 at sea level (1 ata), or 40 percent O2 in a hyperbaric chamber (2 ata) for the same duration results in a similar toxicity profile. Aerobic cells utilize oxygen both as a metabolic substrate for the generation of ATP via the electron transport chain, and as a cofactor in intermediary metabolism involving oxidation or hydroxylation of various substrates. Molecular oxygen (O2 ), per se, is relatively nonreactive and nontoxic. However, modification of molecular oxygen by addition of electrons (e− ) can result in formation of highly reactive free radicals. The consequences of the sequential addition of single electrons to molecular oxygen are illustrated in the following reaction: e−

e− + 2H e− e− + H O2 → O2 ·− → H2 O2 → OH· → H2 O (3)

Superoxide anion (O.− 2 ), hydrogen peroxide (H2 O2 ), and hydroxyl radical (OH·) represent 1-, 2-, and 3-electron reduction products of oxygen, respectively. Singlet oxygen (O2 ·), a potent electrophile, is also generated as a by product of oxygen-dependent metabolism. During normal cellular metabolism, almost all molecular oxygen is converted completely to water, and the enzymes responsible for the reduction reactions (e.g., cytochrome oxidase, cytochrome P450, dopamine-β-hydroxylase) release few or no O2 intermediates. However, under certain conditions, these cellular

2625 Chapter 149

Figure 149-6 Generation of free radicals. Mechanisms for generation of toxic species of oxygen include: (1) superoxide anion (O− 2 ) generation by 1-electron reduction of molecular oxygen (O2 ) through a variety of electron donors (A2+ ); (2) hydrogen peroxide (H2 O2 ) generation by 2-electron reduction of O2 , usually via enzymatic catalysis; (3) interaction of superoxide and hydrogen peroxide in the presence of metals which generate hydroxyl radical; and (4) production of peroxynitrite by diffusion-limited reaction of superoxide and nitric oxide.

enzymes, as well as others, can be misused by serving as incomplete electron donors (i.e., fewer than four electrons) to molecular oxygen, generating and releasing the reactive O2 intermediates shown in Eq. (3) above. Figure 149-6 depicts general mechanisms responsible for generation of toxic metabolites of oxygen reduction. O2 ·− (reaction 1) and H2 O2 (reaction 2) are each generated by both enzymatic and nonenzymatic processes. Although both molecular species may have direct toxic effects, their interaction via the Haber-Weiss cycle, in the presence of metal ions (typically, Fe3+ ), may generate hydroxyl radicals (reaction 3) which represent the most highly reactive and potentially dangerous of the O2 -derived products. Superoxide has also clearly been shown to interact with other molecular species, such as nitric oxide (NO), which result in production of the free radical, peroxynitrite (ONOO), as illustrated in reaction 4 in Fig. 149-6. The second-order rate constant for the reaction of NO and O2 ·− to form peroxynitrite is 6.7 × 109 M−1 s−1 . This represents a reaction rate that is three times faster than the clearance of superoxide by superoxide dismutase.

Mechanisms of Pulmonary Cellular Toxicity The previously described generalized mechanisms of oxygen toxicity and metabolic intermediates are probably operative in the lung. Hyperoxia has been shown to stimulate increases in oxygen radical production in whole rat lungs, lung mitochondria, lung microsomes, lung nuclear membranes, and in cultured pulmonary endothelial cells, providing important support for the free radical hypothesis. Likewise, peroxynitrite formation has been detected in cultured cells in some animal models of acute lung injury, as well as in infants with bronchopulmonary dysplasia. Mitochondria appear to be the major subcellular source of O2 ·− which is produced by the oxidation of ubisemiquinone as part of the normal mitochondrial electron transport chain and by autooxidation of NADH dehydroge-

Oxygen Therapy and Pulmonary Oxygen Toxicity

nase. Additional O2 ·− is generated by: (1) the endoplasmic reticulum (and microsomes), through the auto-oxidation of flavins (e.g., cytochrome P450) or other components, as well as during turnover of NADPH-cytochrome c reductase; and (2) plasma membranes, by auto-oxidation of cytochromes and during prostaglandin synthesis. H2 O2 is produced at most of the aforementioned sites by the dismutation of O2 ·− and via oxidase activity (e.g., urate oxidase) in peroxisomes. HO· is generated where concentrations of O2 ·− and H2 O2 are greatest (i.e., near their production sites). Because peroxynitrite is generated by a diffusion-limited reaction, it may be formed as physiological pH at any cellular sites that contain significant amounts of NO and O2 ·− . The biochemical alterations produced by modification of cellular components by oxygen radicals and peroxynitrite are depicted in Table 149-7. Lipid peroxidation and protein oxidation are thought to represent important mechanisms

Table 149-7 Biochemical Alterations and Cellular Dysfunction from Free Radical Damage Cell Component Oxygen Radicals Lipids Lipid peroxidation Surfactant Eicosanoids Proteins

Nucleic acids Pyridine nucleotides Complex carbohydrates Peroxynitrite Proteins Nitrotyrosine formation Sulfhydryl groups Nucleic acids 8-Nitroguanine formation Lipid peroxidation

Cellular Manifestation Damage to cell and organelle membranes Altered lung mechanics Changes in cellular metabolism and intracellular signaling Inactivation of enzymes and transport proteins; Altered cellular and intercellular permeability Inhibition of cell growth and division Altered intermediary metabolism Altered recognition of macromolecules

Inactivation of enzymes and transport proteins

Cell death Cell and organellar membrane damage

2626 Part XVII

Acute Respiratory Failure

of direct O2 radical toxicity. Lipids containing unsaturated fatty acids are particularly susceptible to injury. Lipid hydroperoxides produced as intermediates are extremely toxic and can propagate the peroxidation process in an autocatalytic manner. Proteins are inactivated by reaction of radicals with sulfhydryl groups, through cross-linkage of proteins, or oxidation of constituent amino acids. Destruction of lipid and protein results in damage to cellular and organellar membranes, inactivation of key enzymes, and disruption of cellular transport mechanisms. In addition, DNA, pyridine nucleotides, and complex carbohydrates are susceptible to oxidative processes, leading to mutagenesis, growth inhibition, and alteration of intermediary metabolism. Peroxynitrite is a powerful oxidant and, as such, has been shown to oxidize many cellular components. Of particular interest is its interaction with proteins, resulting in oxidation of sulfhydryl groups and formation of nitrotyrosine residues.

Cellular Antioxidant Defenses The half-life and tissue levels of most reactive oxygen species are low, in part due to an elaborate network of cellular antioxidant defenses. Antioxidant mechanisms include any cellular process which (1) prevents formation of free radicals, (2) converts oxidants to less reactive species, (3) “compartmentalizes” reactive species away from important cellular structures, or (4) initiates repair of molecular injury by free radicals. Cellular oxygen radical defenses are classified into three basic categories: (1) enzymatic scavenging systems, which directly catalyze removal of free radicals; (2) enzyme-cofactor systems, which use a recyclable (renewable) intermediate to remove or prevent formation of O2 radicals; and (3) nonenzymatic free radical scavengers, which re-reduce O2 radicals or quench radical-producing reactions. The major enzymatic O2 radical scavenger in the lungs is superoxide dismutase (SOD). SOD is a metalloprotein present in three distinct forms, each of which has a metallic cofactor. Copper-zinc SOD is a dimeric protein which is predominantly cytosolic; manganese SOD is found mainly in mitochondria. Copper SOD, a tetrameric peptide, has been isolated from plasma. All forms of SOD catalyze the dismutation of O2 ·− to H2 O2 at very high rates. Hydrogen peroxide is subsequently removed enzymatically by either the glutathione (GSH) redox cycle (see below) or by catalase. The GSH redox cycle is the most important cellular scavenger of H2 O2 . It represents a unique system that uses multiple enzymes and a renewable, low-molecular-weight scavenger. GSH peroxidase removes both H2 O2 and lipid peroxides at the expense of GSH oxidation. GSH is regenerated by GSH reductase, using NADPH as a cofactor. Low-molecular-weight, nonenzymatic free radical scavengers include ascorbic acid (vitamin C), α-tocopherol (vitamin E), and β-carotene (vitamin A). These nonrecyclable compounds are derived from extrinsic (dietary) sources.

PATHOPHYSIOLOGY OF OXYGEN TOXICITY The toxic effects of oxygen on the lung occur when free radical production during hyperoxic exposure overwhelms intrinsic antioxidant defenses. Excess free radicals interact with cellular components, resulting in cytotoxic events which produce a characteristic cascade of biochemical, cellular, morphologic, and physiological changes. The biochemical reactions, in turn, result in a sequence of characteristic cellular and morphologic changes.

Primary Morphologic and Cellular Changes Based primarily on data from animal models and some limited human studies, four basic phases constitute the development of oxygen toxicity in lung tissue. The first three phases— initiation, inflammation, and destruction—occur during exposure to both lethal and sublethal doses of hyperoxia. The fourth phase—proliferation and fibrosis—occurs if there is re-exposure to sublethal oxygen levels. If lethal exposure persists, ongoing tissue destruction and death are observed. Initiation Phase The initiation phase of oxygen toxicity comprises the first few hours and continues throughout the duration of exposure. Initiation follows short-term exposure to lethal doses of O2 and occurs over longer periods, with sublethal hyperoxia. In each setting, the initiation phase is associated with enhanced rates of oxygen radical formation; however, there is no significant evidence of morphologic injury. Decreased rates of protein synthesis, alterations in tracheobronchial clearance of particulates, and changes in endothelial cell function have been described. Inflammatory Phase The earliest morphologic changes in the lung in response to hyperoxia occur as a consequence of primary cellular damage. They involve subtle changes in endothelial cell structure, resulting in pericapillary accumulation of fluid. Increased leakage from the pulmonary microcirculation via disruptions in the endothelial lining follows, along with accumulation of proteinaceous fluid, formation of hyaline membranes, and an influx of inflammatory blood cell elements with release of mediators. This combination of events gives rise to a pathological picture resembling noncardiogenic pulmonary edema, including morphologic characteristics of diffuse alveolar damage—a process frequently associated with acute respiratory distress syndrome (ARDS) and other forms of lung injury (see Chapters 144 and 145). Destruction Phase Overt cellular destruction begins shortly after the inflammatory phase. From a large body of in vitro and in vivo evidence it now appears that two major patterns of cell death, apoptosis and necrosis, occur in the lung in response

2627 Chapter 149

to hyperoxia. Apoptotic signaling pathways appear to involve both the cell death receptor (CD40-CD40 ligand) and mitochondria-dependent pathways with activation of caspase family members. The earliest evidence for impending cellular destruction appears at the ultrastructural level. Observed changes in lung epithelial and endothelial cells include membrane damage, vacuolarization of cytoplasm, mitochondrial swelling, and nuclear degeneration. Soon thereafter, frank cell death is seen, and exposure of the basement membrane occurs. Proliferation and Fibrosis Phase If exposure to toxic levels of O2 is terminated, a subacute or chronic stage, termed the proliferative phase, develops. The cellular proliferative response blunts the destructive phase and may enhance survival. Proliferation of type II pneumocytes occurs as alveolar remodeling takes place. In addition, an influx and proliferation of interstitial cells (fibroblasts, monocytes, and macrophages) appears to be mediated by both cytokine and autocrine factors; collagen deposition is seen as well. In baboons, lung histology and function have been shown to return to normal within 6 months of recovery from severe oxygen toxicity. However, in other settings, the end result may be, instead, varying degrees of fibrosis or emphysema. The complete complement of regulating factors remains to be defined. In the aggregate, the pathophysiological and morphologic changes associated with hyperoxic stress are similar to other forms of diffuse alveolar damage. An initial inflammatory response (exudative phase) is followed by fibrosis and repair (proliferative phase), a sequence not dissimilar from other forms of ARDS.

Oxygen Therapy and Pulmonary Oxygen Toxicity

Table 149-8 Sequence of Pulmonary Changes during Hyperoxic Exposure in Humans O2 at 1 atm

Exposure Duration


>12 h

>24 h >36 h

>48 h

>60 h

Manifestions Decreased tracheobronchial clearance; decreased forced vital capacity; cough; chest pain Altered endothelial function Increased alveolar-arterial oxygen gradient; decreased carbon monoxide diffusing capacity Increasing alveolar permeability; pulmonary edema; surfactant inactivation Acute respiratory distress syndrome


7 days

Mild chest discomfort without changes in lung mechanics; possible changes in morphometry



Subclinical pathological changes; no clinical toxicity documented

Secondary Changes The cellular changes that occur in response to toxic oxygen exposure also produce secondary changes in lung function. The increased capillary permeability that occurs with cellular damage results in decreased lung compliance, an increased alveolar-arterial oxygen gradient, and a decreased carbon monoxide diffusing capacity. Hyperoxia has also been reported to alter the pulmonary surfactant system. Alveolar surfactant material recovered from animals exposed to hyperoxic conditions exhibits markedly decreased surface tensionâ&#x20AC;&#x201C; lowering capabilities. One potential explanation appears to be inactivation of the biophysical activity of surfactant by serum proteins which leak into the alveolar space.

CLINICAL SYNDROMES OF OXYGEN TOXICITY The scenario of clinical events following exposure to hyperoxic environments is well-described as summarized in Table 149-8.

Acute Toxicity: Tracheobronchitis and Acute Respiratory Distress Syndrome (ARDS) Normal volunteers exposed to 100 percent O2 experience symptoms within 12 to 24 h. The earliest manifestations represent effects on the tracheobronchial mucosa and include substernal chest pain and nonproductive cough. Measurements of tracheobronchial function show decreased particle clearance as early as 6 h after the start of exposure to 100 percent O2 . Systemic symptoms, including malaise, nausea, anorexia, and headache may be seen. The onset of acute pulmonary oxygen toxicity usually follows an asymptomatic period during which no physiological changes are seen. In normal volunteer subjects given 100 percent O2 for 6 to 12 h, no abnormalities were noted in the alveolar-arterial oxygen gradient, pulmonary artery pressure, vascular resistance, cardiac output, pulmonary extravascular lung water, or chest radiograph. By 24 h, significant decreases in their vital capacities were found, and at 48 h of exposure to 98 percent oxygen, decrements in static compliance and carbon monoxide diffusing capacity were seen. In patients with irreversible brain damage given 100 percent O2 , the

2628 Part XVII

Acute Respiratory Failure

alveolar-arterial gradient increased precipitously after 40 to 60 h. The longest voluntary exposure to 100 percent O2 reported is 110 h; the subject developed severe dyspnea, a marked decrease in pulmonary function, and acute respiratory failure.

Chronic Pulmonary Syndromes Although not well understood in humans, the subacute and chronic phases of oxygen toxicity are well documented in animals and appear to be related to dose and duration of exposure. The best-known clinical syndrome of chronic pulmonary oxygen toxicity occurs in newborns receiving oxygen for treatment of neonatal respiratory distress syndrome. Persistent morphologic changes with healing may produce the chronic disorder bronchopulmonary dysplasia. The effects of long-term exposure of adults to inspired oxygen concentrations of 60 to 100 percent are less clear, although morphometric changes after 13 days of exposure in braindead patients have been described. Data on longer exposures, including exposure to lower levels of inspired oxygen, are unavailable. Diagnosis Pulmonary oxygen toxicity develops insidiously after a variable lag period, during which the biochemical and cellular changes described previously occur. Early clinical detection of oxygen toxicity during this lag period is impossible; tests to identify biochemical changes (e.g., lipid peroxidation) would improve diagnostic accuracy. However, such tests are currently unavailable for clinical use. Although reversible (early) physiological, anatomic, and biochemical changes can be detected following short exposure to hyperoxia, humans can tolerate 100 percent oxygen at sea level for 24 h without serious pulmonary injury. Currently, the diagnosis of hyperoxic lung injury depends on a nonspecific symptom complex or abnormal pulmonary function in the proper clinical setting. Symptoms and Signs Development of chest pain, tachypnea, or cough in a patient breathing elevated concentrations of oxygen should alert the clinician to the possibility of oxygen toxicity. The best index of oxygen toxicity may be the individualâ&#x20AC;&#x2122;s subjective symptom of retrosternal chest pain. Unfortunately, in a critically ill patient who requires mechanical ventilation or who has an altered mental status, detection of subjective complaints is difficult or impossible. On physical examination, the presence of crackles suggestive of interstitial or alveolar edema may be noted as a nonspecific finding. Pulmonary Function Tests Decreases in vital capacity, pulmonary compliance, or carbon monoxide diffusing capacity, as well as a widening of the alveolar-arterial oxygen gradient, have been observed during

hyperoxic exposures. Monitoring serial changes in vital capacity has been proposed as a means of detecting and following injury from oxygen exposure. However, the practicality and cost-effectiveness of such testing remains unsubstantiated. Radiographic Changes The chest radiographic findings of increased interstitial markings or alveolar filling are similar to those found in other causes of diffuse alveolar damage; the findings are nonspecific and are insensitive as early markers.

Potentiation of Oxygen Toxicity Susceptibility of cells or organisms to oxygen toxicity can be modified by factors other than intrinsic cellular antioxidant mechanisms. Many therapeutic drugs act synergistically with hyperoxia, accelerating free radical production and worsening oxygen toxicity. Bleomycin has been shown to increase lung injury and fibrosis through enhanced production of O2 .â&#x2C6;&#x2019; . Potentiation of oxygen toxicity by disulfiram occurs through inhibition of cytosolic superoxide dismutase by diethyldithiocarbamate, which is produced in vivo from the conversion (reduction) of disulfiram. The metabolism of nitrofurantoin and paraquat results in production of superoxide or hydroxyl radicals, and O2 has been shown to increase their cytotoxicity. Variability of dietary intake can also modify oxygen tolerance. Protein malnutrition, as well as dietary deficiency of any of the antioxidant quenchers, may alter the response to hyperoxia. Protein deficiency is thought to potentiate toxicity from hyperoxia due to a lack of sulfur-containing amino acids which are crucial for GSH synthesis. The adverse effects of vitamin A and vitamin E deficiencies are also well described.

Prevention and Therapy As with other drugs, oxygen should be administered judiciously, in doses designed to achieve therapeutic efficacy with limited toxicity. Because early detection of oxygen toxicity has remained elusive and specific therapy is lacking, avoidance of pulmonary toxicity during oxygen therapy remains the cornerstone of management. The best approach is to monitor the efficacy of the inspired oxygen concentration and to adhere to guidelines to use doses that have not been found to be associated with major side effects. The primary therapeutic goal associated with use of supplemental oxygen is assurance of adequate tissue oxygenation without use of toxic levels of Fio2 . A significant obstacle in achieving this goal centers around monitoring the efficacy of oxygen therapy and assessing the adequacy of tissue oxygenation. As noted previously, the clinical approach entails correction of arterial hypoxemia as the cause of tissue hypoxia and assessment of the response to supplemental oxygen administration through measurement of Pao2 or use of continuous, cutaneous, infrared pulse oximetry.

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Extrapolations about the state of tissue oxygenation from measurement of vo2 using an indwelling pulmonary artery catheter can be used in the critical care setting. Transcutaneous estimations of tissue Po2 and, hence, intracellular oxygen sufficiency, remain experimental. Based upon general consensus, the following guidelines can be offered regarding oxygen administration at 1 atmosphere. Oxygen in concentrations up to 100 percent can be administered in the transport and initial management of critically ill patients. In patients who are not on mechanical ventilation, evidence of respiratory depression should be monitored. If needed, an Fio2 of 1.0 can be used for up to 24 h without significant lung injury. During this period, management should be directed toward improving pulmonary gas exchange, optimizing oxygen delivery, and limiting tissue metabolic demands so that inspired O2 concentration can be decreased to the lowest possible levels. Oxygen at an Fio2 of 0.5 or less can be administered safely to most patients for weeks, although factors specific to individual patients (e.g., prior bleomycin use) may dictate a lower tolerance. The maximal safe duration for oxygen exposures between an Fio2 of 0.5 and 1.0 is less certain, although these concentrations probably can be tolerated longer than 24 h. The safe upper limit of Fio2 for chronic oxygen therapy in the ambulatory setting is largely undefined.

SUMMARY Use of supplemental oxygen is a powerful tool in the management of critically ill patients as well as those with chronic cardiopulmonary disease, but it represents a double-edged sword. Concomitant with initiation of its use in management of hypoxemia, careful assessment for the underlying etiology of the hypoxemia and implementation of therapeutic measures aimed at its reversal should be undertaken. The proper prescription of oxygen is based upon general principles that are applied to the administration of any other drug. Knowledge of the various techniques of oxygen administration, establishment of clear therapeutic end points, monitoring of the efficacy of treatment, and awareness of the potential toxicity of oxygen are required.

SUGGESTED READING Barber RE, Lee J, Hamilton WK: Oxygen toxicity in man. A prospective study in patients with irreversible brain damage. N Engl J Med 283:1478–1484, 1970. Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and the ugly. Am J Physiol (Cell Physiol ) 40:C1424–C1437, 1996.

Oxygen Therapy and Pulmonary Oxygen Toxicity

Caldwell PR, Lee WL Jr, Schildkraut HS, et al: Changes in lung volume, diffusing capacity, and blood gases in men breathing oxygen. J Appl Physiol 21:1477–1483, 1966. Celli BR, MacNee W: Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004. Chance B: Reaction of oxygen with the respiratory chain in cells and tissues. J Gen Physiol 49:163–195, 1965. Christopher KL, Spofford BT, Petrun MD, et al: A program for transtracheal oxygen delivery. Assessment of safety and efficacy. Ann Intern Med 107:802–808, 1987. Cottrell JJ, Openbrier D, Lave JR, et al: Home oxygen therapy. A comparison of 2- vs 6-month patient reevaluation. Chest 107:358–361, 1995. Crapo JD: Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 48:721–731, 1986. DesRosiers A, Russo R: Long-term oxygen therapy. Respir Care Clin N Am 6:625–644, 2000. Freeman BA, Crapo JD: Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J Biol Chem 256:10986–10992, 1981. Fulmer JD, Snider GL: American College of Chest Physicians (ACCP)—National Heart, Lung, and Blood Institute (NHLBI) Conference on Oxygen Therapy. Arch Intern Med 144:1645–1655, 1984. Harabin AL, Homer LD, Weathersby PK, et al: An analysis of decrements in vital capacity as an index of pulmonary oxygen toxicity. J Appl Physiol 63:1130–1135, 1987. Hoffman LA, Dauber JH, Ferson PF, et al: Patient response to transtracheal oxygen delivery. Am Rev Respir Dis 135:153– 156, 1987. Jeffrey AA, Ray S, Douglas NJ: Accuracy of inpatient oxygen administration. Thorax 44:1036–1037, 1989. Kacmarek RM, Dimas S (eds): Essentials of Respiratory Care. St. Louis, Mosby, 2005. Levi-Valensi P, Weitzenblum E, Pedinielli JL, et al: Threemonth follow-up of arterial blood gas determinations in candidates for long-term oxygen therapy. A multicentric study. Am Rev Respir Dis 133:547–551, 1986. Lodato RF: Oxygen-toxicity. Crit Care Clin 6:749–765, 1990. Lorrain-Smith J: The pathological effects due to increase of oxygen tension in the air breathed. J Physiol 24:19–35, 1899. Meakins J: Observations on the gases in human arterial blood in certain pathological pulmonary conditions, and their treatment with oxygen. J Pathol Bacteriol 24:79–90, 1921. Medical Research Council Working Party: Long-term domiciliary oxygen therapy in chronic hypoxia cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1:681–686, 1981. Nocturnal Oxygen Therapy Trial Group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. A clinical trial. Ann Intern Med 93:391–398, 1980.

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Odonohue WJ, Plummer AL: Magnitude of usage and cost of home oxygen-therapy in the United States. Chest 107:301– 302, 1995. Sackner MA, Landa J, Hirsch J, et al: Pulmonary effects of oxygen breathing. A 6-hour study in normal men. Ann Intern Med 82:40–43, 1975.

Tarpey S: Long-term oxygen therapy. N Engl J Med 333:710– 714, 1995. Van De Water JM, Kagey KS, Miller IT, et al:. Response of the lung to six to 12 hours of 100 per cent oxygen inhalation in normal man. N Engl J Med 283:621–626, 1970.

150 Pulmonary Pharmacotherapy Karen J. Tietze

Scott Manaker

I. BRONCHODILATORS β-Adrenergic Agonists Anticholinergics Methylxanthines Magnesium Sulfate Inhaled Diuretics II. ANTI-INFLAMMATORY AGENTS Corticosteroids Corticosteroid-Sparing Agents Mast Cell Stabilizers Leukotriene Antagonists and Inhibitors Immunoglobulin E Antibody III. MUCOKINETIC AGENTS Dornase Alpha N-Acetylcysteine

A wide spectrum of therapeutic agents are currently employed in the treatment of respiratory disorders, including obstructive lung diseases. This chapter reviews the rationale for, and clinical use of, these agents in current clinical practice. A brief discussion of potentially useful therapeutic drug strategies for the future is also provided.

BRONCHODILATORS Pharmacologic management of obstructive airway diseases is based heavily upon bronchodilation produced by βadrenergic agonists, muscarinic antagonists, and methylxanthines. In addition, magnesium and inhaled diuretics may ultimately prove to be effective bronchodilators suitable for clinical use.

β-Adrenergic Agonists The β-adrenergic agonists mimic the actions of norepinephrine at neuroeffector and synaptic junctions. Norepi-

Iodinated Agents Sodium Bicarbonate Guaifenesin IV. PHYSIOLOGICAL REPLACEMENTS α1 -Antitrypsin Pulmonary Surfactant V. RESPIRATORY STIMULANTS Acetazolamide Almitrine Methylxanthines Doxapram Medroxyprogesterone Protriptyline

nephrine is the major neurotransmitter in the sympathetic nervous system; therefore, this class of drugs is referred to as adrenergic agonists or sympathomimetics. Adrenergic receptor stimulation catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′ 5′ -adenosine monophosphate (cAMP) by activating adenyl cyclase, a cofactor in the production of cAMP. The increase in cAMP triggers the intracellular events that mediate pulmonary and extrapulmonary responses. The two major types of adrenergic receptors are the alpha and beta receptors; at least two alpha and two beta receptor subtypes have been identified. The β-adrenergic agonists (Table 150-1) are indicated in the treatment of bronchospasm associated with acute and chronic asthma, bronchitis, emphysema, exercise, and other obstructive pulmonary diseases. Selection of a specific agent and route of administration depends on underlying patient risk factors and the receptor specificity of the drug. Pharmacology Adrenergic receptor stimulation produces a wide range of responses, depending on the effector organ and the specific

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 150-1 Adrenergic Agonists Receptor Activity

Dosage Forms







+ + +

+ + +

Very Short Short Short


Resorcinols Metaproterenol Terbutaline

± ±

++ +++

Short Short


Saligenins Albuterol Levalbuterol Salmeterol

± ± ±

+++ +++ +++

Short Short Long

X‡ X§

Other Pirbuterol Formoterol

± ±

+++ +++

Short Long








Agent Catecholamines Epinephrine Isoproterenol Isoetharine




X#,∗∗ X# X#,¶,∗∗



Duration: short = 2 to 6 h; long = 8 to 12 h Note: Abbreviation: MDI = metered dose inhaler; Neb = solution for nebulization; Inj = injectable dosage form; X = marketed dosage formulation; ± = present but minimal effect; + = mild effect; ++ = considerable effect; + + + = major effect. ∗ Nonprescription product. † Contains chlorofluorocarbons. ‡ Some products contain chlorofluorocarbon and some products contain hydrofluoroalkane. § Contains hydrofluoroalkane. # Immediate-release dosage formulation. ¶ Sustained-release dosage formulation. ∗∗ Syrup.

receptor. Although bronchial smooth-muscle relaxation results from β2 -adrenergic receptor stimulation, none of the currently marketed agonists are completely specific for β2 -adrenergic receptors. The α-adrenergic receptor is generally associated with constrictor/contractor responses, including constriction of arteries and veins and contraction of the uterus, radial and sphincter muscles of the iris, urinary bladder, and stomach sphincters. β1 -Adrenergic receptor stimulation increases heart rate, atrial and ventricular contractility, and cardiac conduction velocity. Effects from β2 -adrenergic receptor stimulation include relaxation of bronchial and uterine smooth muscle, dilatation of arteries and veins, and several metabolic effects, including glycogenolysis, gluconeogenesis, and induction of hepatic pancreatic beta cell secretion. Structure-Activity Relationships The parent compound for the adrenergic agonists, phenylethylamine (Fig. 150-1), consists of a benzene ring and

an ethylamine side chain. Substituents can be added to the alpha or beta carbons of the ethylamine side chain, the terminal amine group, or one or more of the carbons in the aromatic ring. The basic chemical structures of the adrenergic agonists include the catecholamines, resorcinols, and saligenins (Fig. 150-1). The catecholamines were the first adrenergic agonists to be marketed. The resorcinols (metaproterenol and terbutaline) have hydroxyls at positions 3 and 5 of the aromatic ring. This promotes oral bioavailablity and prolongs the duration of effect by protecting the molecules from catechol-o-methyl transferase degradation. Terbutaline, with a large substituent on the terminal amine, is selective for β2 -adrenergic receptors. The saligenins (albuterol and salmeterol) have a hydroxyl at position 4, various carbon moieties on position 3 of the aromatic ring, and large substituents on the terminal amine. These large substituents confer a longer duration of action and β2 -adrenergic receptor specificity, particularly for salmeterol. Salmeterol’s long side chain results in increased lipophilicity, protecting the structure from

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Pulmonary Pharmacotherapy

CPC β α D5 6 G 1 C O CH 2 O CH 2 O NH 2 C4 M 3 2 J COC Phenylethylamine

CPC D G C O CH 2 O CH 2 O NH 2 HO O C M J COC D HO Catecholamine HO G CPC D G C C O CH 2 O CH 2 O NH O R M J COC D Resorcinol HO CPC D G C O CH 2 O CH 2 O NH O R HO O C M J COC D Saligenin R

OH CPC A D G HO O C C O CH O CH 2 O NH 2 M J COC D HO Epinephrine HO G OH CH 3 CPC A A D G C C O CH O CH 2 O NH O C O CH 3 M J A COC CH 3 D Terbutaline HO OH CPC CPC A D G D G C O CH O CH 2 O NH O (CH2 )6 O O O(CH2 )4 O C C HO O C M J M J COC COC D Salmeterol CH 2 D HO

Figure 150-1 Structures of adrenergic agonists.

metabolism by catechol-o-methyl transferase and allowing the compound to bind both to the beta receptor and to an adjacent exoreceptor site. In theory, the exoreceptor binding site anchors the drug close to the beta receptor, further prolonging its action. Albuterol is a 1:1 mixture of the Rand S-enantiomers. The R-albuterol enantiomer is the active moiety; the S-albuterol enantiomer is inactive. Although early animal and clinical studies suggested that the S-albuterol enantiomer might antagonize the effects of the R-albuterol enantiomer, a clear clinical advantage of levalbuterol, the first pure enantiomer (R-albuterol) has not been demonstrated. Formoterol is a phenylethanolamine derivative with a phenyl-isopropyl group attached to the terminal amine. Physicochemical properties account for formoterol’s long duration of action. Pirbuterol differs from all other adrenergic agonists in that the aromatic ring is a pyridine, instead of a benzene. Drug Delivery The β-adrenergic agonists may be administered systemically or by inhalation; however, not all drugs are marketed in every dosage form. Systemic dosage forms include oral, subcutaneous, and intravenous preparations. Systemic administration decreases the β2 -adrenergic receptor selectivity of the drug due to exposure to various metabolic enzymes, including catechol-o-methyl transferase, monoamine oxidase, and sulfatase. These enzymes change the chemical structure of the drug, decreasing the β2 -adrenergic receptor selectivity. The oral route of administration is generally reserved for patients who cannot successfully use metered-dose inhalers (e.g., children or the elderly). Sustained-release, oral dosage

forms may be useful in controlling nocturnal symptoms of asthma, although not as effectively as the long-acting, inhaled adrenergic agonists. The subcutaneous route is generally reserved for patients too dyspneic to inhale the drug, and parenteral drug administration is generally employed for pediatric patients. The preferred route of β-adrenergic agonist administration is by inhalation. Local application of small amounts of drug directly to the airways decreases the amount available for systemic absorption, minimizing systemic side effects. Inhaled β-adrenergic agonists are available in several dosage forms, including wet aerosols, aerosols from metered-dose inhalers, and dry powder forms. Most commonly, wet aerosols are delivered by jet or ultrasonic nebulizer, whereas metereddose inhalers are primarily marketed as “press and breathe” devices. Historically, nebulized drug delivery was standard practice for children, emergency treatment of asthma exacerbations, hospitalized patients, and severely obstructed patients. However, nebulized drug delivery is labor intensive; significant cost savings can be realized, without sacrificing efficacy, by using metered-dose inhalers coupled with spacer devices. Drug delivery by metered-dose inhaler is highly dependent on administration technique. Less than 10 percent of the dose is delivered to the lung using optimal inhalation technique; the rest of the drug is deposited in the mouth. Spacer devices eliminate the split-second timing necessary with proper metered-dose inhaler technique and decrease the amount of drug deposited in the oropharynx (an important factor with inhaled corticosteroids); however, they do not provide a therapeutic advantage over correct use of a metered-dose inhaler alone.

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Metered-dose inhalers initially contained chlorofluorocarbon (CFC) propellants. In 1978, international concerns regarding the ozone-depeleting properties of CFCs led to a generalized ban on CFC-containing products. In 2005, the Food and Drug Administration (FDA) announced that CFCcontaining MDIs, previously exempt from the ban on CFC production and importation, will not be produced, marketed, or sold in the United States after December 31, 2008. CFCcontaining MDIs are being replaced by hydrofluoroalkane (HFA)-containing MDIs and a variety of dry powder inhalers (DPIs). Clinical Use The β2 -adrenergic agonists are considered first-line drugs in the treatment of both asthma and chronic obstructive pulmonary disease (COPD). In asthma, the short-acting inhaled β2 -adrenergic agonists are preferred for treating acute symptoms and for preventing exercise-induced bronchospasm. The subcutaneous route of administration is generally reserved for patients unresponsive to frequent, high-dose, inhaled β2 -adrenergic agonists; uncooperative patients; or patients too severely dyspneic to inhale the dose. Subcutaneous or parenteral administration should not be used in patients with angina or a recent history of myocardial infarction. Oral adrenergic agonists may be appropriate for children too young to cooperate with inhaled drug administration; sustained-release, oral adrenergic agonists decrease nocturnal symptoms, but they are less effective than long-acting β2 -adrenergic agonists. In COPD, β2 -adrenergic agonists provide modest symptomatic relief and improvement in pulmonary function. Long-acting inhaled β2 -adrenergic agonists are standard bronchodilator therapy for patients with moderate and severe COPD. Standard doses of inhaled β2 -adrenergic agonists appear as effective as inhaled anticholinergic drugs for relief of acute exacerbations of COPD. The value of subcutaneous drugs and high-dose short-acting bronchodilators in the management of COPD has not been determined. The intensity and duration of response to β2 adrenergic agonists is dose- and frequency dependent. For patients with asthma, higher doses result in incrementally greater bronchodilation. The dose-response relationships are less well defined for COPD. The dose-response curve in asthma led to the development of intensive inhaled β2 -adrenergic agonist drug regimens for the treatment of severe, acute exacerbations. Typically, the nebulized drug is administered every 20 min for three to six doses; some patients respond better to continuous nebulized drug delivery. These regimens are generally well tolerated, although cardiac stimulation is common. The long-acting β2 -adrenergic agonists are add-on agents for patients with moderate or severe asthma when usual doses of inhaled corticosteroids are inadequate and for patients with moderate to severe COPD. The long-acting β2 -adrenergic agonists are also alternate add-on agents for patients with symptoms of nocturnal asthma. The long-acting

β2 -adrenergic agonists have no role in the treatment of acute asthma or an acute exacerbation of COPD; all patients should have a short-acting inhaler and should be instructed on how and when to use each type of β2 -adrenergic agonist. Tolerance Tolerance, or receptor subsensitivity, is defined as a decreased response to receptor stimulation. Although tolerance to the nonbronchodilator effects of β-adrenergic agonists, including tremor, tachycardia, prolongation of the QTc interval on the electrocardiogram, hypoglycemia, hypokalemia, and vasodilator response, has been demonstrated, data on tolerance to the bronchodilator effects of β-adrenergic agonists are limited and conflicting. Tolerance to the long-acting drugs may make patients less responsive to short-acting β2 -adrenergic agonists during an acute attack or may mask inadequate control of inflammation. Although the mechanism for tolerance to the long-acting drugs has not been precisely identified, one hypothesis is that prolonged drug-receptor interaction may induce receptor down-regulation. Concomitant diseasemodifying drug therapy (e.g., corticosteroids) may also modify the development of tolerance by modulating adrenoceptor function. Safety The β2 -selective adrenergic agonists produce less cardiovascular toxicity than do the nonselective agents, but β2 selectivity does not protect from all adverse events. Biochemical abnormalities associated with the β2 -adrenergic agonists include hyperglycemia, hyperinsulinemia, lipolysis, hypokalemia, hypomagnesemia, and lactic acidosis. These side effects are most pronounced with parenteral and oral drug administration; they are minimal with usual doses of inhaled agents. Furthermore, the biochemical abnormalities are more pronounced in drug-na¨ıve normal volunteers than in asthmatic patients, suggesting that tolerance develops following chronic drug administration. β2 -adrenergic agonists cause dose- and routedependent hyperglycemia by stimulating glycogenolysis and gluconeogenesis. This effect may be clinically most important in asthmatic patients with diabetes mellitus or during pregnancy. β2 -adrenergic agonists increase plasma insulin by directly stimulating pancreatic islet cells; indirect increases occur secondary to the hyperglycemic response. β2 adrenergic agonists induce the release of free fatty acids from adipose tissue. Although hyperinsulinemia and high concentrations of free fatty acids have been linked with cardiovascular morbidity and mortality, tolerance minimizes these effects. β2 -adrenergic receptor stimulation also induces muscle glycogenolysis, increasing lactate production. The β2 -adrenergic agonists induce hypokalemia by directly stimulating the uptake of potassium into skeletal muscle cells. β2 -adrenergic receptor stimulation induces the cellular uptake of magnesium; hypomagnesemia may induce arrhythmias or worsen symptoms of coronary artery disease. Other

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adverse β2 -adrenergic agonist effects include: (a) an increased baseline tremor by creating an imbalance in fast- and slowtwitch muscle groups; (b) tachycardia by direct chronotropy and through reflex peripheral vasodilatation and decreased venous return; and (c) central nervous symptoms, such as appetite suppression, headache, nausea, and sleep disturbances. The nervousness reported by many patients is probably a response to the peripheral tremors rather than a result of direct stimulation of the central nervous system. β-adrenergic agonist use has increased coincident with the increase in asthma morbidity and mortality in the United States and other countries. This observation has promoted interest in the possible relationship between asthma mortality and use of these agents. The first link was made during the 1960s when the newly marketed nonselective βadrenergic agonist isoproterenol was associated with an increase in asthma morbidity and mortality in the United Kingdom. Although never conclusively proved, the increase in asthma morbidity and mortality was blamed partly on the lipolytic effect of the drug, which increases the potential for myocardial ischemia, and partly on the high-dose formulation. In the 1970s, when fenoterol was linked to an increased death rate in New Zealand, part of the increased mortality was attributed to the hypokalemic effect of fenoterol. Interest in the association between regular use of shortand long-acting β-adrenergic agonists and asthma morbidity and mortality was heightened by several reports that use of multiple fenoterol or albuterol inhalers per month was associated with an increased risk of death. A subsequent metaanalysis of case-control studies reported only a very weak, although statistically significant, relationship between the use of nebulized β agonists and death from asthma. Although this weak relationship was more likely in adults than adolescents, data from large, well-designed trials are needed to assess accurately the risk of death associated with long-acting β-adrenergic agonists.

Anticholinergics Atropine and other anticholinergic alkaloids from plant extracts have been used for thousands of years to relieve respiratory symptoms in humans with airway diseases. Historically, clinical use of atropine and atropinelike agents has been limited by anticholinergic side effects, including dry mouth and skin, tachycardia, and meiosis; higher doses produce difficulties in speaking, swallowing, urinating, and mentating, as well as other neurologic side effects. Pharmacology Muscarinic receptors control airway smooth muscle function. Activation of airway M1 and M3 muscarinic receptors results in bronchial smooth muscle contraction and mucus secretion. M2 “autoreceptor” activation results in decreased acetylcholine (Ach) release; blockade of M2 receptors increases airway Ach. The ideal anticholinergic drug would selectively

Pulmonary Pharmacotherapy

block M1 and M3 receptors and have no effect on M2 receptors. Quaternary ammonium atropine derivatives were developed to avoid the systemic side effects associated with tertiary derivatives, such as atropine. The quaternary ammonium compounds do not penetrate the blood-brain barrier, are minimally absorbed systemically, and have longer durations of action than atropine. Ipratropium bromide (FDA approved in 1998) and tiotropium bromide (FDA approved in 2004) are closely related quaternary ammonium drugs that differ in terms of muscarinic receptor binding affinities and receptor-drug complex half-lives. Ipratropium bromide nonselectively blocks M1 , M2 , and M3 receptors. Tiotropium bromide has a greater affinity for muscarinic receptors than ipratropium bromide, but it dissociates rapidly from M2 receptors, resulting in prolonged M1 - and M3 -drug complex half-lives compared to ipratropium bromide. Inhalation of ipratropium bromide produces bronchodilation in seconds to minutes, with a peak effect after 1 to 2 h. Inhalation of a single dose of tiotropium bromide produces a peak FEV1 in 1 to 3 h; the duration of effect is about 32 h. The trough FEV1 increases after multiple doses, reflecting carryover bronchodilation from the prolonged half-life. Clinical Use Ipratropium bromide and tiotropium bromide are most efficacious in patients with COPD, including emphysema and chronic bronchitis. In such patients, ipratropium bromide and tiotropium bromide are equally or more effective than β-adrenergic agonists in increasing FEV1 and reducing airway resistance. Limited data suggest that tiotropium bromide may be superior to ipratropium bromide and the long-acting β2 -adrenergic agonist, salmeterol, in long-term management of moderate to severe COPD. The increased cost of tiotropium bromide may be offset by reduced overall health care expenditures. Chronic inhalation of ipratropium bromide or tiotropium bromide does not lead to development of tolerance or tachyphylaxis. The combination of inhaled anticholinergic and βadrenergic agonist produces greater improvement in FEV1 and specific conductance than does administration of either agent alone. Most large-scale studies of patients with COPD demonstrate that the addition of oral corticosteroids does not increase maximal flow over that achieved by the administration of a β-adrenergic agonist with inhaled ipratropium bromide. In contrast, ipratropium bromide is less effective than β-adrenergic agonists in the treatment of chronic asthma, and the role of tiotropium is not established. Some asthmatics may gain more relief of bronchospasm from inhalation of ipratropium bromide than β-adrenergic agonists. However, this unusual response requires initial evaluation with an empiric trial of ipratropium bromide and should be reserved only for patients whose moderate to severe asthma is difficult to control. A recent meta-analysis of 32 randomized controlled trials of anticholinergics in treatment of children

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and adults with acute asthma found that compared with use of inhaled β2 -adrenergic agonists alone, addition of inhaled anticholinergics significantly reduced hospitalizations and increased spirometric parameters 1 to 2 h after treatment.

Safety Consistent with their very low systemic bioavailability, both ipratropium bromide and tiotropium bromide are remarkably free of side effects. Transient dry mouth of mild intensity has been reported in 16 percent of patients inhaling tiotropium bromide and in up to 10 percent of patients inhaling ipratropium bromide. Side effects of tiotropium bromide typically appear after 3 to 5 wk of continued use, reflecting the slow linear tissue accumulation of the drug. Neither ipratropium bromide nor tiotropium bromide change pulmonary hemodynamics, ventilation-perfusion matching, oxyhemoglobin saturation, heart rate, or urinary flow; however, blurred vision and pupillary dilation may occur if either drug inadvertently contacts the eye. Both drugs should be used with caution in patients with myasthenia gravis, narrowangle glaucoma, prostatic hyperplasia, or bladder neck obstruction. Tiotropium bromide should be used with caution in patients with moderate to severe renal insufficiency (Clcr less than 30 to 50 ml/min). Although systemic administration of muscarinic anticholinergics decreases mucus formation, neither ipratropium bromide nor tiotropium bromide have much effect on respiratory secretions. Ipratropium bromide inhalation produces a clinically insignificant decrease in mucus viscosity and does not change mucus transport or ciliary beat frequency. Tiotropium bromide does not appear to adversely affect mucus transport. Concomitant use of drugs with anticholinergic properties may increase the risk of side effects with either ipratropium bromide and tiotropium bromide.

Methylxanthines Theophylline and aminophylline, the ethylenediamine salt of theophylline, are used to treat asthma and the obstructive component of COPD. Other pulmonary diseases for which theophylline may have a role include obstructive sleep apnea, apnea of prematurity, and airway obstruction secondary to pulmonary edema. Potentially beneficial therapeutic effects of theophylline include bronchial smooth-muscle relaxation, enhanced mucociliary transport, inhibition of mediator release, suppression of permeability edema, decreased pulmonary hypertension, increased right ventricular ejection fraction, improved diaphragmatic contractility, and central stimulation of ventilation. Although bronchial smooth-muscle relaxation is most likely responsible for the majority of theophylline’s beneficial therapeutic effects in the treatment of obstructive lung disease, the anti-inflammatory and diaphragmatic effects may contribute to the overall efficacy of the drug.

Pharmacology Despite having been marketed and studied for several decades, the precise cellular mechanism of theophylline’s bronchodilating action is unknown. It is unlikely that theophylline bronchodilates via adenosine antagonism. However, many of the extrapulmonary effects associated with theophylline, including cardiac stimulation, anxiety, tremors, seizures, diuresis, gastric secretion, and free fatty acid release have been attributed to adenosine antagonism. Anti-inflammatory Effects

Anti-inflammatory actions attributed to theophylline include inhibition of neutrophil and mononuclear cell migration, leukotriene B4 generation, T-cell proliferation, and lymphokine production; increased activity and number of suppressor T cells; and stabilization or inactivation of macrophages and platelets. The anti-inflammatory effect of theophylline appears to be qualitatively different than that of corticosteroids, resulting from the selective inhibition of phosphodiesterase IV at low serum theophylline concentrations. Although there has been a great deal of interest in the immunomodulatory effect of the methylxanthines, the clinical relevance of this effect remains unknown. Diaphragmatic Effects

Theophylline increases diaphragmatic strength and contractility, actions potentially mediated by transmembrane calcium movement. Most data are from in vitro studies or from normal volunteers; results from controlled clinical trials in patients with COPD are limited and conflicting. Theophylline may be potentially most beneficial in patients with hypoxic and hypercapnic COPD when dosed to midtherapeutic plasma concentrations. Structure-Activity Relationships Theophylline and aminophylline are 1,3-dimethylxanthines. Other methylxanthines, including theobromine (3,7dimethylxanthine) and caffeine (1,3,7-trimethylxanthine), differ in the positions of the methyl substituents on the xanthine molecule. N-1 substituents are important for adenosine antagonism, whereas N-3 substituents augment bronchodilator activity. Substituents at N-7 decrease bronchodilator potency; substituents at N-9 decrease the potency of the xanthine. Clinical Use For bronchodilation, the target theophylline serum concentration is generally accepted as 10 to 20 mg/L. The therapeutic range for other effects (e.g., anti-inflammatory properties, enhanced diaphragm capability, respiratory stimulation) may be different, prompting interest in a lower (5 to 15 mg/L) target range. Approximately 50 percent of maximal bronchodilation is achieved at a serum level of 10 mg/L; only an additional 17 percent increase is observed at 20 mg/L. The precise clinical role of theophylline is unclear. Relatively noncontroversial indications include severe

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bronchodilator-dependent COPD; severe, systemic, corticosteroid-dependent asthma; nocturnal asthma uncontrolled with adrenergic agonists; and acute, severe asthma progressing to respiratory failure. Safety Adverse effects associated with theophylline include nausea, vomiting, diarrhea, irritability, insomnia, supraventricular tachycardia, ventricular arrhythmias, and seizures. Although the risk of adverse effects increases at serum concentrations greater than 20 mg/L, patients also may experience serious adverse effects within the usual therapeutic range. Because of this narrow therapeutic index, emphasis should be placed on achieving the midtherapeutic range for serum theophylline levels (10 to 15 mg/L), while accepting a broader range (5 to 20 mg/L) as appropriate.

Magnesium Sulfate Magnesium blocks calcium entry into smooth-muscle cells, thereby relaxing muscle fibers. Several small trials randomized patients upon presentation to the emergency room to receive either 2 g of magnesium sulfate intravenously over 20 min or placebo, in addition to standard therapy. Intravenous magnesium administration demonstrated no overall beneficial effect, although in retrospective analysis, the degree of airflow obstruction and rate of hospital admission were reduced for patients with severe asthma. Subsequent case reports and small series suggested similar results could be obtained with inhalation of various doses of inhaled magnesium. The few randomized clinical trials reported to date seem to demonstrate similar small reductions in the degree of airflow obstruction and rate of hospital admission following magnesium sulfate inhalation in patients with severe asthma presenting to the emergency room setting. Despite these limited clinical data demonstrating efficacy of magnesium sulfate, the recommendation from the Global Initiative for Asthma is that intravenous magnesium sulfate be considered in therapy of acute severe asthma. Recent survey data reveal that 21 percent of children receiving intensive care for asthma in the United States between 2000 and 2003 received parenteral or inhaled magnesium sulfate therapy during their hospitalization.

Inhaled Diuretics While inhaled magnesium may act as a direct bronchodilator, inhaled diuretics may act upon the airways through a variety of mechanisms to achieve bronchodilation, reduce mucosal inflammation, or interrupt sensory nerve reflex responses to irritiants. Inhaled furosemide has no role in the treatment of exacerbations of acute asthma, and additional information is needed before use of inhaled diuretics can be recommended for prevention of exercise- or irritant-induced asthma.

Pulmonary Pharmacotherapy

ANTI-INFLAMMATORY AGENTS Corticosteroids are the mainstay of current antiinflammatory regimens; other agents in clinical use include mast cell stabilizers, leukotriene receptor antagonists, and synthetic inhibitors of leukotrienes.

Corticosteroids Corticosteroids are cortisollike drugs that influence metabolic pathways and have an anti-inflammatory effect. By reducing airway inflammation, corticosteroids are clearly useful in the management of asthma, but they have a more limited and targeted role in the management of COPD. Pharmacology Glucocorticoids (i.e., cortisol) are produced by the adrenal cortex via the hypothalamic-pituitary axis in response to physical and emotional distress. Although the usual daily secretion of cortisol is approximately 10 to 20 mg, as much as 400 to 500 mg per day can be secreted during periods of severe stress. Although the cellular mechanisms are incompletely understood, corticosteroids stimulate the transcription and creation of certain proteins, such as lipocortin-1, and inhibit DNA transcription, resulting in decreased cytokine production. The clinical effects of corticosteroids are delayed for several hours following administration, reflecting the time needed to create new proteins or inhibit cytokine production. Leukocytes, mucous glands, and blood vessels are glucocorticoid targets. The inhaled glucocorticoids differ in potency, lipophilicity, relative receptor binding affinity, and pharmacokinetics. Since glucocorticoid preparations are marketed and prescribed in relatively equipotent doses, potency may be the least important differentiating characteristic. However, lipophilicity and relative glucocorticoid receptor binding and dissociation affinities are important discriminants among the inhaled corticosteroids. These characteristics determine the rate of receptor association and dissociation and the amount of drug absorbed systemically following inhalation. All corticosteroids undergo hepatic metabolism. Orally administered drugs, including drug swallowed after inhalation, undergo significant first-pass metabolism. Mometasone furoate and fluticasone propionate, with an esterified lipophilic group at the 17-Îą positon, are the most lipophilic of the marketed inhaled corticosteroids; beclomethasone dipropionate, budesonide, triamcinolone acetonide, and flunisolide follow in descending order of lipophilicity. The relative receptor binding affinity and receptor association follow the same order as lipophilicity. Mometasone furoate differs from other inhaled corticosteroids in that it is less specific for glucocorticoid receptors; in addition, the drug demonstrates agonist activity at progesterone receptors and partial agonist activity at mineralocorticoid receptors.

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Clinical Use Corticosteroids are the cornerstone of therapy in the treatment of asthma; the role of glucocorticoid therapy in COPD is more limited.

inhaled corticosteroids. Twice-daily dosage regimens may be more effective for patients with severe or difficult-to-control asthma. Chronic Obstructive Pulmonary Disease


The role of airway inflammation in asthma is well established, and high-dose systemic (parenteral or oral) corticosteroids are standard therapy for patients experiencing severe acute exacerbations of asthma. Parenteral administration of corticosteroids is often used preferentially due to the inability of some patients to swallow medications while in respiratory distress or because of lack of oral access after intubation. Dose-ranging studies of intravenous corticosteroids have not established a minimum effective dose, although as little as 120 mg/d of methylprednisolone (in divided doses administered every 6 h) is effective in asthmatic adults having an acute exacerbation. The time to initial response, as evidenced by augmentation of FEV1 with bronchodilator administration, begins as early as 1 h after corticosteroid administration; maximal response is achieved in 8 to 12 h. Parenteral corticosteroid therapy is usually maintained for 24 to 72 h, with subsequent conversion to oral prednisone at 60 mg daily when the FEV1 reaches a threshold of 50 percent of predicted normal. This dose may be maintained for 2 to 7 d, followed by gradual tapering of the dose over 1 to 3 wk. Parenteral methylprednisolone is emerging as the corticosteroid of choice, due to its lower mineralocorticoid and greater glucocorticoid effects than hydrocortisone. Oral corticosteroid therapy is seldom indicated for chronic stable asthma. Oral therapy is maintained at the lowest dose possible to sustain control of symptoms and optimize peak expiratory flow in conjunction with inhaled β2 -adrenergic agonists. Hydrocortisone, methylprednisolone, or prednisone are most commonly used. Unlike prednisone, the first two agents do not require hepatic metabolism for therapeutic activity and are preferred in patients with significant liver disease. Inhaled corticosteroids offer direct delivery to the lung and reduced risk of systemic effects. To achieve the same effect as higher potency agents, the lower potency agents are given in higher doses; adverse effects are more likely to occur. The combination of an inhaled corticosteroid and a long-acting bronchodilator is better than either agent alone in terms of improving lung function and preventing asthma exacerbations; in patients with moderate-to-severe asthma, the combination of low-dose inhaled corticosteroid appears to be as effective as high-dose inhaled corticosteroid alone. Poor adherence with inhaled corticosteroid regimens is an ongoing issue. Inhaled corticosteroids initially required four-times-a-day dosing schedules, but they are now usually prescribed twice daily. Mometasone furoate, the newest inhaled corticosteroid, is FDA approved for once daily administration. Although data are limited, patients with stable mild to moderate asthma might benefit from a trial of once-daily

The mechanism underlying the beneficial effects of corticosteroids in COPD is not fully known, but changes in inflammatory gene transcription and modulation of β2 -adrenergic receptor function appear to play a role. No evidence exists that systemic corticosteroids prevent exacerbations in patients with stable COPD or that steroid responsiveness can be predicted. A common clinical practice has been to test steroid response by measuring the change in FEV1 following a trial of systemic corticosteroids and then limiting subsequent corticosteroid therapy to steroid responders. However, in a 3-y, large, randomized, double-blind, placebocontrolled prospective trial, no significant relationship between initial steroid response and subsequent FEV1 decline was found. Short courses (10 to 15 d) of moderate doses (40 mg/d of prednisone) of systemic corticosteroids in combination with standard bronchodilator therapies are effective for treating acute exacerbations of COPD in outpatients, inpatients, and patients in the emergency room who have moderate or severe COPD. However, the role of systemic corticosteroids in the treatment of patients with COPD who are receiving mechanical ventilation is unknown. Chronic maintenance therapy with inhaled corticosteroids reduces the incidence of acute exacerbations by 20 to 30 percent and improves health status in patients with stage III or IV COPD and a history of frequent exacerbations. Definitive data regarding the clinical usefulness of combining inhaled corticosteroids and long-acting bronchodilators are lacking. Guidelines published in 2004 recommend the combination of inhaled corticosteroid and long-acting bronchodilator for patients with severe or very severe disease and frequent exacerbations. Safety Short-term use (less than 14 d) of systemic corticosteroids is associated with mild glucose intolerance, fluid retention that may progress to edema and hypertension, proximal muscle weakness (especially with large parenteral doses), and mood alteration. Long-term systemic corticosteroids prolong the short-term effects; in addition, peptic ulcer disease, cataracts, increased risk of infection, and impaired wound healing occur. Truncal obesity, hirsutism, acne, moon-shaped facies, striae, and ecchymoses contribute to a cushingoid appearance. Disruption of bone metabolism predisposes patients to osteoporosis and resultant vertebral and long-bone fractures; inhibition of long-bone growth is the major complication in children who receive systemic corticosteroids. Suppression of the hypothalamic-pituitary-adrenal axis diminishes body cortisol stores, which, in turn, reduces the capacity of the body to confront stress, such as trauma, surgery, or infection.

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Inhaled corticosteroids are less systemically bioavailable due to poor absorption from the tracheobronchial tree. The most common adverse effect is local irritation of the oropharynx, cough, and bronchospasm. Dysphonia may arise from vocal cord myopathy induced by the presence of corticosteroid in the oropharynx. Thrush is easily avoided by rinsing the mouth after each use of a corticosteroid inhaler, using a spacer device to decrease deposition of drug particles in the mouth, and keeping the inhaler mouthpiece clean. Newer inhaled corticosteroids, such as fluticasone, undergo extensive first-pass metabolism to inactive substances, thereby decreasing concentrations of active drug and the potential for systemic adverse effects. Long-term studies of inhaled corticosteroids have not documented significant adrenal suppression. Steroid Resistance Patients with asthma who are unresponsive to usually sufficient doses of corticosteroids are described as steroid resistant. Steroid resistance has been formally defined by a smaller than 15 percent increase in FEV1 after 7 d of oral prednisolone administered at a dose of 20 mg daily in bronchodilatorresponsive asthmatics. Steroid resistance must be distinguished from steroid dependency, which is usually defined as the need for systemic corticosteroids for maintaining control of asthma. Steroid resistance may involve reduced metabolism of oral corticosteroids to the active compound or accelerated drug clearance. An impaired cellular response to corticosteroids has been observed in steroid-resistant asthmatics, and altered receptor binding or the presence of antilipocortin antibodies may contribute to the phenomenon.

Corticosteroid-Sparing Agents Chronic systemic corticosteroid therapy required for the treatment of severe airflow obstruction often results in numerous side effects. Therefore, many anti-inflammatory agents have been evaluated in an effort to identify alternatives to systemic corticosteroid therapy. Troleandomycin Since the 1960s, anecdotal clinical observations suggested that the macrolide antibiotic, troleandomycin, might reduce corticosteroid requirements in patients with severe asthma by decreasing steroid metabolism. However, results from doubleblind, randomized trials are mixed. To date, the weight of evidence suggests that troleandomycin has little or no clinical effect at relieving airway obstruction or inflammation independent of its effects on corticosteroid metabolism. Troleandomycin has little role in the current therapy of severe, steroid-dependent asthma. Methotrexate From initial observations in patients with rheumatoid arthritis and coexistent asthma, methotrexate therapy appeared

Pulmonary Pharmacotherapy

to ameliorate both asthmatic and arthritic symptoms. Currently, no clear documentation exists of the clinical efficacy of methotrexate administration in severe, steroid-dependent asthma. Due to significant side effects, potentially fatal complications and long-term toxicity concerns, prudency argues for limiting methotrexate administration in severe, steroiddependent asthmatics to empiric trials in individual patients or investigations in large-scale, controlled clinical trials. Cyclosporine Used widely in organ transplantation, cyclosporine inhibits lymphokine synthesis, thereby blocking the activation of T cells. The absence of significant drug interactions with β-adrenergic agonists, corticosteroids, or theophylline makes cyclosporine particularly attractive as an anti-inflammatory agent for use in asthma. However, only one of three small, double-blind, placebo-controlled studies suggested that cyclosporine increased peak expiratory flow and FEV1 , reduced exacerbations of airway obstruction, or reduced oral prednisolone dosage by over 60 percent. Hypertrichosis, hypertension, reversible nephrotoxicity, and a large number of nonspecific side effects limit widespread use of cyclosporine in the management of asthma. Other Agents The search continues for anti-inflammatory agents with potential efficacy in asthma. A broad spectrum of agents have been touted, including gold salts, pooled immunoglobulins, azathioprine, colchicine, dapsone, hydroxychloroquine, ketotifen, nonsteroidal anti-inflammatory agents, and inhaled heparin. The original studies purporting the efficacy of these various agents comprise mainly anecdotal reports or small case series. Use of these drugs in obstructive airway disease should be restricted to well-designed, controlled clinical trials.

Mast Cell Stabilizers Cromolyn sodium and nedocromil exert anti-inflammatory actions by stabilizing mast cells. This blockade of mast cell degranulation prevents inflammatory mediator release, which is partially responsible for the bronchoconstriction and epithelial injury that are characteristic of asthma. Cromolyn Sodium Cromolyn sodium was the first mast cell stabilizer to be approved for clinical use in asthma and is widely employed in pediatric asthmatics. Pharmacology

Cromolyn sodium is a potent inhibitor of inflammatory responses. Cromolyn sodium diminishes early phase reactions in asthma by blocking the release of intracellular calcium and inhibiting enzymes responsible for mast cell degranulation; cromolyn reduces late phase reactions in asthma by inhibiting production of the enzymes necessary for superoxide

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generation. Cromolyn sodium may also exhibit tachykinin antagonism, accounting for some of its anti-inflammatory properties. In vitro, cromolyn sodium potentially inhibits the activation of inflammatory cells, antibody-induced granulocyte cytotoxicity, IgE production by atopic cells, and monocyte IgG production. Clinical Use

Cromolyn sodium is indicated for the management of asthma in children and atopic young adults. Cromolyn sodium, alone or in combination with β2 -adrenergic agonists, improves exercise tolerance, enhances sleep quality, reduces asthma exacerbations, and facilitates patient acceptance of therapy. Patients diagnosed with asthma prior to the age of 4 years, patients less than 17 years of age, and patients with longterm asthma (more than 5 y) may experience maximal benefit from cromolyn sodium therapy. Cromolyn sodium significantly improves seasonal allergic asthma symptoms. Longterm use of cromolyn sodium (at least 12 wk) four times daily is recommended for effective control of chronic bronchial hyperresponsiveness, while a shorter treatment duration (up to 6 wk) usually suffices for control of seasonal allergic attacks. Cromolyn sodium prophylaxes against exerciseinduced asthma in children as efficaciously as do beta2 agonists. Premedication with cromolyn sodium, inhaled β2 -adrenergic agonist, or both, 15 to 30 min prior to vigorous exercise is recommended for children and adults. Cromolyn sodium is a useful adjunct to bronchodilators in adults with atopic asthma; it may provide added benefit when administered in conjunction with inhaled corticosteroids. Safety

Cromolyn sodium causes few adverse effects, even after longterm use. Its efficacy in preventing childhood asthma symptoms and safety record make cromolyn sodium a first-line agent, in conjunction with β2 -adrenergic agonists, in management of asthma in children. Nedocromil Nedocromil also stabilizes mast cells in the bronchial mucosa, but it has a broader anti-inflammatory spectrum than cromolyn sodium. Nedocromil blocks activation of eosinophils and neutrophils, further reducing inflammation. Dose-dependent inhibition of IL-4-induced IgE and IgG production has been demonstrated in vitro. Nedocromil is useful prophylactically against asthma exacerbations, but not therapeutically for acute bronchospasm. The similar pharmacology of cromolyn sodium and nedocromil have prompted direct comparisons of the two agents in asthmatics. Nedocromil appears to be more effective as a bronchodilator-sparing agent than cromolyn sodium in adults, but it provides a similar level of protection against exercise-induced asthma in children. Lack of long-term experience with nedocromil relegates it to second-line status as an adjunct to bronchodilators in the management of asthma.

Leukotriene Antagonists and Inhibitors The leukotriene antagonists and inhibitors are the first new class of asthma drugs to be developed in several decades. Advances in our understanding of the inflammatory pathogenesis of asthma and the role of leukotrienes as inflammatory mediators have generated great interest in the development of and therapeutic potential for these drugs. Leukotrienes are synthesized from arachidonic acid, a fatty acid stored in phospholipids of cell walls. Numerous stimuli, including IgE receptor activation, antigen-antibody interactions, and activation of phospholipase A2 induce release of arachidonic acid from phospholipids. Arachidonic acid is converted to a variety of products via several unrelated pathways; the 5-lipoxygenase pathway is the pathway of importance in asthma. Leukotriene A4 (LTA4 ) is metabolized by two different pathways to either the nonpeptide LTB4 or the cysteinyl leukotrienes (LTC4 , LTD4 , and LTE4 ). LTB4 recruits and activates inflammatory cells but has no effect on bronchial tone or reactivity. The cysteinyl leukotrienes stimulate smooth-muscle contraction, increase vascular permeability, and enhance bronchial hyperresponsiveness; thus, they have a major role in the pathogenesis of asthma. Leukotriene action may be inhibited by either selective receptor blockade or interference with synthesis. Most clinical experience has been with the LTD4 receptor antagonists, since LTC4 , LTD4 , and LTE4 interact with a common LTD4 receptor. Inhibition of 5-lipoxygenase (5-LO) reduces the generation of all leukotrienes. Clinical Use Two LTD4 receptor antagonists (montelukast and zafirlukast) and one 5-LO inhibitor are FDA-approved and marketed in the United States. The leukotriene receptor antagonists are alternate anti-inflammatory medications for long-term use in children and adults with mild to moderate asthma, including aspirin- or exercise-induced asthma and asthma associated with concomitant allergic rhinitis. To date, data are insufficient to assess the role of antileukotriene receptor antagonists in the management of acute exacerbations of asthma or COPD. Inhaled glucocorticosteroids in doses of 400 µg/d of beclomethasone equivalent are more effective than the leukotriene receptor antagonists in adults with mild or moderate asthma. However, addition of a leukotriene receptor antagonist to therapy that includes an inhaled corticosteroid results in some further improvement in lung function. Safety Montelukast and zafirlukast are well tolerated. Montelukast chewable tablets contain phenylalanine and therefore are contraindicated in patients with phenylketonuria. Hepatotoxicity has been reported with zileuton. Zileuton is contraindicated in patients with active liver disease and in patients with serum transaminase levels exceeding three times the upper limit of normal. Baseline liver function tests should be obtained prior to initiating therapy with zileuton, and patients should be monitored closely for the duration of therapy. Zileuton must

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be discontinued if serum transaminase levels exceed five times the upper limit of normal. The leukotriene receptor antagonists have numerous drug interactions.

Pulmonary Pharmacotherapy

Nonetheless, close observation, including frequent assessment of vital signs, is recommended for at least 2 h following initial drug administration; similar monitoring is warranted for at least 1 h following each subsequent administration.

Immunoglobulin E Antibody Pharmacology Omalizumab is a recombinant humanized antibody developed for therapy of allergic diseases that has significant efficacy in severe atopic asthmatics. By specifically binding with high affinity to immunoglobulin E (IgE), but not to other immunoglobulins, omalizumab does not activate mast cells or basophils. Clinical efficacy depends upon almost total elimination of circulating IgE; therefore, the role of omalizumab is limited to those asthmatics with elevated IgE levels. Parenteral administration of omalizumab produces rapid binding of circulating IgE, with serum levels slowly rebounding over the subsequent 4 to 6 wk. Several randomized, double-blind placebo controlled studies of omalizumab have been completed in patients more than 12 years of age with moderate to severe atopic asthma refractory to high-dose inhaled corticosteroids; patients also received inhaled, long-acting β agonists and oral leukotriene antagonists. Use of omalizumab resulted in reproducible decreases in asthmatic flares, reduced inhaled and oral steroid dosage, and improved quality of life. Clinical Use Omalizumab therapy is indicated for moderate to severe asthmatics who have serum IgE levels exceeding 30 IU/ml (75 ng/ml) and an allergic basis for their asthma, as demonstrated by positive skin testing or radioallergosorbent tests (RAST) to common antigens. As a chronic therapy, omalizumab treatment should not be initiated in the setting of an acute asthma flare. Subcutaneous administration of omalizumab every 2 to 4 wk is required to maintain reductions in circulating IgE, with required dose and frequency dependent upon body weight and initial serum IgE level. Up to three separate subcutaneous injections, each not exceeding 150 mg at a single site, may be required at each administration. Subsequent serum IgE measurements are unnecessary, as levels are expected to plummet to negligible levels and slowly rebound after each administration of the drug. The total duration of necessary therapy is unclear, although a review every 6 to 12 mo is commonly employed to assess whether improved asthma control has been achieved (as indicated by reduced inhaled and oral steroid usage, fewer emergency medical encounters and hospitalizations, and decreased overall medical costs). Safety Minor local skin reactions at the injection sites occur in almost one-half of patients. A diffuse urticarial rash has been reported, but it is extremely uncommon. Severe hypersensitivity reactions, including anaphylaxis, are rarely observed.

MUCOKINETIC AGENTS Chronic sputum production or inspissated airway secretions plague most patients with obstructive lung disease. Some mucokinetic agents are effective in promoting the clearance of obstructed airways.

Dornase Alpha Purulent, viscous secretions contribute to airway obstruction and chronic pulmonary infections in patients with cystic fibrosis, chronic bronchitis, and bronchiectasis. High concentrations of mucus contribute to the increased viscosity of bronchial secretions in these conditions. Polymorphonuclear leukocytes recruited to ward off chronic pulmonary infections eventually degenerate, releasing DNA into the extracellular environment. Although recombinant human deoxyribonuclease I (DNAse) metabolizes DNA liberated from airway leukocytes, the high concentration of DNA released in these chronic conditions overwhelms the endogenous ability of the lungs to clear the DNA. Exogenous administration of DNAse promots clearance of airway DNA by reducing mucus viscosity, increasing mucus clearance, diminishing airway obstruction, and preventing recurrent pulmonary infections. Results of randomized clinical trials of nebulized DNAse as short-term adjunctive therapy in patients with cystic fibrosis demonstrate modest dose-dependent improvement in pulmonary function and reduction in symptoms. Placebo-controlled investigations of DNAse in adults with chronic bronchitis or bronchiectasias not due to cystic fibrosis reveal prolonged antibiotic therapy requirements, no enhancement of pulmonary function, and no improvement in quality of life.

N-Acetylcysteine N-acetylcysteine (NAC) lyses disulfide bonds in mucus proteins, reducing airway mucus viscosity. Increased mobilization of mucus and decreased inspissation with use of inhaled NAC has been reported in patients with asthma or COPD. However, randomized placebo-controlled trials in COPD have demonstrated no objective benefit of treatment with NAC. Due to the in vivo conversion of NAC to the potent antioxidants, glutathione and cysteine, recent investigations have focused on NAC as an immunomodulator. Since antioxidant formation is distinct from the local mucolytic effect, oral NAC has been investigated in most studies. Unfortunately, intravenous NAC in patients with acute lung injury

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or the acute respiratory distress syndrome (ARDS) offers no significant reduction in mortality or disease progression.

Iodinated Agents Some iodinated compounds have mucolytic-expectorant properties. When ingested, iodide is liberated and stored in secretory glands of the tracheobronchial tree. Upon stimulation by coughing or inhalation of irritant substances, iodide promotes secretion of respiratory tract fluid and mucoproteins and augments ciliary activity. Increased mucus mobilization and decreased mucus viscosity result. Adverse events appear to be infrequent, although thyroid dysfunction may be induced by the iodine load and has been reported after long-term use in elderly patients with COPD. Clinicians should use iodinated compounds with caution in elderly patients or those with preexisting thyroid dysfunction.

Sodium Bicarbonate Sodium bicarbonate solutions (2 to 7.5 percent) are frequently used as vehicles for bronchodilators and Nacetylcysteine. By raising the pH of the respiratory tract fluids, aerosolized sodium bicarbonate weakens the saccharide structure of airway mucus, increasing its susceptibility to proteases and promoting its removal through enhanced ciliary activity. These effects are additive when used with N-acetylcysteine and cause reduction in mucus viscosity. Local irritation from hypertonic sodium bicarbonate solutions may occur; cough and bronchospasm have been observed in some patients. Therefore, bronchodilators should be given prior to sodium bicarbonate aerosols.

Guaifenesin Guaifenesin remains the only agent approved by the FDA as an expectorant, based upon a single placebo-controlled trial in patients with chronic bronchitis in whom guaifenesin significantly reduced sputum volume and improved sputum quality. These patients also experienced subjective relief of respiratory congestion, and no adverse effects were reported. However, the purported expectorant properties of guaifenesin have not been substantiated in well-controlled studies.

PHYSIOLOGICAL REPLACEMENTS Replacement therapy comprises a novel class of agents to replace deficient, or augment existing, endogenous substances. To date, replacement therapy has been employed only in adults with α1 -antitrypsin deficiency or neonates with respiratory distress syndrome. However, clinical studies of replacement therapy are underway in patients with a wide spectrum of obstructive and other lung diseases.

α1 -Antitrypsin α1 -Antitrypsin is a glycoprotein synthesized and secreted by hepatocytes. A protease inhibitor, α1 -antitrypsin, blocks the actions of neutrophil-derived elastase in the lung. Inherited deficiency of α1 -antitrypsin promotes development of emphysema in adulthood; tobacco smoking rapidly accelerates the clinical presentation and severity of the emphysema. Since 1988, α1 -antitrypsin replacement therapy has been available for intravenous administration as a purified product derived from pooled human plasma. Clinical Use Weekly or monthly intravenous infusion of α1 -antitrypsin to deficient patients increases α1 -antitrypsin levels in serum and bronchoalveolar lavage specimens and restores antielastase activity in serum and alveolar lining fluid. Numerous case reports and small series dispute whether α1 -antitrypsin replacement reduces the accelerated rate of decline in pulmonary function associated with α1 -antitrypsin deficiency. Currently, α1 -antitrypsin replacement therapy is recommended for patients with α1 -antitrypsin deficiency who are older than 18 years of age and have both abnormal pulmonary function tests and a serum α1 -antitrypsin level less than 11 mM. Replacement therapy for α1 -antitrypsin deficient patients is not recommended after lung transplantation. Side Effects α1 -Antitrypsin replacement therapy is remarkably nontoxic, and current preparations have few side effects other than mild fever. Repeated administration of α1 -antitrypsin does not shorten the serum half-life, suggesting that α1 -antitrypsin antibodies do not develop, even in patients with complete deficiency.

Pulmonary Surfactant The administration of pulmonary surfactant to premature infants with, or at risk for, respiratory distress syndrome has become the standard of care. Surfactant administration decreases mortality from respiratory distress syndrome by 30 to 40 percent and reduces morbidity due to pneumothoraces, interstitial emphysema, bronchopulmonary dysplasia, and intraventricular hemorrhage. Endogenous pulmonary surfactant is an emulsion of phospholipids, cholesterol, and apoproteins that reduces surface tension within alveoli. Natural surfactant is commercially available and is prepared from lung tissue or lavages from a variety of species. Synthetic surfactant is available from a number of commercial sources, although the optimal composition of the material remains to be determined. Pulmonary surfactants reduce oxygen toxicity by scavenging free radicals, and the surfactants may be cytoprotective for alveolar cell surfaces. Pulmonary surfactants suppress mediator release by inflammatory cells and may deactivate inflammatory mediators upon release. In vitro studies indicate that surfactant suppresses lymphocyte mitogenic

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responses, leading to a decrease in inflammatory cell influx. Pulmonary surfactant has both antibacterial and antiviral properties which are mediated by an increase in alveolar macrophage phagocytosis. Surfactant may promote airway clearance by changing the physical properties of mucus, as well as by increasing ciliary beat frequency. Finally, pulmonary surfactant may directly relax airway smooth muscle. This spectrum of putative biologic activities may directly interrupt the pathogensis of airway inflammation, chronic infection, and bronchoconstriction seen in most obstructive lung diseases. Limited clinical data are available to document the effects of pulmonary surfactant in adults. In anecdotal case reports and small patient series, surfactant administration to patients with respiratory failure has produced occasional increases in Pao2 , although usually no change in radiographic, physiological, or respiratory findings were reported. However, in two large, double-blind, randomized, placebo-controlled trials, administration of synthetic surfactant for 5 days yielded no demonstrable physiological benefit and no significant decrease in mortality rate measured at 30 days.

Pulmonary Pharmacotherapy

patients with hypercapnic obstructive lung disease, acetazolamide produces modest reductions in Paco2 and pH, while improving Pao2 . Long-term safety and efficacy data are unavailable, and larger studies will be required before acetazolamide therapy can be recommended for hypoventilation associated with either sleep-disordered breathing or hypercapnic obstructive lung disease.

Almitrine Almitrine bismesylate stimulates peripheral chemoreceptors in the carotid body and has no central respiratory stimulant effect. Also a pulmonary vasoconstrictor, almitrine improves ventilation-perfusion matching and, therefore, has received attention in small case series as adjunctive therapy for hypoxemic respiratory failure from ARDS. Although marketed in Europe, almitrine bismesylate is not available in the United States. Toxicities and side effects include right ventricular strain from pulmonary arterial vasoconstriction, peripheral neuropathy, weight loss during long-term therapy, and diuretic activity.

Methylxanthines RESPIRATORY STIMULANTS Respiratory stimulants are a group of pharmacologically unrelated agents used to treat diverse pathophysiological conditions, including obstructive or central sleep apnea, COPD, postanesthesia respiratory depression, and acute mountain sickness.

Aminophylline and theophylline are methylxanthine bronchodilators that augment the central ventilatory response to hypoxia, likely through adenosine receptor activation in the carotid body and or brain stem ventilatory control centers. Limited data suggest theophylline reduces periodic breathing at high altitude. Used to treat apnea of prematurity and infants with periodic breathing, methylxanthines are less useful in the treatment of obstructive sleep apnea or in stimulating adult respiration in normobaric environments.

Acetazolamide Acetazolamide is a noncompetitive inhibitor of carbonic anhydrase that induces a weak diuresis and mild metabolic acidosis. Currently, acetazolamide is approved for the prophylaxis of acute mountain sickness and has been proposed as an alternative therapy for chronic mountain sickness. Sometimes used to treat patients with chronic hypercapnia and druginduced or compensatory metabolic alkalosis, acetazolamide may have both indirect and direct respiratory stimulant properties. The increased hydrogen concentration indirectly stimulates respiration via peripheral and medullary chemoreceptor stimulation. Acetazolamide may also directly stimulate respiration by increasing cerebral blood flow through mechanisms unrelated to the metabolic acidosis. Recently, a small, double-blind, placebo-controlled study demonstrated acetazolamide improves nocturnal oxyhemoglobin saturations and reduces hematocrit in patients with chronic mountain sickness. However, further large scale studies will be required before acetazolamide can be recommended over standard therapies, including phlebotomy or relocation to lower altitude. Limited data from short-term trials of acetazolamide in hypercapnic patients are available. In small numbers of

Doxapram Doxapram is a short-acting, parenterally administered, peripheral chemoreceptor agonist and central respiratory stimulant. Doxapram has been approved for postanesthesia respiratory depression or apnea, drug-induced central nervous system respiratory depression, and short-term use as a respiratory stimulant in acute respiratory insufficiency superimposed on chronic pulmonary disease. Limited case reports and small studies describe doxapram as a respiratory stimulant in COPD complicated by acute respiratory failure.

Medroxyprogesterone Medroxyprogesterone is a gestational respiratory stimulant. Although its mechanism of action is unclear, medroxyprogesterone increases minute ventilation and produces hypocapnia in normal subjects. However, it does not improve breathing disturbances during sleep in normocapnic patients with obstructive sleep apnea. Limited data reveal medroxyprogesterone stimulates minute ventilation in patients with hypercapnic obstructive lung disease, without improving nocturnal oxygenation.

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Protriptyline Protriptyline is a tricyclic antidepressant that is cited frequently as an effective respiratory stimulant in patients with obstructive sleep apnea. The mechanism of action may include suppression of rapid eye movement (REM) sleep and increased tone in the upper airway muscles. Protriptyline is contraindicated in patients with glaucoma or prostatic hypertrophy, and anticholinergic side effects limit its usefulness.

SUGGESTED READING Anzueto A, Baughman RP, Guntapalli KK, et al: Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med 334:1417–1421, 1996. Blitz M, Blitz S, Hughes R, et al: Aerosolized magnesium sulfate for acute asthma. Chest 128:337–344, 2005. Boulet L-P: Once-daily inhaled corticosteoirds for the treatment of asthma. Curr Opin Pulm Med 10:15–21, 2003. Bowton DL, Goldsmith WM, Haponik EF: Substitution of metered-dose inhalers for hand-held nebulizers. Success and cost savings in a large, acute-care hospital. Chest 101:305–308, 1993. Bratton SL, Odetola FO, McCollegan J, et al: Regional variation in ICU care for pediatric patients with asthma. J Pediatr 147:355–361, 2005. Brusasco V, Hodder R, Miravitlles M, et al: Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 58:399–404, 2003. Burge PS, Calerley PMA, Jones PW, et al: Prednisolone response in patients with chronic obstructive pulmonary disease: results for the ISOLDE study. Thorax 58:654–658, 2003. Ducharme FM: Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: Systematic review of current evidence. Br Med J 326:621–625, 2003. Federal Register: Use of ozone-depleting substances: Removal of essential-use designations. Fed Reg 70:17168–17192, 2005. Fischer R, Lang SM, Leitl M, et al: Theophylline and acetazolamide reduce sleep-disordered breathing at high altitude. Eur Respir J 23:47–52, 2004.

Greenstone M, Lasserson TJ: Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database 2000:CD000223, 2003. Gross NJ: Tiotropium bromide. Chest 126;1946–1953, 2004. Irwin RS: Systemic corticosteorids for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 348:2679–2681, 2003. Kattan M: Mirror images: Is levalbuterol the fairest of them all? J Pediatr 143:702–704, 2003. Lock SH, Kay AB, Barnes NC: Double-blind, placebocontrolled study of cyclosporin A as a corticosteroidsparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 153:509–514, 1996. Man SF, Sin DD: Inhaled corticosteroids in chronic obstructive pulmonary disease. Drugs 65:579–591, 2005. Marcus PM: Incorporating anti-IgE (omalizumab) therapy into the pulmonary medicine practice: Practice management implications. Chest 129:466–474, 2006. McDonald NJ, Bara AI: Anticholinergic therapy for chronic asthma in children over two years of age. Cochrane Database 3:CD003535, 2003. Mullen M, Mullen B, Carey M: The association between βagonist use and death from asthma. JAMA 270:1842–1845, 1993. Niven AS, Argyros G: Alternate treatments in asthma. Chest 123:1254–1265, 2003. Richalet J-P, Rivera M, Bouchet P, et al: Acetazolamide: A treatment for chronic mountain sickness. Am J Resp Crit Care Med 172:1427–1433, 2005. Rodrigo GJ, Castro-Rodriguez JA: Anticholinergics in the treatment of children and adults with acute asthma: A systematic review with meta-analysis. Thorax 60:740–746, 2005. Rowe BH, Bretzlaff JA, Bourdon C, et al: Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database 4:1–22, 2005 Vincken W, van Noord JA, Greefhorst APM, et al: Improved health outcomes in patients with COPD during 1 year’s treatment with tiotroprium. Eur Respir J 19;209–216, 2002. Wagenaar M, Vos P, Heijdra Y, et al: Comparison of acetazolamide and medroxyprogesterone as respiratory stimulants in hypercapneic patients with COPD. Chest 123:1450–1459, 2003. Westby M, Benson M, Gibson P: Anticholinergic agents for chronic asthma in adults. Cochrane Database 3:CD003269, 2004.

151 Intubation and Upper Airway Management C. William Hanson III

Erica R. Thaler




The first known use of positive pressure ventilation (PPV) as a medical intervention dates back to the sixteenth century, as described in Vesalius’ de Humani Corporis Fabrica: But that life may in a manner of speaking be restored to the animal, an opening must be attempted in the trunk of the trachea, into which a tube of reed or cane should be put; you will then blow into this, so that the lung may rise again and the animal take in air. Indeed with the slight breath in the case of the living animal, the lung will swell to the full extent of the thoracic cavity, and the heart become strong . . . for when the lung, long flaccid, has collapsed, the beat of the heart and arteries appears wavy, creepy, twisting; but when the lung is inflated at intervals, the motion of the heart and arteries does not stop. . . .

Vesalius subsequently resuscitated a Spanish nobleman by inflating his lungs through the trachea, resulting in resumption of cardiac activity and nearly in Vesalius’ death at the hands of the Inquisitors. Vesalius, an excellent anatomist who disproved many of the cherished teachings of Galen that had been accepted as absolute truth for 13 centuries, was viewed as a heretic by his peers. In fact, one described him as “an impious madman who is poisoning all of Europe with his vaporings.” Because of lack of enthusiasm in response to Vesalius’ findings, a 100-year hiatus attended the next attempt at

endotracheal ventilation. In 1667, Robert Hooke, a prominent mathematician, geologist, and paleontologist kept a dog alive by intermittently insufflating air into its trachea using a set of bellows. One century later, in 1744, John Fothergill, one of the founders of the British Humane Society, described successful mouth-to-mouth resuscitation. Because of concerns over development of emphysema and tension pneumothorax as complications of PPV (recognized as early as 1827), research on artificial ventilation in the nineteenth and early twentieth centuries focused on negative-pressure ventilation (NPV). Iron lungs, tank ventilators, cuirass ventilators, and a variety of strange and remarkable differential pressure chambers and boxes were developed in the United States and Europe. The devices were powered by hand, water, steam, or electricity, and, in some cases, by the patient himself. However, PPV became incorporated into the resuscitation strategy of the Dutch Humane Society, which advocated mouth-to-mouth ventilation in conjunction with external thoracic and abdominal compression. In 1776, John Hunter described an apparatus that blew fresh air into the lungs with one set of bellows and sucked “bad” air out with a second set. By the end of the nineteenth century, a surge in the evolution of thoracic surgery led to the use of tracheal intubation and PPV through cuffed tubes as acceptable components of medical care. An American surgeon, Joseph O’Dwyer,

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designed a series of metal tubes that were inserted between the vocal cords of children afflicted with diphtheria. Rudolph Matas referred to O’Dwyer’s devices in describing “intralaryngeal intubation” and “insufflation” and noted that, “the procedure that promises the most benefit in preventing pulmonary collapse in operations is . . . the rhythmic maintenance of artificial respiration by a tube in the glottis.” In the early part of the twentieth century, Franz Kuhn, a German surgeon, described techniques for oral and nasal intubation using flexible metal tubes introduced into the trachea with the assistance of the operator’s index finger; the procedure was preceded by application of topical anesthesia using cocaine. The airway was then sealed with a supralaryngeal flange and gauze packing. Among the further advances that followed was the first laryngoscope created by Alfred Kirstein in Berlin. However, his model was never widely accepted. Chevalier Jackson developed a U-shaped laryngoscope that otorhinolaryngologists still use for endoscopy but was never adopted by anesthesiologists. In 1913, Janeway described an endotracheal tube with a removable cuff, an anesthesia ventilator, and a batterypowered laryngoscope. From 1900 to 1920, Dorrance, Elsberg, L¨owen, and Sievers published methods for tracheal intubation and PPV. The most influential figure in the history of endotracheal intubation is Sir Ivan Magill. Along with Stanley Rowbotham, he used anesthetics on Royal Army casualties during World War I (in particular, on patients with disfiguring facial injuries). Their patients were often intubated nasally to allow freer access to the face by the surgeon. Magill’s inventions include the Magill forceps, which is still used to facilitate nasal intubation, semirigid endotracheal tubes fashioned from mineralized rubber, and the Magill circuit, an L-shaped laryngoscope. He is also credited with describing the “sniffing position.”

Arthur Guedel, an American contemporary of Magill, refined the cuffed endotracheal tube and, by extensive experimentation on animal tracheas, determined that the best position for the cuff was just below the vocal cords. He popularized use of the cuffed endotracheal tube by publicly anesthetizing his pet dog, “Airway,” and immersing the animal in a tank of water. Upon awakening, the dog shook itself off and departed the arena. In current practice, access to the trachea through the nasopharynx or oropharynx takes advantage of laryngoscope blades invented in the 1940s by Robert Miller, a Texas clinician, and Robert Macintosh, an Oxford professor. The Miller blade was an advance over similar straight blades; it was designed to pick up the epiglottis and expose the vocal cords. The curved Macintosh blade differed from previous models and was designed for insertion between the epiglottis and tongue. Although many variants of the two blades are available today, including those with different angulations, prisms, and fiberoptic bundles, the Miller and the Macintosh blades remain the mainstays of the anesthesiologist’s armamentarium. The first departments of anesthesiology were founded in the early 1940s. Thereafter, the skills required for management of the upper airway and endotracheal intubation became widely disseminated in the United States and the United Kingdom.

UPPER AIRWAY ANATOMY AND CLINICAL RELEVANCE The two functional conduits between the trachea and atmosphere—the oropharynx and the nasopharynx (Fig. 151-1)—join at the level of the base of the skull to form the hypopharynx. The oropharynx includes the base of the tongue,

Figure 151-1 Comparative anatomy of adult and infant airways. (Courtesy of Barash P, et al (eds.): Clinical Anesthesia, Philadelphia, Lippincott, 1989, p 544, D. Factor, illustrator.)

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uvula, and tonsils. The nasopharynx is separated from the oropharynx by the mobile soft palate. The hypopharynx includes the vallecula, which is the space posterior to the tongue and anterior to the cervical esophageal inlet. Typically, the adult epiglottis is crescentic, moderately stiff, and thin. Because of its ligamentous attachments, the adult epiglottis can be lifted indirectly using a curved laryngoscope blade applied to the base of the tongue. The U-shaped infant epiglottis is longer and floppier than the epiglottis of the adult. Therefore, a straight blade is typically required to lift the infant epiglottis directly during endotracheal intubation. The adult and infant airways differ in several other respects. The narrowest portion of the adult airway is the rima glottidis, the area between the vocal cords; in contradistinction, the cricoid is the narrowest portion of the infant’s airway. The infant larynx is also situated relatively more cephalad than the larynx of the adult; in addition, the vocal cords of the infant are angled, whereas the vocal cords of the adult are perpendicular to the airway. In an awake patient, with the head in the neutral position (i.e., neither flexed nor extended), air moves freely through both the oropharynx and nasopharynx. In most normal subjects, the same is true during sleep. Abnormalities of any of the component parts of the upper airway can impede airflow during respiration while awake; alternatively, impeded airflow may only become evident during sleep (e.g., as snoring or obstructive apnea). Consequently, a directed history and physical examination should be performed prior to any procedure on the airway. A history of nasal polyps or nasal septal deviation mandates caution prior to nasotracheal intubation, transnasal passage of a fiberoptic scope, or insertion of a nasal airway. The patient’s sleeping partner is often the best source of information about snoring and apnea, manifestations that may result from a variety of upper airway abnormalities, including soft tissue redundancy, masses, polyps, stenosis, or lymphoid hypertrophy from the nose to the hypopharynx and larynx. Vocal changes or abnormalities may suggest abnormalities of the vocal cords and warrant preintubation evaluation. The physical examination of the airway is preceded by a conversation with the patient. Hoarseness, stridor, tachypnea, and coughing suggest potential upper airway problems. The examination then can be pursued systematically beginning with the nasopharynx. The patient’s ability to breathe through a single nostril (when the mouth is closed and the other nostril occluded) indicates that the passage is relatively patent. Asymmetry often exists between the two sides and, whenever possible, instrumentation should be performed on the more patent side. The ability to open the mouth is limited in patients with temporomandibular joint disease. The temporalis muscle may be scarred or fibrotic (e.g., secondary to prior radiation) resulting in restricted mandibular mobility. Fractures to the mandible produce limited ability to open the mouth that, when the limitation is caused by muscle spasm, disappears with anesthesia. Some fractures functionally affect the mobility of the jaw, irrespective of anesthetic state. Inability

Intubation and Upper Airway Management

to open the mouth more than 40 mm is considered to be clinically significant. The patient’s dentition should also be assessed prior to elective management of the airway. Protruding maxillary incisors (“buck teeth”) interfere with direct laryngoscopy by restricting the extent to which the laryngoscope blade can be aligned with the trachea. Dental caps and other prostheses are fragile and easily damaged during laryngoscopy. The laryngoscope may become lodged in gaps between the maxillary teeth during instrumentation and interfere with intubation. Severe dental caries or periodontal diseases make it easier to dislodge teeth during airway instrumentation. The edentulous patient often has an atrophic mandible and large tongue and may be difficult to ventilate by mask because of poor fit of the mask. Intubation of the trachea in such a patient becomes difficult because the tongue, no longer constrained by the teeth, interferes with visualization of the larynx. Abnormalities of the tongue, hard palate, tonsillar pillars, and hypopharyngeal structures can impede or prevent intubation. Normally the tongue is small and sufficiently flexible to be displaced by a laryngoscope blade during visualization of the vocal cords. However, the tongue is enlarged in obese patients, those with angioedema or impaired lymphatic drainage (e.g., after cervical surgical procedures or trauma), or in the setting of certain neoplasms. Burns, scars, or radiation of the submandibular soft tissue prevent lateral displacement of the tongue into the oropharynx during laryngoscopy. Similarly, in patients with small jaws (“receding chins”), displacement or flattening of the tongue during laryngoscopy is difficult, making intubation a challenge. A hyomental distance (the distance from the hyoid bone to tip of the mandible) of less than 6 cm should raise awareness of potential difficulty with intubation. A cleft or high, arched palate is seen in a variety of congenital abnormalities of the facial bones, including the Treacher-Collins, Pierre Robin, Klippel-Feil, Goldenhar, Beckwith-Wiedemann, and Crouzon’s syndromes, as well as the mucopolysaccharidoses. Affected patients are difficult or impossible to intubate using standard approaches. Intraoral, oropharyngeal, hypopharyngeal, and laryngeal lesions, as well as tonsillar hypertrophy, can interfere with both laryngoscopy and ventilation by mask. The epiglottis can be infiltrated, inflamed, floppy, or enlarged by fat. The retropharyngeal and lateral pharyngeal spaces are continuous with and therefore subject to expansion by processes that involve the mediastinum (e.g., the presence of edema, blood, pus, or soft-tissue emphysema). Patients with epiglottitis and parapharyngeal swelling often exhibit a characteristic posture, sitting upright in the sniffing position and drooling. The preferred position for visualization of the vocal cords is the sniffing position (Fig. 151-2). However, this position may be unsuitable in some patients or impossible to achieve in others. The normal range for flexion and extension of the neck ranges from 90 to 165 degrees. A variety of disorders limit this range. Patients with cervical osteophytes or ankylosing spondylitis, who are often fixed in an anteroflexed head

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objectively the airwayâ&#x20AC;&#x2122;s suitability for placement of the endotracheal tube. The ability to visualize the soft palate, fauces, tonsillar pillars, and uvula is used to predict the degree of difficulty in exposing the larynx. A careful examination of the airway, coupled with attention to difficulties during prior procedures and the physical features described above, permit adequate preparation for instrumentation of the difficult airway.

UPPER AIRWAY MANAGEMENT Figure 151-2 The sniffing position with the oral, pharyngeal, and tracheal axes.

position, may be difficult to intubate. Halo fixation imposes similar constraints. Rheumatoid arthritis, which may affect the cervical spine even in asymptomatic patients, may be problematic. By the age of 75 years, the normal aging process results in as much as a 20 percent reduction in cervical spine mobility. Injury to the cervical spine or the presence of a cervical collar also impairs the ability of the laryngoscopist to position the head. Finally, patients with short, muscular necks have limited neck mobility and redundant soft tissue in the mouth and submandibular space, making airway visualization a challenge. A variety of other anatomic features, including large breasts or a barrel chest, can complicate airway management by interfering with the excursion of the butt of the laryngoscope blade. During pregnancy, the oral and pharyngeal mucosae are swollen and bleed easily. When associated with a diminished functional residual capacity and increased volume of acidic gastric contents, intubation becomes quite hazardous. Based upon anatomical considerations, clinicians commonly employ the Mallampati scale (Table 151-1) to evaluate

Table 151-1 Mallampati Scale for Characterizing the Airway Class I Soft palate, fauces, uvula, and tonsillar pillars visible Class II Soft palate, fauces, and uvula visible Class III Soft palate and base of uvula visible Class IV Soft palate only visible

Airway management is well suited to the use of algorithms. The American Society of Anesthesiologists has a â&#x20AC;&#x153;difficult airwayâ&#x20AC;? algorithm for use in the operating room. In addition, algorithms for the critical care unit and trauma setting have been developed. In using an algorithm-based approach, the first decision branch point typically addresses the need for endotracheal intubation, since short-term respiratory insufficiency often can be managed noninvasively. Factors that must be considered in the care of patients with respiratory compromise include the level of consciousness, clinical context (e.g., the perioperative setting, emergency circumstances, etc.), anticipated duration of respiratory problem, risk of gastric aspiration, airway patency, concurrent medical problems, and anticipated relative ease of noninvasive (i.e., spontaneous or mask ventilation) vs. invasive (i.e., endotracheal intubation) management of the airway. In the patient with neurological depression due to injury of the central nervous system, noninvasive management is usually inappropriate due to the potential for developing hypercarbia or hypoxia and exacerbation of the primary injury. Conversely, in the patient sedated or obtunded by drugs or seizures, the clinical state is often brief in duration, so temporizing measures may be appropriate. Several factors differentiate elective perioperative airway management from emergency care. During surgery, an anesthesiologist or anesthetist is constantly present; the patient is properly prepared (i.e., the stomach is empty and a drying agent has been administered) and the environment is designed to facilitate airway management (i.e., there is ready access to suction, a ventilator, etc.). Under these circumstances, caregivers may choose to sedate the patient to the point of semiobtundation. Conversely, in an emergency, the setting is usually less than optimal. Airway management is usually only one component of the care rendered during cardiac or trauma resuscitation, and definitive airway intervention is essential in order to allow care providers to concentrate on other problems. Potentially quickly reversible processes (e.g., some attacks of asthma or episodes of pulmonary edema) may be appropriately managed without intubation. In other instances (e.g., blunt chest injury), the initial problem can be expected to worsen, and early intubation is warranted.

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The volume and acidity of the patient’s gastric contents must be factored into any decision about management of the airway. Aspiration of solid food can be catastrophic, as can large volumes of acidic, enzymatically active gastric fluid. Most studies have indicated that aspirated stomach contents with a pH lower than 2.5 or volume greater than 0.5 to 1.0 cc/kg are likely to cause lung damage. The lung damage is manifested by loss of ciliated and nonciliated epithelial cells in the trachea, destruction of type I and II pneumocytes, depletion of surfactant, and increased vascular permeability (see Chapter 144). Pain and narcotics may alter gastric emptying or change gastric pH, as can a number of disease states, such as intestinal obstruction, diabetic gastroparesis, and obesity. Unless the patient has fasted for more than 8 h and is not subject to the confounding factors noted above, a full stomach should be presumed, and airway management handled accordingly. The patient’s coexisting medical problems and expected course must also be considered in management of the airway. For example, endotracheal intubation can be a dangerous stress to a patient with coronary artery disease and can be performed more safely after suitable preparation than under emergency circumstances. As another example, a patient with Fournier’s gangrene and normal lungs is appropriately managed by maintaining intubation and sedation between trips to the operating room for debridement, rather than by performing multiple extubations and reintubations. Similarly, elective intubation and mechanical ventilation can prevent aspiration or atelectasis in a patient with hepatic encephalopathy who is awaiting liver transplantation, thereby improving the likelihood of a successful outcome. Some degree of airway obstruction can be managed without intubation by proper positioning of the head, use of an oral or nasal airway, or application of positive airway pressure (PAP) by mask. A rolled towel or small pillow placed behind the neck or occiput reproduces the sniffing position. Oral and nasal airways can alleviate airway obstruction due to redundant airway soft tissue or muscle relaxation. The application of positive pressure to the mouth and nose (mask continuous positive airway pressure or mask CPAP) distends the soft tissue of the airway. For this reason, nasal mask CPAP is frequently used in the management of obstructive sleep apnea (see Chapter 97). These measures can be used as shortterm, temporizing alternatives to intubation in the patient who is ventilating spontaneously in the intensive care unit or operative setting. Although a growing literature exists on the use of noninvasive ventilation in a variety of settings that previously would have mandated endotracheal intubation, anesthesia is frequently administered in the operating room by mask using positive pressure. True mask ventilation is readily accomplished in the anatomically normal patient. However, some anatomic features, such as a beard, flat or sharp nose, or sunken cheeks (in the edentulous patient) can make maskassisted ventilation difficult or impossible. Indications for tracheal intubation (Table 151-2) fall broadly under several categories: respiratory failure, airway

Intubation and Upper Airway Management

Table 151-2 Indications for Intubation of the Trachea Ventilatory failure Cardiac arrest, primary lung disease, neuromuscular disease or weakness Airway obstruction Primary airway process, neurogenic obstruction Airway protection Upper airway bleeding or injury (burn), central nervous system depression Pulmonary toilet Inability to manage secretions

protection, hemodynamic instability, and perioperative management. If intubation is indicated, the clinician must decide upon the route and technique.

TECHNIQUES AND EQUIPMENT Although expertise is a function of experience, several principles are generally applicable in any approach to airway management. The first applies to correct head positioning, which facilitates mask management, oral or nasotracheal intubation, and fiberoptic examination of the airway. Incorrect positioning impedes each procedure. The previously noted sniffing position refers to extension of the head on the neck while the neck is flexed on the thorax (Fig. 151-3). The hypopharynx is at its maximal circumference in this position, and the tongue is farthest from the posterior pharyngeal wall. Anterior displacement of the jaw can be accomplished by pulling it forward or applying pressure on the angle of the mandible (the “jaw thrust” maneuver).

Figure 151-3 The sniffing position modified by additional head extension for oral intubation, with alignment of the oral, pharyngeal, and tracheal axes.

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This serves to open further the retrolingual space. Pulling the tongue forward while grasping it with gauze or an instrument accomplishes the same goal. The position is appropriate for spontaneous respiration because it limits soft-tissue obstruction to airflow. Nasotracheal intubation is easiest in the sniffing position, because the tip of the endotracheal tube is best aligned with the larynx and least likely to be deflected by the walls of the pharynx. Nasal and oral fiberoptic procedures are also easier in this position in which the oral, pharyngeal, and tracheal axes are well aligned (Fig. 151-3). The sniffing position may be modified by further head extension and flattening of the back of the tongue by the laryngoscope blade during oral intubation. A second general principle underlining airway management is that saliva and blood interfere with mask ventilation, direct visualization of the airway, and fiberoptic procedures. When circumstances permit, pretreatment with an antisialogogue, such as atropine, glycopyrrolate, or scopolamine, significantly diminishes saliva production. Suction must be available prior to initiation of any elective procedure (as well as on the emergency cart) to clear secretions or deal with regurgitation of gastric contents. A suction tip with a large bore, such as the Yankauer tonsil suction tip, is commonly used; suction should be maximized in order to clear thick, viscous oral secretions. A third general principle of airway management refers to preparation of the patient and airway. Small, titrated doses of sedatives, topical anesthesia, and vasoconstrictor agents markedly enhance the ease with which procedures, such as fiberoptic, nasotracheal, or oral intubation, are performed while the patient is awake. Narcotics are more likely to suppress the cough reflex than are other agents. Topical cocaine has anesthetic and vasoconstrictor properties, but because of its classification as a controlled agent, the combination of lidocaine and phenylephrine is often used as an alternative. The light source of a laryngoscope or fiberoptic scope should be checked prior to instrumentation, and, with the latter, the focus adjusted. Finally, a backup plan for airway management is essential in case the primary plan should go awry. Finally, perhaps the most important principle of airway management is that a source of oxygen and means of ventilation should be available. This implies that the pressure in nearby oxygen tanks should be checked, as should the proximity of a source of wall oxygen. In the absence of an oxygen source, a self-inflating resuscitation bag can provide a method for ventilation, obviously using only room air (see below). Bags used for most anesthesia circuits require a gas source for inflation.

Figure 151-4 Oral and nasal airways and face masks.

a beveled tip, permitting insertion through narrow nasal passages. Oral airways are curved, designed to lie over and behind the tongue. Some are fashioned with slots for ready passage of a suction catheter, whereas others have a central channel designed to accommodate a fiberoptic scope. Binasal airways are designed to be fitted to a ventilation circuit, permitting ventilation in anesthetized patients without endotracheal intubation.

RESUSCITATION BAGS Resuscitation bags are available in many styles (Fig. 151-5) and are designed with several common features. They are self-inflating, and can, therefore, be used in the absence of a gas source. An internal flap valve system directs inflowing gas to the patient or reservoir, permitting application of positive pressure by mask or endotracheal tube and venting exhaled gas to the atmosphere. Inspired oxygen concentration is ordinarily limited to 40 to 60 percent when oxygen inflow is 10 L/min; bag reinflation is rapid, since room air is entrained with each breath. Addition of an oxygen reservoir, usually in the form of a sleeve or tail at the back of the bag, permits administration of oxygen concentrations of 75 to 90 percent at 10 to 15 L/min. Some bags are equipped with adjustable valves for application of positive end-expiratory pressure.

AIRWAYS MASKS A large variety of nasal and oral airways, designed for children and adults of different sizes (Fig. 151-4), are available. Nasal airways are generally made of flexible rubber and have

Although a large variety of masks are available (Fig. 1514), all have three features in common: the body, seal, and

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Figure 151-5 Self-inflating resuscitation bag.

connector. The body is usually made of malleable or moldable material and adjustable to individual facial anatomy. The body of some masks is made of clear plastic to allow diagnosis of regurgitation of gastric contents. The seal is usually a cushioned rim (which can be inflated or deflated) attached to the body, although some are detachable. Some seals are flanged and not cushioned. The connector is designed with a universal fitting (22-mm internal diameter) for attachment to any ventilating circuit. Many are equipped with retaining straps for attachment to mask straps (which pass behind the patient’s head, freeing the hand of the operator).

hypopharynx; its correct positioning is verified by assessment of breath sounds. The LTA is similar to the LMA. The device has two cuffs, one of which is designed to seal the lower pharynx and esophagus and the other the upper pharynx. A lumen exists between the two. The esophageal obturator airway (EOA) is similar to the LTA in that it also has two cuffs and a single lumen. However, the distal end of the device is designed to lie in the esophagus. A newer device, the Combitube (Armstrong Medical Industries), addresses a concern that the tip of the EOA may inadvertently enter the trachea, making ventilation impossible. The Combitube is designed to permit ventilation and airway isolation regardless of whether its tip lies in the esophagus or trachea.

EXTRAGLOTTIC AIRWAY DEVICES A number of extraglottic or supraglottic airway devices exist, and new ones are described every year. Some are cuffed, while others are uncuffed; some are nasally inserted, while others are orally inserted. A few devices are based on cannulation of the esophagus. The most familiar devices are cuffed, orally inserted, hypopharyngeal airways, such as the laryngeal mask airway (LMA) and the laryngeal tube airway (LTA). The LMA (Fig. 151-6) is analogous to the facial mask: It has a compliant cuff that is applied to the dorsal surface of the larynx, isolating the airway from the mouth and esophagus. The LMA came into common intraoperative usage in the early 1990s. While used most extensively in surgical patients, the LMA has also been used for awake, fiberoptic bronchoscopy, in the intensive care unit, and in emergency resuscitation. Variants are specifically designed to be flexible, disposable, or to permit passage of an endotracheal tube through the device’s lumen. The LMA is inserted through the mouth into the

TRACHEAL INTUBATION Four approaches are commonly employed in tracheal cannulation: nasal, oral, laryngeal, and tracheal. The first two are noninvasive, whereas the latter two require surgical incisions. Nasotracheal intubation can be done “blindly” (i.e., without tracheal lumen visualization) or using a laryngoscope and forceps. A blind nasotracheal intubation, when performed by a skilled operator, allows rapid control of the airway in an awake patient and minimal suppression of protective airway reflexes. The technique is used widely by paramedics in prehospital patient care, as a component of many difficult airway algorithms, and as an integral part of Advanced Trauma Life Support algorithms. In performing blind nasotracheal intubation in a nonemergency setting, the operator examines the nasal passages for patency, septal deviation, or the presence of polyps.

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Figure 151-6 The laryngeal mask airway.

If the patient is able to cooperate, the larger nasal passage is selected by alternately occluding each nostril and choosing the one with better airflow. A topical anesthetic and vasoconstrictor agent are sprayed in the nostril or applied with cotton pledgets. Anesthetic is also sprayed into the back of the mouth in order to anesthetize the hypopharynx. An appropriately sized tube (6 to 7 mm for women, 7 to 8 mm for men) is selected and lubricated. Lubrication eases passage of the tube and minimizes abrasion of the nasal

mucosa, making bleeding less likely. The patient is placed in the sniffing position and the tube inserted and advanced using slow, firm pressure. The natural slope of the tube is oriented so that the tip initially points toward the occiput and curves in a caudad direction as it is advanced. During the procedure in an awake patient, the operator listens for breath sounds as the tip approaches the vocal cords. A commercially available whistle attachment (Bamm, Great Plains Ballistics, Inc., Lubbock, TX) enhances the operatorâ&#x20AC;&#x2122;s ability to hear breath sounds (Fig. 151-7). The tube is

Figure 151-7 Standard endotracheal tube with whistle tip attachment to amplify breath sounds during blind nasal intubation.

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Figure 151-8 Endotracheal tube modified with a ‘‘trigger” permitting anteroflexion of the tip of the tube during blind nasal intubation. Univent tube for lung isolation (see text).

advanced into the airway during inspiration. Slight clockwise or counterclockwise rotation of the tube at the nose can be used to correct for lateral misalignment. A commercially available endotracheal tube (Endotrol, Mallinckrodt, Athlone, Ireland) allows the operator to anteroflex the tip of the tube with a “trigger” at the connector (Fig. 151-8). This is especially effective in patients with anteriorly positioned vocal cords or those who cannot assume the sniffing position (e.g., due to the presence of a cervical collar). When nasotracheal intubation is performed in an anesthetized patient, the endotracheal tube tip is advanced into the hypopharynx above the vocal cords, laryngoscopy is performed, and the tube is then advanced into the trachea under direct visualization. Magill forceps (Fig. 151-9) are often used to grasp the tube and direct its tip between the vocal cords. Care must be taken to avoid grasping the tube by the cuff, which is easily perforated. Correct position of the tube can be verified using a number of methods. Audible or palpable air passage (in the spontaneously breathing patient), a visible vapor trail within the tube, or auscultatory evidence of breath sounds over the lung fields are standard approaches. End-tidal capnometry showing phasic variation in carbon dioxide levels is the gold standard and has become more feasible in nonoperative settings because of the development of portable and disposable devices. Extensive literature exists on the pros and cons of nasal versus oral intubation in the intensive care environ-

ment. Nasal intubation is associated with a higher incidence of bleeding, nasal discomfort, and hemodynamic alterations during tube placement. A minimal increase in the dead space of the equipment (less than 10 cc) without significant difference in airflow resistance occurs with nasotracheal intubation compared with the orotracheal route. Literature regarding the incidence of sinusitis and pneumonia as a result of each of the two methods is conflicting; one prospective, randomized trial showed no differences. In general, early tracheostomy is increasingly preferred in critically ill patients who are likely to be intubated for prolonged periods. By far, direct laryngoscopy with orotracheal intubation is the most common approach that is applied to secure the airway. With the patient’s head in the sniffing position, the operator inserts a Macintosh or Miller blade (Fig. 151-10) into the right side of the mouth using the left hand (regardless of the handedness of the operator). While some anatomic situations make it advantageous to use one blade rather than the other (e.g., the Miller blade in the setting of an anatomically anterior larynx), most operators become familiar with one blade and use it preferentially. The blades of both instruments are flanged to keep the tongue to the left and out of the visual field. Larger adult blades (Macintosh no. 4 or Miller no. 3) are used for patients with long mandibles, whereas shorter blades (Macintosh no. 3 or Miller no. 2) are used in normal patients. Smaller blades are used for children.

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Figure 151-9 Magill forceps (see text) and light wand for transillumination of the trachea during blind oral intubation.

Figure 151-10 Macintosh and Miller blades.

During the procedure, the operatorâ&#x20AC;&#x2122;s right hand pulls the upper and lower lips out of the way, so that they are not caught and injured between the blade and teeth. The tip of the laryngoscope blade is advanced along the tongue until the epiglottis is visible. If the Macintosh blade is used, it is advanced between the tongue and epiglottis; when the Miller blade is used, the epiglottis is elevated directly. The cords should be visible immediately below the epiglottis. Most infants are intubated using a Miller blade. The shape, length, and pliancy of the infant epiglottis are such that it must be â&#x20AC;&#x153;picked upâ&#x20AC;? by the tip of the Miller laryngoscope so that the cords can be seen. Because some patients are difficult to intubate due to anatomic considerations, a number of alternate approaches have evolved. These include fiberoptic laryngoscopy, by which the trachea is entered using a bronchoscope and an endotracheal tube advanced into the airway over the device. A flexible light wand (see Fig. 151-9) can be used to transilluminate and identify the airway; an endotracheal tube is then advanced into the airway using the wand as a stylet. Retrograde techniques involve percutaneous cannulation of the trachea in the neck and retrograde passage of a wire or catheter into the oropharynx. The wire is grasped and secured to an endotracheal tube and used to guide its passage back into the trachea. Percutaneous cricothyrotomy kits are available for emergency access to the airway, as are percutaneous tracheostomy kits. Percutaneous ventilation has been taught in airway management portions of Advanced Cardiac Life Support (ACLS), Advanced Trauma Life Support (ATLS), and

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Table 151-3 Indicators of a Potentially Difficult Airway Poor mouth opening Temporomandibular joint disease Mandibular fracture Dental problems “Buck” anterior teeth Caries Dental hardware (caps, dentures) Gaps Abnormalities of the tongue Large (e.g., in obesity) Swollen Edema (surgical) Angioedema (allergic) Fixed Scarring (radiation) Tumor Presence of other intraoral structures Tumors Enlarged tonsils Small jaw “Anterior larynx” Decreased neck mobility Cervical disease or injury Suspected fracture Rheumatoid arthritis Ankylosing spondylitis Increased age (presence of cervical osteophytes) Congenital syndromes Cleft palate Treacher-Collins Pierre Robin Klippel-Feil

Intubation and Upper Airway Management

Pediatric Advanced Life Support (PALS) courses. The technique requires insertion of a needle or intravenous catheter through the cricothyroid membrane in order to insufflate oxygen during emergency airway management. Anatomic features indicative of the difficult airway are listed in Table 151-3. While a full discussion of the management of the potentially problematic airway is beyond the scope of this chapter, adequate preparation by the operator can prevent a catastrophe. Early assessment of the anatomy to determine whether difficulty with intubation alone or intubation and ventilation should be anticipated is important. An anteriorly placed larynx is usually associated with difficulty in intubation alone, whereas an obese patient is more likely to present a challenge with regard to both intubation and ventilation. An additional important determination is whether interventional airway management is actually necessary. Can the procedure be performed under regional, rather than general, anesthesia? If regional anesthesia cannot be employed, awake intubation using sedation and topical airway anesthesia may be an excellent alternative. Direct laryngoscopy and fiberoptic bronchoscopy are equally appropriate adjuncts in intubating cooperative patients. If difficulty in airway management is unexpectedly encountered in an already anesthetized patient, ensuring adequate ventilation and oxygenation is critical. A mask or, if necessary, one of the invasive approaches described above, may be used. Establishment of reliable ventilation allows time for alternate approaches, including abandonment of the procedure (allowing the patient to awaken) or tracheostomy. A large number of endotracheal tubes are commonly employed in a variety of clinical settings. Single-lumen, reusable, red rubber tubes with separate cuffs were used as recently as the mid-1970s, and red rubber double-lumen tubes were in common use 5 to 10 years ago. Disposable tubes are now widely available, and a host of different design modifications have been made to make the tubes safer and accommodate different surgical procedures. The cuff of the adult tube has been changed from a low-volume, noncompliant cuff to a higher volume, very compliant cuff; a corresponding decrease in the incidence of tracheal stenosis has been observed. Pediatric tubes are generally uncuffed because children are more vulnerable to development of subglottic stenosis due to tube contact with the trachea. Uncuffed tubes also maximize the cross-sectional area of the airway. Oral and nasal RAE tubes (Fig. 151-11) are preconfigured to permit facial and oral surgery without interference from the proximal portion of the endotracheal tube. A variety of special tubes are used for laser surgery. These tubes are less likely to burn when contacted by the laser beam. Reinforced or anode tubes have an embedded wire or nylon filament spiral in the wall of the tube that prevents kinking or collapse due to external pressure (see Fig. 151-11). The Hi-Lo Jet endotracheal tube (Mallinckrodt) has four

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Figure 151-11 Oral and nasal preshaped tubes (RAE tubes). Anode, wire-wrapped tubes to prevent kinking.

Figure 151-12 Endotracheal tube tip with Murphy eye and bevel (see text).

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Figure 151-13 Right- and left-sided double-lumen endotracheal tubes. Note oblique bronchial cuff on the rightsided tube to accommodate right upper-lobe bronchial orifice.

lumens: one for entrained gas, a second for jet ventilation, a third for cuff inflation, and a fourth for pressure monitoring. All single lumen tubes have a 15 mm outer diameter and connect to any standard ventilation device. Most also have a radioopaque stripe that permits tube localization on chest roentgenograms. The tip of the tube is beveled (Fig. 151-12); the bevel faces to the left because endotracheal tubes are generally inserted from the right by right-handed operators. An extra hole (Murphy eye) lies opposite to the bevel on many tubes and is designed to permit suctioning or antegrade gas flow if the bevel becomes occluded. Finally, disposable double-lumen endotracheal tubes are now available. The Carlens and White tubes that were used in the past were equipped with a carinal hook for correct tube placement. These tubes have largely been abandoned in favor of the Robertshaw design, which has tracheal and bronchial cuffs and no hook. The tube is available in four adult sizes (35, 37, 39, and 41 French) in both right- and left-sided designs (Fig. 151-13). The right-sided tube has an oblique bronchial cuff to accommodate the takeoff of the right upper lobe orifice. Correct placement of a double-lumen tube has become easier with development of bronchoscopes small enough to pass through the narrow tube lumens. An alternative to the double-lumen tube (the Univent tube, introduced in 1982) has a self-contained endobronchial blocker. The tube is inserted in the standard fashion, and the endobronchial blocker is then advanced (blindly or under direct vision) into the right or left main bronchus. A central lumen in the endobronchial blocker allows for inflation or deflation. While the bronchial blocker is integrated into the Univent tube construction, the same functionality can be achieved by using the Arndt wire-guided endobronchial

blocker (Cook Critical Care, Bloomington, IN). The device is a multiport airway adapter, which can be used without a tube change (unlike the Univent tube) and can be “swapped” for a standard Y-piece connector, when desired.

CONCLUSION While some of the skills developed by the early pioneers may be lost to current practitioners (Fig. 151-14), advances in pharmacology, equipment, and equipment manufacturing

Figure 151-14 Earlier diagnostic airway intervention. (From Kirstein: Archiv Laryngol Rhinol 3:156–164, 1895. Courtesy of Cushing/ Whitney Medical Library.)

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standards have greatly facilitated airway management and have made new surgical procedures possible.

SUGGESTED READING Ahrens T, Kollef MH: Early tracheostomy: Has its time arrived? Crit Care Med 32:1796–1797, 2004. American Society of Anesthesiologists Task Force on Management of the Difficult Airway: Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269– 1277, 2003. Asai T, Morris S: The laryngeal mask airway: Its features, effects and role. Can J Anaesthesiol 41:930–960, 1994. ATLS Manual, 7th ed. American College of Surgeons, Chicago, IL 2005. Blot F, Melot C, Commission d’Epidemiologie et de Recherche Clinique: Indications, timing, and techniques of tracheostomy in 152 French ICUs. Chest 127:1347–1352, 2005. Brimacombe J: A proposed classification system for extraglottic airway devices. Anesthesiology 101:559, 2004. Brimacombe J, Berry A, Verghese C: The laryngeal mask airway in critical care medicine. Int Care Med 21:361–364, 1995. Calverlay RK: Arthur E. Guedel (1883–1956), in Rupreht J, van Lieburg MJ, Lee JA, et al (eds), Anaesthesia Essays on Its History. Berlin, Springer Verlag, 1985, pp 49–53. Cuvelier A, Muir JF: Acute and chronic respiratory failure in patients with obesity-hypoventilation syndrome: A new challenge for noninvasive ventilation. Chest 128:483–485, 2005. Esteban A, Frutos-Vivar F, Ferguson ND, et al: Noninvasive positive-pressure ventilation for respiratory fail-

ure after extubation. N Engl J Med 350:2452–2460, 2004. Griffiths J, Barber VS, Morgan L, et al: Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. Br Med J 330:1243, 2005. Holzapfel L, Chevret S, Madinier G, et al: Influence of longterm oro- or nasotracheal intubation on nosocomial maxillary sinusitis and pneumonia: Results of a prospective, randomized, clinical trial. Crit Care Med 21:1132–1138, 1993. Keenan SP, Sinuff T, Cook DJ, et al: Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review. Crit Care Med 32:2516–2523, 2004. L’Her E: Noninvasive ventilation outside the intensive care unit: A new standard of care? Crit Care Med 33:1642–1643, 2005. Majid A, Hill NS: Noninvasive ventilation for acute respiratory failure. Curr Opin Crit Care 11:77–81, 2005. Mallampati SR, Gatt SP, Gugino LD, et al: A clinical sign to predict difficult tracheal intubation: A prospective study. Can Anaesth Soc J 32:429, 1985. Moller MG, Slaikeu JD, Bonelli P, et al: Early tracheostomy versus late tracheostomy in the surgical intensive care unit. Am J Surg 189:293–296, 2005. Morch ET: History of mechanical ventilation, in Kirby RR, Banner MJ, Downs JB (eds), Clinical Applications of Ventilatory Support. New York, Churchill Livingstone, revised edition 1999:1–61. Murphy FJ: Two improved intratracheal catheters. Anesth Analg 20:102–105, 1941. Reynolds SF, Heffner J: Airway management of the critically ill patient: Rapid-sequence intubation. Chest 127:1397– 1412, 2005. Smith DW: Recognizable Patterns of Human Malformation, 3rd ed. Philadelphia, WB Saunders, 1987.

152 Hemodynamic and Respiratory Monitoring in Acute Respiratory Failure Barry D. Fuchs

Patrick Neligan

I. GENERAL PRINCIPLES II. INDICATIONS FOR MONITORING HEMODYNAMICS III. METHODS FOR MONITORING HEMODYNAMICS History and Physical Examination Arterial Blood Pressure Laboratory Tests Central Venous Catheterization Pulmonary Artery Catheterization Noninvasive Alternatives to the Pulmonary Artery Catheter

GENERAL PRINCIPLES Patients with acute respiratory failure (ARF) sustain significant morbidity and mortality, with adverse outcomes resulting from both the primary insult responsible for the ARF and secondary complications, many of which are preventable. Admission of these patients to the intensive care unit (ICU) allows more for intensive monitoring in an attempt to diminish risks and guide therapeutic interventions. This chapter reviews methods currently available for monitoring hemodynamics and respiratory function in patients with ARF. A number of important goals of ICU monitoring can be identified. One is to ensure adequacy of respiratory and circulatory functions in patients who appear clinically stable. Another is to provide close surveillance for early signs of respiratory and circulatory instability, with the presumption that early detection improves outcome. In addition, measurement of the response to therapeutic interventions, including application of supportive devices, such as endotracheal tubes and mechanical ventilators, is routinely performed in the ICU. Although life-saving, these devices, like all therapeutic interventions, are associated with risks that must be monitored.

IV. METHODS FOR MONITORING RESPIRATORY FUNCTION Oxygenation Ventilation Endotracheal Tube Placement Respiratory System Mechanics Ventilator Waveforms Inspiratory Muscle Strength Imaging in Acute Lung Injury

Finally, monitoring respiratory and hemodynamic derangements over hours to days provides valuable insight about prognosis, since the trend in physiological derangements over time predicts outcomes far better than does the severity of abnormalities on admission. Consequently, failure to improve over days, despite full support and appropriate treatment, suggests the need for alternative therapeutic strategies, including patient comfort as the primary goal of care. Physiological parameters normally vary in critically ill patients. Furthermore, the devices used to measure these parameters are often imprecise and, at times, inaccurate. Therefore, clinical assessment and decision making should not be based, in general, on single data points. Rather, trends in data add reliability to interpretation of measurements.

INDICATIONS FOR MONITORING HEMODYNAMICS When managing patients with ARF, intensivists are regularly required to make judgments about circulatory function

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that can often be made confidently using routine monitoring equipment. However, several clinical questions become more challenging without application of more invasive or sophisticated measuring devices. These questions include: 1. For the patient with pulmonary edema, is the edema cardiogenic or noncardiogenic in origin? 2. Is hypoperfusion causing, or contributing to, the patientâ&#x20AC;&#x2122;s end-organ dysfunction? 3. Recognizing the risk of worsening hypoxemia in ARF following administration of intravenous fluids, should the patient with ARF who presents with or develops shock be given fluids? If so, how much? 4. For those patients with volume overload, given the risk of causing or exacerbating organ dysfunction, how much fluid should be removed by using diuretics or dialysis to reduce lung water and improve respiratory function? The first question requires an estimate of ventricular preload, the second an estimate of cardiac output, and the third and fourth an assessment of the inter-relationship of both preload and cardiac output. Varieties of both noninvasive and invasive techniques are available to monitor hemodynamics and are discussed below.

resulted in no change in vital signs. In addition, a variety of nonhemodynamic conditions (e.g., pain or anxiety) may cause significant changes in vital signs. The remainder of the physical examination may provide information about the adequacy of perfusion and help to establish the type and cause of shock. The adequacy of cardiac output is assessed by evaluating heart rate, mean arterial pressure, pulse pressure, urine output, mental status, and extremity and skin perfusion (as reflected by peripheral temperature, capillary refill, and absence of mottling or livedo reticularis). Estimates of right and left ventricular filling pressure based on assessment of jugular venous distention or the presence or absence of lung crackles provides a presumptive diagnosis of the type of shock and helps guide initial resuscitation. When coupled with other physical findings (e.g. unequal breath sounds) the specific etiology of shock may be determined. Despite the potential usefulness of a careful physical examination, several studies have shown that clinical assessment correlates poorly with objective measurements of central hemodynamics, including cardiac filling pressures and cardiac output. Thus, if accurate hemodynamic measurements are needed to make safe clinical decisions, use of more sophisticated monitoring devices or diagnostic evaluation is required.

Arterial Blood Pressure METHODS FOR MONITORING HEMODYNAMICS Assessment and monitoring of hemodynamics are based on a spectrum of clinical tools, ranging from a detailed history and physical examination to a variety of noninvasive and invasive techniques.

History and Physical Examination While patients with ARF may require heavy sedation, some do not, and the clinician should routinely attempt to obtain a focused history from all intubated patients. The physical examination is equally important, providing valuable visual, auditory, and tactile information. Alterations in the general appearance of the patient, including restlessness, agitation, delirium or ventilator dyssynchrony, may be readily apparent and should be investigated as a potential first sign of a serious underlying circulatory problem, particularly in the heavily sedated patient. Alterations in heart rate and blood pressure often accompany significant pathophysiological changes (e.g., severe hypoxemia), but they may also be seen as a side effect of medications or cardiac ischemia. A reduction in blood pressure, while attributable to many potential causes, may be a late manifestation of shock and always requires emergent evaluation. Unfortunately, changes in vital signs have limited sensitivity and specificity. In one study of normal subjects, a 25 percent reduction in blood volume

Mean arterial pressure (MAP) is the primary determinant of cerebral and myocardial blood flow. In the setting of hypotension, cardiovascular homeostatic mechanisms maintain MAP in a narrow range, in part through compensatory vasoconstriction in other, less vital, organs. However, MAP is not a useful measure of the adequacy of cardiac output. A low MAP may accompany shock, but it is a late manifestation, occurring when cardiovascular reserves are exhausted. Conversely, acute elevations in MAP may also be associated with injury to vital organs. Patients with chronic hypertension should be maintained at a higher MAP, given the likelihood of vascular wall thickening which may limit vasodilator capacity for autoregulation. A general rule is that the MAP should be maintained within 25 percent of the patientâ&#x20AC;&#x2122;s baseline value in order to minimize the likelihood of myocardial or cerebral ischemia. In contrast, patients with chronic liver disease may have adequate organ perfusion despite a low MAP. Nevertheless, normalizing the MAP is a primary goal in circulatory resuscitation. In patients with a normal baseline MAP, resuscitation to a goal greater than or equal to 65 mmHg has been recommended, since higher resuscitation targets fail to improve organ perfusion. Once the MAP resuscitation goal is met, other parameters more sensitive to organ perfusion are used to guide the adequacy of resuscitation. Measurement of arterial blood pressure may be accomplished using invasive or noninvasive methods. Although in healthy patients noninvasive measurements of blood pressure

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correlate well with invasive measurements, invasive methods are preferred in patients with ARF. Noninvasive methods are unreliable in shock states, which are not uncommon in patients with ARF. Continuous monitoring of arterial blood pressure during resuscitation or titration of vasoactive agents minimizes the chance of missing a critically low or high recording between measurements. Furthermore, an indwelling arterial catheter is often required for monitoring arterial blood gases. In contrast to MAP, the pulse pressure provides information about cardiac output that is useful in the assessment of shock. Pulse pressure is determined primarily by stroke volume and aortic compliance. Since the latter doesn’t change beat-to-beat and is assumed to be normal in most patients (except the elderly), pulse pressure changes in proportion to stroke volume. Thus, in a patient with tachycardia, a normal or stable pulse pressure suggests normal or high cardiac output, while a reduced pulse pressure indicates a low cardiac output. In animals subjected to graded hemorrhage, the magnitude of respiratory phase-related changes in systolic arterial pressure and pulse pressure correlate with the degree of hypovolemia. Numerous studies have corroborated these findings, establishing a potential role for use of systolic and pulse pressure variation in determining fluid responsiveness in critically ill patients. Indeed, in the hypovolemic patient, central veins collapse more easily following a positive pressure breath, and ventilator-induced changes in right atrial pressure are greatest when the right atrium is underfilled and most compliant. Furthermore, hypovolemia increases the likelihood that mechanical insufflation will collapse pulmonary capillaries, increasing pulmonary vascular resistance and decreasing left ventricular filling. Finally, when the left ventricle is underfilled and operating on the steep (linear) portion of its Starling curve, it is more sensitive to changes in right ventricular output. Hence, the greater the variation in systolic and pulse pressure during a single cycle of mechanical ventilation, the more underfilled the ventricles and the more likely the response to a fluid challenge (“preload responsiveness”). These principles may also be used to monitor the titration of positive end-expiratory pressure (PEEP) by assessing variation in systolic or pulse pressure as PEEP is applied. PEEP can reduce cardiac output, thereby limiting or negating any improvement in arterial oxygenation on oxygen delivery. When systolic or pulse pressure begins to vary with each mechanical breath, the level of PEEP has likely decreased cardiac preload, suggesting the need for a fluid challenge. Respiratory variations in systolic and pulse pressure have been shown to accurately predict fluid responsiveness in critically ill patients with respiratory failure, with or without septic shock. Once validated, these findings may be more useful in predicting fluid responsiveness than other, more traditional, estimates of cardiac preload, including central venous pressure, pulmonary artery occlusion pressure, or left ventricular end-diastolic volume (LVEDV).

Hemodynamic and Respiratory Monitoring in Acute Respiratory Failure

Laboratory Tests Two laboratory tests deserve special mention for their potential role in hemodynamic monitoring: B-type natriuretic peptide (BNP) and lactic acid. Serum levels of BNP (either B-type or N-terminal proB-type) correlate with the degree of cardiac dysfunction and have shown promise as a tool to diagnose, monitor, and predict outcome of patients with congestive heart failure (CHF) in outpatient and emergency department settings. Accordingly, interest has arisen in using BNP as a noninvasive test to monitor volume status in critically ill patients. Unfortunately, in patients with ARF, BNP levels do not correlate with pulmonary artery occlusion pressure. BNP increases with right heart dysfunction, sepsis (with or without cardiac dysfunction), and ARF, reflecting low test specificity. Furthermore, hypotensive patients who are in a non–steadystate condition may present acutely with an elevated BNP, despite hypovolemia, because of preexisting cardiac disease. On the other hand, a low BNP level may be useful in ruling out cardiac dysfunction. In assessing the net “result” of cardiac performance, namely, end-organ perfusion, an absolute value for cardiac output or index cannot be used to diagnose shock. In addition to the physical examination and assessment of selected parameters, including urine output and central or mixed venous oxygen saturation (see below), measurement of venous lactate levels represents a useful screening tool for determining the adequacy of global and regional hemodynamics. Elevated lactate levels have also been shown to correlate with patient outcome in the ICU, although in individual patients, lactate clearance (change in level over time) is a more accurate predictor of outcome. With newer assays and sampling techniques (e.g., by finger stick) lactate levels are readily available. In patients with ARF, lactic acidosis is most commonly caused by cellular hypoxia due to hypoperfusion or hypoxemia. Although cellular hypoxia may contribute to lactic acidosis associated with sepsis, particularly early in its course, endotoxin and other mediators may also cause lactate release due to cytopathic hypoxia via direct inhibition of the mitochondrial enzyme that metabolizes pyruvate. When a patient has an elevated lactate not explained by hypoxemia, global and regional hypoperfusion must be excluded immediately. If the physical examination and central or mixed venous oxygen saturations (see below) are normal (suggesting normal cardiac output), ischemic bowel or extremity compartment syndrome must be considered, as should “occult sepsis,” certain drugs, or liver disease.

Central Venous Catheterization Since most patients with ARF require a central venous catheter (CVC) for administration of medications, no additional rationale or risk-benefit considerations are required to justify insertion of the line. However, the type of catheter inserted determines the extent of monitoring permitted. All

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CVCs, regardless of lumen diameter or length, can be used to transduce central venous pressure (CVP) and measure central venous blood oxygen saturation (Scvo2 ), a surrogate for true mixed venous oxygen saturation (Sco2 ). However, in order to monitor Scvo2 continuously, a special oximetric catheter (Pre-SEP, Edwards Scientific) is required. The internal jugular (IJ) or subclavian vein (SV) is the preferred access site, since femoral lines are associated with increased rates of infection and deep venous thrombosis. The choice between SV and IJ sites is dependent on many factors, but, in general, the IJ is safer because the vein is compressible, amenable to ultrasound localization, and associated with a reduced rate of pneumothorax. However, the Centers for Disease Control and Prevention (CDC) recommends the SV site over the IJ because of a presumed lower risk of infection. Both sites are reasonable, and the decision is a function of specific patient issues and operator experience and preference. Central Venous Pressure CVP is the downstream pressure that governs the rate of venous return to the right heart; it represents a good approximation of mean right atrial (RA) pressure. CVP can be measured accurately through a variety of catheter types, including triple lumen, tunneled, and percutaneously placed varieties. Commonly employed CVP catheter sites include the IJ, subclavian, and femoral veins. CVP has been used to assess volume status in the diagnosis and management of shock and to infer the etiology of pulmonary edema. However, numerous studies have demonstrated flaws in this approach. Although, in some cases, a very low (less than 5 mmHg) or a very high (greater than 20 mmHg) CVP may be helpful in guiding decisions about volume status, in most patients, a single CVP value is rarely helpful. The central venous or RA pressure is the pressure within the RA relative to atmospheric pressure. However, right ventricular preload, which is best defined as right ventricular end-diastolic volume (RVEDV), is equally dependent on the extracardiac (i.e., intrathoracic) pressure and right ventricular compliance, neither of which can be determined reliably at the bedside. Applied or intrinsic PEEP and intra-abdominal hypertension, among other conditions, may also increase extracardiac pressure. Even if CVP correlated with RVEDV, the latter correlates poorly with LVEDV in patients with ARF because of discordance in ventricular afterload and contractility. Indeed, lung disease and the PEEP used to treat it increase pulmonary vascular resistance and may produce right ventricular failure. Furthermore, since the pericardium limits ventricular dilatation, ventricular interdependence further increases the disparity in LVEDVs and RVEDVs when differential contractility or loading conditions are present. This occurs because ventricular dilatation displaces the septum laterally and compresses the adjacent ventricle. Use of CVP in lieu of measurement of pulmonary artery occlusion pressure (PAOP) in

determining whether pulmonary edema is of cardiogenic or noncardiogenic origin is equally tenuous. In contrast, measurement of dynamic changes in CVP and the diameters of the superior and inferior vena cavae in response to changes in intrathoracic pressure provides more clinically useful information about cardiac preload. The basis for these dynamic responses is similar to that discussed previously. Unfortunately, lack of standardization, rigorous validation of the techniques, or outcome studies preclude recommending routine clinical use. Mixed Venous Oxygen Saturation Normally, the circulation delivers oxygen to tissues at a rate sufficient to maintain an intracellular (mitochondrial) oxygen tension above a critical threshold. If oxygen delivery (Do2 ) fails to meet tissue oxygen requirements (Vo2 ), shock exists and anaerobic metabolism ensues; if prolonged, cell death occurs. If Do2 decreases and tissue Vo2 remains constant, a reduction in the oxygen content in mixed venous blood (Svo2 ) is observed, reflecting an increase in oxygen extraction which occurs as a result of increased diffusion. The reduced Do2 causes mitochondrial and tissue Po2 to fall, which, in turn, increases the gradient for oxygen diffusion from capillary blood to tissue. The result is a reduction in end-capillary and, hence, venous Po2 . Since blood flow to organs is not equally distributed, and since rates of oxygen utilization are heterogeneous among organs, the venous oxygen content of blood draining from organs varies. The mixed venous oxygen content measured in the pulmonary artery (Svo2 ), which reflects “global” oxygen delivery, represents a weighted average of the product of blood flow and oxygen content from all organs. Thus, Svo2 is not sensitive to localized tissue ischemia (e.g., bowel ischemia)— an important limitation of this monitoring tool. Based on an understanding of the determinants of Svo2 , the clinician can use the Fick equation (Eq. 1, below) to elucidate the mechanism of shock and, perhaps, to target therapy: Vo2 = CO × (arterial O2 content − venous O2 content) (1) where CO is cardiac output. Recalling that O2 content of either arterial or venous blood is the sum of hemoglobin (Hgb)-bound oxygen (1.34 ml O2 /g Hgb × [Hgb]/100 ml blood × % hemoglobin saturation) and dissolved oxygen (0.003 ml O2 /mm Hg), the following expression (Eq. 2) for mixed venous O2 is derived: Svo2 ∼ (arterial O2 content × [Hgb] × CO)/Vo2


Thus, if Sao2 is stable, Svo2 decreases if either CO or [Hgb] decreases or Vo2 increases. Since Sao2 and [Hgb] are readily measured and changes in Vo2 can be grossly estimated, the cause of a decrease in Svo2 can usually be determined quickly. Compared with alternative methods of monitoring CO, Svo2 reflects the adequacy of CO relative to oxygen requirements, which is a more valuable measurement than is

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the absolute CO. In this regard, Svo2 is also more sensitive than measurement of blood lactate (see below) as a measure of the adequacy of CO.

drostatic pressure. If PAOP never exceeds 18 mmHg, hydrostatic pulmonary edema can be excluded; however, transient spikes in left atrial pressure occurring between normal PAOP measurements can be missed. A PAOP greater than 18 mmHg is consistent with a hydrostatic cause of pulmonary edema, but high-permeability edema cannot be excluded.

Goal-Directed Therapy Recent studies indicate that when a central venous oxygen saturation (Scvo2 ) of greater than or equal to 70 percent is achieved early in the resuscitation of patients with severe sepsis, survival increases significantly. Indeed, achievement of this target as part of “goal-directed therapy” has been embraced by the critical care community, and a consensus guideline for treatment of sepsis has been published. The guideline, developed by experts from 11 multidisciplinary, international critical care societies, recommends routine monitoring of central venous oxygen saturation to guide initial resuscitation of patients with severe sepsis.

Pulmonary Artery Catheterization The pulmonary artery catheter (PAC) was first introduced into clinical practice in 1970. Since that time, the PAC has been the most commonly used device for monitoring hemodynamics in critically ill patients. It is also the most controversial. The PAC represents a reference standard for testing the accuracy and precision of noninvasive methods of assessing volume status and hemodynamic parameters. Indeed, the breadth of directly measured and derived parameters obtained using a PAC is unparalleled. However, more recently, use of the catheter has been curtailed because of data suggesting increased complications with its use and no evidence of any benefit to patient outcome. Pulmonary Artery Occlusion Pressure The PAC is used to estimate right and left ventricular filling pressures, PAOP or “wedge” pressure, and cardiac output. When the balloon of the catheter, “wedged” into a branch of the pulmonary artery, is inflated, a static column of blood is created downstream from the catheter tip, which extends to the point of confluence with other, unoccluded pulmonary veins. Without blood flow, a pressure drop across the static column of blood is absent, making the column a direct extension of the fluid column between the tip of the PAC and the pressure transducer. In the absence of disease in the pulmonary veins, left atrium, or mitral valve, the mean endexpiratory PAOP approximates left ventricular end-diastolic pressure (LVEDP). If “a” and “v” waves are visible in the transduced pressure recording, the mean value of the “a” wave (halfway between the top of the “a” wave and the bottom of x descent) is used to indicate the PAOP. PAOP is also used to estimate pulmonary capillary pressure in determining whether pulmonary edema is due to increased capillary permeability or hydrostatic pressure. In contrast to measuring PAOP as an estimate of LVEDP, the mean of the end-expiratory tracing is always used, even when large “v” waves are present, since the systolic pressure spike (‘v” wave) is transmitted with an equal contribution to the capillary hy-

Cardiac Output Cardiac output (CO) is measured routinely in the ICU using the thermodilution (TD) technique. The principle of TD is that by lowering the temperature of blood flowing through the right heart by injecting a bolus of saline at room temperature, the resultant change in blood temperature over time, as recorded by a thermistor at the distal port of the PAC (i.e., the area under the curve of a plot of temperature versus time), will provide an approximation of CO. With TD, CO can be measured intermittently using manual methods, or continuously using automated techniques. The manual method is based on the average value determined from 4 to 6 successive 10-ml boluses of saline injected into the proximal right atrial port of the PAC. For continuous measurements a specialized catheter with a proximal thermal filament, which heats the blood repeatedly using a brief thermal pulse, is used. Although limitations of TD methods are recognized—most notably, errors in measurement in the setting of tricuspid regurgitation—the technique provides a reasonably accurate measurement of CO. Measurement of CO using TD and a PAC is considered the gold standard to which other CO technologies are compared. CO can also be measured indirectly with the PAC using the Fick method, based on the fact that CO is equal to oxygen consumption (Vo2 ) divided by the difference in O2 content across the circulation (i.e., the arteriovenous O2 difference). Since Vo2 is usually not measured directly, the method is limited by inaccuracies in estimating Vo2 using body surface area alone in a critically ill patient. Hence, in patients with ARF, CO should be measured using TD unless significant tricuspid regurgitation is present. Application of the Fick method may be reasonable when values obtained by TD are unexpected. Oxygen consumption varies significantly over time in any given patient and among patients with ARF. Furthermore, since CO normally increases directly in proportion to Vo2 and inversely with hemoglobin concentration and O2 saturation, no normal or range of normal for CO has been established in patients with ARF. Normalizing CO to body surface area for comparison with reference values is also tenuous. From a management perspective, the most important questions in these patients are whether CO is adequate for the patient’s needs, whether CO can be improved with intravenous fluids, and whether fluid can be removed by diuresis or dialysis without significant compromise of CO. Outcome Studies In the mid-1990s, a study addressing the effectiveness of the PAC purported to show that use of the PAC increased

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mortality. The report stimulated a great deal of concern about the safety and use of the PAC and promoted significant efforts at improving education about use of the catheter. Use of the PAC fell dramatically following publication of the study. Subsequently, several randomized controlled trials were conducted to assess the value of the PAC in a variety of critically ill patients. The findings can be summarized as follows: use of the PAC does not alter patient outcome in patients undergoing high-risk surgery, those with septic shock, acute respiratory distress syndrome (ARDS) or CHF, or in patients deemed critically ill enough to require the PAC. Cautions in Using Pulmonary Artery Catheters Based on the outcome studies summarized previously, one can legitimately question whether the PAC should be used at all in patients with ARF. Proponents of PAC use cite several observations as the basis for their argument. The studies only evaluated whether use of the PAC improved overall outcome. None included explicit, standardized treatment protocols to direct patient management using the catheter. In addition, no systematic effort was made to minimize errors in measurement and interpretation of data, particularly errors due to respiratory variation (see below). In all but one of the studies inclusion criteria were based on disease or condition, rather than a specific clinical question, thus making it difficult to rule out a potential benefit with more selective application of the catheter. Given all of the information provided by use of the PAC, why have studies failed to show improved patient outcomes? Several hypotheses have been proposed, including an adverse physical effect of the PAC, inaccurate data, and misinterpretation of data, promoting misguided therapeutic interventions. Although physical complications from use of the PAC are well recognized, most are related to insertion of the central venous catheter through which the PAC is inserted. The few physical complications attributable to PAC, itself, are rare. In contrast, studies do support the notion that inaccuracies in pressure measurements or misinterpretation of data may lead to misguided treatment decisions and adverse outcomes. Studies using standardized tests demonstrate that clinicians from a variety of countries, disciplines, and levels of experience have inadequate knowledge about the PAC and difficulty reading pressure measurements accurately. In one study, the difficulty in reading tracings was due primarily to misidentification of end-expiration; interobserver variability in PAOP measurements was greatest when recordings showed marked phasic respiratory variation. Traditionally, clinicians have been taught to record all vascular pressures at end-expiration in order to minimize the effect of intrathoracic (i.e., juxtacardiac) pressure. Unfortunately, widely available resources for PAC education have misleading instructions on identification of end-expiration; in particular, these resources suggest that end-expiration in patients on mechanical ventilation is defined by the lowest point on the vascular pressure waveform. However, it is well known that patients may actively inspire during assist-control



Figure 152-1 A. In this patient on mechanical ventilation in the AC-mode, pulmonary artery occlusion pressure (PAOP) is read conventionally at the lowest vascular pressure (arrow), which is 3 mmHg. B . With airway pressure (PAW ) displayed concurrently, in place of the electrocardiogram tracing, it becomes obvious that vascular pressure falls throughout inspiration due to inspiratory effort. The true end-expiratory time point is shown by the arrow, which is a PAOP of 15 mmHg.

mechanical ventilation, causing intrathoracic (and, hence, vascular) pressure to fall, rather than rise. Consequently, in such patients the lowest point on the vascular pressure waveform corresponds to end-inspiration, while end-expiration coincides with the highest point on the tracing (Fig. 1521A). Erroneous selection of the nadir pressure results in vascular pressure readings (including CVP and PAOP) that may markedly underestimate the true values; the magnitude of the error is proportional to patient inspiratory effort. The significance of this potential error has likely increased in the last 5 years because of a trend toward use of minimal sedation and reduced tidal volumes in patients with ARF, each of which may increase respiratory effort and further lower pleural pressure during inspiration. Attempts to visually quantify and coordinate patient ventilatory efforts with the waveform displayed on a bedside monitor can be problematic, especially with higher respiratory frequencies observed in patients ventilated with lower tidal volumes. Addition of a simultaneous airway pressure (PAW ) signal to strip chart recordings of CVP and PAOP may provide a reliable signal for accurately timing end-expiration and significantly reduce interobserver variability (Fig. 1521B). Intensivists who use the PAC should consider concurrent

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30 — 20 — 10 — 0— A

30 —

Figure 152-2 A. In this patient on mechanical ventilation in AC-mode, an airway pressure (PAW ) tracing (not shown) confirms that end-expiratory pulmonary artery occlusion pressure (PAOP) is 25 mmHg (arrows) with respiratory variation of greater than 20 mmHg. B . Immediately after paralysis with succinylcholine repeat PAOP is 12 mmHg with minimal respiratory variation.

20 — 10 — 0— B

1. How does one account for the effect of forced expiration when interpreting CVP or PAOP? 2. How does one recognize when forced expiration is present? With regard to the first question, studies performed in patients with significant respiratory variation in PAOP demonstrated that the PAOP before and after muscular paralysis was similar to the PAOP measured as the midpoint between values recorded at end-expiration (peak) and end-inspiration (nadir) prior to paralysis—a value more closely approximated by the mean PAOP (Figs. 152-2 and 152-3). Recognition of forced expiration is necessary to determine when to apply this “midpoint” rule in the measurement of PAOP. In the absence of significant (greater than 8 mmHg) respiratory variation in PAOP, one can rule out forced expiration. Abdominal inspection and palpation usually confirm forced expiration if inward movement of the lateral and anterior abdominal walls occurs during expiration. Of note, if sig-

nificant respiratory variation occurs in the absence of forced expiration (from isolated inspiratory muscle effort alone), the pressures read at end-expiration are accurate. If it is not clear from the physical examination whether forced expiration is present, simultaneous measurement of CVP or PAOP and intra-abdominal pressure can be performed. Forced expiration is easily identified if PAOP and intra-abdominal pressure increase concordantly during expiration (Fig. 152-4), and is ruled out if the phasic changes in the two pressure recordings are discordant. Additional factors may result in misinterpretation of PAOP as an estimate of left ventricular preload. For example, PAOP may correlate poorly with LVEDV because of alterations in juxtacardiac pressure (e.g., from increases from set or occult PEEP or intra-abdominal hypertension) or ventricular compliance (e.g., due to ischemia or hypoxia). Finally,

40 Mid-point (mmHg)

monitor display of PAW and vascular pressures when recordings show significant (greater than 8 mmHg) respiratory variation in CVP or PAOP. Patients with significant phasic respiratory variation may also exhale forcefully, and significant errors in interpretation of hemodynamic data may occur despite measurement of PAW . Expiratory muscle use during exhalation increases abdominal pressure, which is transmitted directly across the relaxed diaphragm, resulting in increased end-expiratory pleural pressure. This, in turn, increases all vascular pressures in the thorax. Since transmural filling pressures of the right and left ventricles are unchanged, if unrecognized, forced expiration causes CVP and PAOP to be overestimated by an amount directly proportional to expiratory muscle effort (Fig. 152-2). The significance of forced expiration raises two important questions:



10 r = 0.77 0





Relaxed Ppao (mmHg)

Figure 152-3 Relationship between the relaxed pulmonary artery occlusion pressure (PAOP) (post-paralysis) and the midpoint PAOP (obtained during active respiratory effort). (From Hoyt JD, Leatherman JW: Interpretation of the pulmonary artery occlusion pressure in mechanically ventilated patients with large respiratory excursions in intrathoracic pressure. Intensive Care Med 23:1125, 1997.) (Reproduced with permission.)

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Figure 152-4 Arrows indicate end-exhalation. A. In this strip chart recording from a patient on AC-mechanical ventilation, there is minimal respiratory variation in pulmonary artery occlusion pressure (PAOP). Note, intra-abdominal blood pressure (IABP) rises during inhalation and falls during exhalation, paralleling the change in PAOP. B . On the same ventilator settings with less sedation, there is marked respiratory variation (â&#x2C6;ź30 mmHg) in PAOP. PAOP falls during inspiration consistent with active respiratory effort. Forced exhalation is confirmed by seeing a rise in IABP during exhalation (â&#x2C6;ź20 mmHg), in parallel with the PAOP. If IABP falls during exhalation in this setting, forced exhalation can be ruled out (not shown).

because of pericardial constraint of ventricular enlargement, right ventricular overload may cause PAOP and LVEDV to change reciprocally (increases in PAOP associated with decreases in LVEDV). Given the limitations of using pressure measurements to estimate cardiac preload (end-diastolic volume), a modified PAC was developed to allow continuous measurements of RVEDV using TD. The catheter contains a proximally located thermal filament which emits thermal pulses to heat the blood, while a sensitive and rapidly responsive thermistor located at the distal end of the catheter records temperature in the pulmonary artery. Input from the electrocardiogram allows timing of ventricular systole and a beat-to-beat analysis of the temperature decay curve. Right ventricular ejection fraction is computed from the exponential slope of the temperature decay curve and mean heart rate; RVEDV is calculated as stroke volume divided by ejection fraction. Studies have shown that RVEDV correlates well with CO, and specified thresholds of RVEDV may distinguish patients with hypovolemia who are fluid-responsive. However, other studies have not corroborated these thresholds and have failed to show that RVEDV can reliably predict preload responsiveness. Thus, routine use of these catheters cannot be recommended.

Even if the problems with measuring, recording, and interpreting PAOP and CO could be eliminated, PAC-guided care will likely be limited by lack of standardized guidelines for treatment based on the hemodynamic data obtained.

Noninvasive Alternatives to the Pulmonary Artery Catheter A variety of noninvasive techniques, including echocardiography, have been used as alternatives to PACs. They are described briefly below. Echocardiography Echocardiography is the most commonly used technique for cardiac imaging in critically ill patients, providing unique and important diagnostic information for the evaluation of shock, including assessment of biventricular volumes, contractility, valvular function, and pericardial anatomy. In patients who are adequately resuscitated, but who continue to have low output shock, early use of echocardiography to assess biventricular volumes and function is important. In the setting of an elevated PAOP and low CO, systolic dysfunction cannot be differentiated from any of the many states of ventricular compression, including cardiac

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tamponade, massive pleural effusion, mediastinal fluid collections, auto-PEEP, pneumothorax, or ventricular interdependence. When right ventricular dysfunction is suspected as the primary cause of shock, echocardiographic findings may assist in establishing the etiology. The presence of pulmonary arterial hypertension, which can be estimated in most critically ill patients, suggests pulmonary embolism, nonthrombotic pulmonary embolism, ARDS, or severe lung hyperinflation; right ventricular infarction is unlikely. Furthermore, in the setting of pulmonary hypertension, the echocardiogram may point to an acute process (e.g., pulmonary emboli, rather than chronic pulmonary hypertension), if regional akinesia of the right ventricular free wall and normal apical wall motion is found (“McConnell sign”). The diagnosis of acute pulmonary embolism is highly likely if a free floating clot is seen in the right atrium or ventricle, and the diagnosis is confirmed if a clot is visualized in the proximal pulmonary arteries. Both volumetric and Doppler-based techniques have been developed to allow echocardiographic estimates of cardiac preload and CO. Volumetric measurements using twodimensional imaging of ventricular size during diastole and systole provide the basis for estimates of preload, stroke volume, and contractility. Signs of hypovolemia on the twodimensional echocardiogram include a hyperdynamic ventricle and appearance of “kissing walls” at end-systole. CO can be determined using volumetric estimates of stroke volume, calculated as the difference in end-systolic and end-diastolic volumes. However, Doppler-based measurements of CO are more accurate. The Doppler method relies on the principle that flow in a cylinder (e.g., the aorta) is equal to cross-sectional area of the aorta times the blood-flow velocity. Velocity, in turn, is determined according to the principle that when ultrasonic waves are emitted perpendicular to flowing blood, the change in frequency of the sound waves reflected back is proportional to the blood-flow velocity. Stroke volume is derived from these two measurements; when multiplied by heart rate, CO is determined. Doppler-based estimates of CO have been shown to correlate reasonably well with those obtained by TD. Doppler techniques can also be used to estimate PAOP by assessing the relative velocity of blood flow through the mitral valve during early and late diastole. However, estimates of PAOP using this technique do not correlate well with direct measurements using a PAC. In any event, given the limitations of PAOP as a measure of preload, there is little utility in estimating PAOP using this technique, except to provide a rough estimate about whether or not pulmonary edema is on a cardiogenic basis. Echocardiography is performed at the bedside using either the transthoracic esophageal (TTE) or transesophageal (TEE) routes. Since rapidity of diagnosis is important, TTE is the initial study of choice in the ICU, given the technique’s widespread availability. TTE provides adequate assessment in the vast majority of mechanically ventilated patients; morbid obesity and emphysema may necessitate TEE. TEE is also

recommended as the initial study to rule out aortic dissection. Although considered a very low-risk procedure, TEE is not risk free. TTE is associated with trauma to the upper gastrointestinal tract and is contraindicated in patients with known or suspected pathology of the esophagus or cervical spine. One of the major limitations of both TTE and TEE is that neither allows for continuous hemodynamic monitoring. To fill this need, an esophageal catheter with a distal Doppler probe that allows measurement of CO continuously has been developed. The device is easy to use and eliminates the need for a specialist in Doppler signal acquisition, although some operator experience is required to ensure proficiency. Numerous studies have evaluated the accuracy of these devices relative to TD-based assessment of CO. A recent review concluded that esophageal Doppler does not provide accurate assessment of absolute CO, but its validity is high for monitoring changes in CO in critically ill patients. Finally, imaging dynamic changes in the diameter of the central veins and assessment of the velocity of aortic blood flow may predict preload responsiveness. Using portable echocardiography in completely sedated patients in septic shock respiratory collapse of the inferior or superior vena cavae in response to a large (8 to 10 ml/kg) mechanically delivered breath suggests hypovolemia and potential fluid responsiveness. In conclusion, bedside echocardiography is the diagnostic study of choice for unexplained or persistent circulatory shock. For patients who require continuous monitoring of CO, esophageal Doppler is a reasonable alternative to a PAC. The technique can be used to guide fluid resuscitation for optimization of CO in acute shock and guide a diuresis strategy to minimize pulmonary edema without adversely affecting peripheral perfusion. Although esophageal Doppler monitoring has been increasingly used as a substitute for a PAC, we still favor use of the PAC over esophageal Doppler for monitoring hemodynamics continuously in selected patients. Other Methods Several other noninvasive methods have been developed for determining CO, including expired carbon dioxide (CO2 ) analysis (indirect Fick method), lithium dilution method, measurement of thoracic impedance, and pulse contour analysis. The techniques are approved by the Food & Drug Administration (FDA) and are currently available, but none have been validated sufficiently to justify their routine use in critically ill patients. Indirect Fick Method

By imposing a brief period of partial rebreathing through the addition of dead space to the breathing circuit, changes in CO2 elimination and end-tidal CO2 concentration can be effected. Comparison of the new resultant steady-state values compared to baseline allows calculation of CO using the Fick principle. The technique has serious limitations in patients

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with ARF. Spontaneous breathing and hypocapnea limit its accuracy. Steady-state conditions must be achieved to assure accuracy, and intrapulmonary shunt affects the sensitivity of the measurement.

METHODS FOR MONITORING RESPIRATORY FUNCTION A number of respiratory parameters are routinely monitored in patients with ARF and are discussed briefly below.

Thoracic Electrical Bioimpedance

Thoracic electrical bioimpedance is based on the principle that the chest is an electrical conductor whose impedance is altered by changes in blood volume and blood-flow velocity with each heartbeat. By placing electrical currenttransmitting and voltage-sensing electrodes on the chest, stroke volume may be calculated based on an equation incorporating values for the baseline and maximum rate of change in chest impedance. Unfortunately, although noninvasive, measurement of thoracic electrical bioimpedance is confounded by too many factors in patients with ARF to support its routine clinical use. Transpulmonary Indicator Dilution Techniques: Thermodilution and Lithium Dilution

Transpulmonary indicator dilution techniques are based on intravenous injection of an indicator solution (e.g., cold saline or lithium chloride) and measurement of the change in temperature or lithium concentration, respectively, over time using a special arterial catheter. For the TD technique, the catheter is equipped with a thermistor at its tip; for the lithium-based technique, blood samples must be drawn successively for external measurement using a lithium-sensitive electrode. The greater the degree of indicator dilution (i.e., the less the change in temperature or lithium concentration) over time, the greater the CO. Values derived from each of these techniques correlate well with PAC-determined values. However, more data are needed to determine the accuracy of these techniques under a wide variety of clinical conditions. Pulse Contour Analysis

This method is based on the concept that changes in the contour of the arterial pressure waveform are proportional to stroke volume and are dependent on the mechanical properties of the aorta. Since the latter is relatively constant from beat to beat, changes in the pulse pressure correlate with changes in stroke volume. The technique requires calibration with an independent measurement of CO—currently accomplished by combining the indicator dilution technique (to determine mean CO) with assessment of beat-to-beat variability in the arterial pressure waveform (as a measure of stroke volume). Most studies have shown fair to good agreement of the technique with that of PAC-based measurements. Major limitations include the requirements for a femoral or axillary arterial catheter and frequent recalibration in patients who are hemodynamically unstable. Although the technique is promising, more studies are required to validate its usefulness and applicability in critically ill patients with ARF.

Oxygenation In the ICU, oxygenation is generally monitored using pulse oximetry, arterial blood gas analysis, or transcutaneous methods. Pulse Oximetry Pulse oximeters are universally deployed in the monitoring of perioperative and critically ill patients. Unique as monitoring devices, they provide useful data regarding oxyhemoglobin saturation (Spo2 ), heart rate, pulse volume, and tissue perfusion. Pulse oximeters use the spectrophotometric characteristics of pulsatile arterial blood to determine oxygen saturation and heart rate. Oxygenated blood absorbs light at 660 nm (red light), while deoxygenated blood absorbs light preferentially at 940 nm (infrared light). The oximeter consists of two light-emitting diodes (wavelengths, 600 nm and 940 nm) and two light-collecting sensors that measure the amount of red and infrared light emerging from tissues traversed by the light rays. The relative light absorption by oxyhemoglobin and deoxyhemoglobin is analyzed by the device and an oxygen saturation is calculated. The sensing function of the device is directed at pulsatile arterial blood, while local “noise” arising from the tissues is ignored. The result is a continuous qualitative measurement of oxyhemoglobin saturation. Use of pulse oximetry has not been shown to improve clinical outcomes, but epidemiological data have demonstrated a significant reduction in anesthesia-related morbidity. Although the technique accurately predicts arterial oxygen tension, the relationship between Pao2 and Spo2 is nonlinear, as dictated by the oxyhemoglobin dissociation curve. Accuracy falls off substantially at low-oxygen tensions, and saturation readings of less than 80 percent cannot be used reliably to guide oxygen therapy. The use of pulse oximeters is limited by a number of factors. The devices are designed to measure levels of oxygenated and deoxygenated hemoglobin, but no provision is made for measurement error in the presence of dyshemoglobinemias, including carboxyhemoglobinemia and methemoglobinemia. Since carboxyhemoglobin absorbs red light, conventional oximeters cannot distinguish oxy- from carboxyhemoglobin. In clinical situations where carbon monoxide poisoning is suspected, co-oximetry is essential. Co-oximeters measure reduced hemoglobin, oxyhemoglobin, carboxyhemoglobin, and methemoglobin. An additional source of error in using oximeters is abnormal patient movement (e.g., due to agitation). Low blood flow, hypotension, vasoconstriction, or hypothermia reduce pulsatility of capillary blood, resulting in underreading or

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no reading of oxygen saturation. Conversely, increased venous pulsation, such as occurs with tricuspid regurgitation, may result in an erroneously low reading by the device. Finally, oximetry-determined saturation is inaccurate on the steep part of the oxyhemoglobin dissociation curve. While the trend between directly measured arterial saturation and Spo2 appears accurate, the correlation between the two is not; a drop in Spo2 below 90 percent must be considered a potentially significant clinical event.

Ptco2 accurately represents Po2 ; however, the values are not identical, with Ptco2 approximately equal to 80 percent of Pao2 . Under conditions of hypoperfusion, the relationship may vary dramatically. In addition, various tissues have different values for Ptco2 , depending on local perfusion, skin thickness, and anatomic location (e.g., trunk versus limb). In order to prevent burns, the electrodes must be changed every 4 to 6 h, and the membrane must be changed and calibrated before each use. Despite these limitations and lack of widespread use, transcutaneous oxygen monitoring remains a useful device in multicomponent oxygen monitoring systems.

Arterial Blood Gases Blood gas analyzers have been available for 40 years and provide accurate measurement of Pao2 , Paco2 , and pH. From these primary determinations, a number of parameters are calculated, including serum bicarbonate, base deficit or base excess, and oxyhemoglobin saturation. Through application of the alveolar gas equation (see Chapters 11 and 34) arterial blood gas analysis is used commonly in calculating the alveolar-arterial oxygen gradient, a number that reflects the severity of ventilation-perfusion abnormalities. A significant limitation of the alveolar-arterial oxygen gradient is that it varies directly with FIo2 ; consequently, changes in the value may not reflect changes in the underlying disease process. An alternative calculation—the ratio of Pao2 to FIo2 , (“PF ratio”), which does not vary with FIo2 —has been used as a measure permitting comparisons of gas exchange at differing levels of FIo2 . The PF ratio has been incorporated into consensus definitions of ARDS and acute lung injury (ALI). A PF ratio less than or equal to 300 defines ALI; a ratio less than or equal to 200 defines ARDS. Neither the alveolar-arterial oxygen gradient nor the PF ratio takes into account differences in mean airway pressure. Although comparisons using the PF ratio would be more accurate if arterial blood was sampled uniformly at end-expiration and in the absence of PEEP, clinical constraints may preclude such sampling conditions.

Ventilation Clinical assessment of CO2 metabolism is usually considered with regard to the amount of gas that is dissolved in plasma (Paco2 ), the amount present in the exhaled tidal volume (endtidal CO2 ), and the total extracellular content (total CO2 or bicarbonate concentration). In the setting of respiratory failure, these measurements provide information on adequacy of ventilation, percentage of physiological dead space, acid-base balance, and nutritional status. In progressive chronic respiratory failure, as the ability to eliminate CO2 declines, total body CO2 stores (bicarbonate) increase. The ratio of total CO2 to bicarbonate concentration provides an indication of the acuity of the respiratory failure. Changes in Paco2 may also be related to changes in base deficit or excess. Assessment of CO2 elimination forms the basis of calculating the ratio of dead space to tidal volume—a useful physiological construct in gauging the severity of underlying lung disease in respiratory failure. Through application of the modified Bohr equation (see Chapter 34), the ratio of dead space to tidal volume (Vd /Vt ) is calculated in Eq. (3) as follows: Vd /Vt = (Paco2 − PEco2 )/Paco2

Transcutaneous Oxygen Monitoring The commonly employed oxygen electrode is based on a modification of the electrode developed in 1956. The device is constructed of a platinum wire tip surrounded by glass. Covered by a polyurethane membrane which is permeable to oxygen, the electrode responds in a linear fashion to oxygen in the gaseous or liquid phase over a concentration range of 1 to 100 percent. The margin of error is less than 1 percent. Although the oxygen electrode has been employed predominantly for blood gas measurements, it can be modified for use in the continuous, noninvasive measurement of transcutaneous oxygen tension (Ptco2 ). Electrode heating of the skin changes the structure of lipoproteins in the stratum corneum from the gel to the sol state, allowing rapid diffusion of oxygen from subcutaneous tissues through the skin. In addition, electrode heating prevents local vasoconstriction, ensuring that Ptco2 closely reflects Pao2 . In hemodynamically stable patients who have good tissue perfusion,


where PEco2 is mean expired CO2 . PEco2 can be measured using a metabolic monitor that collects expired gas over 5 min. Alternatively, main stream or side stream capnometry can be used to measure PEco2 . In the normal lung, alveolar Pco2 is equivalent to Paco2 and can be estimated by sampling expired end-tidal gas. However, in the presence of significant physiological dead space (as in ARF), end-tidal CO2 grossly underestimates Paco2 . Given this limitation, aside from confirming endotracheal tube placement, end-tidal CO2 measurements are not used routinely in managing patients with ARF.

Endotracheal Tube Placement Monitoring endotracheal tube (ETT) position is an important aspect of critical care. An extremely common complication of intubation is misplacement of the ETT, with passage into the right main bronchus. Ideally, the ETT tip should be located 4 to 5 cm above the carina. In the case of a tracheotomy,

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the tube tip should be located about halfway between the tracheotomy stoma and the carina. ETT placement can be confirmed in several ways: (1) by assessing for the presence of bilateral breath sounds during breath delivery, (2) by palpation of the ETT cuff in the jugular notch, (3) with chest radiography, or (4) using fiberoptic bronchoscopy. In addition to tube placement, pressure within the ETT cuff should be measured regularly. The cuff is inflated to create a seal between the side wall of the ETT and the tracheal wall. Since capillary perfusion pressure of the tracheal mucosa is approximately 25 cm H2 O, cuff pressure should be kept below this level to prevent ischemia, which may lead to ulceration, inflammation, and, if severe, tracheal dilatation. In addition, the injured tracheal segment may develop fibrosis and, ultimately, stenosis. On the other hand, evidence exists that low cuff pressures may increase the risk of pneumonia, presumably by promoting microaspiration. Thus, the current recommendation for optimal tracheal cuff pressure is 20 to 25 cm H2 O. Following intubation and ETT positioning, the tube cuff should be slowly and progressively inflated just to the point of loss of gas leak occurring with ventilation—the socalled “minimal occluding pressure” technique (some experts advocate use of the “minimal leak” technique). To measure cuff pressure, an aneroid manometer is connected to the cuff ’s pilot tube (the tube from which the balloon is inflated). If excessive cuff pressure is required to maintain an adequate tracheal seal, the ETT is likely too narrow for the patient’s trachea. If cuff pressure increases over time, tracheomalacia should be suspected and the tube changed to one with a foam cuff. The presence of a cuff leak may be problematic, particularly in patients who are critically ill. Signs of leak include an audible noise during inspiration, audible patient phonation, frothy mouth secretions with each breath, a difference between set and exhaled tidal volumes, inadequate ventilatory volumes, hypoxemia, and the presence of a thrill over the trachea. Cuff leaks may be caused by rupture or herniation of the cuff, proximal displacement of the ETT, pilot tube valve malfunction, or inadvertent cuff deflation.

Respiratory System Mechanics Assessment of respiratory system mechanics may be useful in differentiating the etiology of ARF (e.g., restrictive versus obstructive disease or upper versus lower airway obstruction), troubleshooting the cause of new episodes of clinical instability, assessing the effectiveness of therapeutic interventions (e.g., use of bronchodilators or application of PEEP), or minimizing the risk of ventilator-induced lung injury. Airway Pressure Airway pressure is an important variable which is routinely monitored during mechanical ventilation. Respiratory pressures are usually referenced to atmospheric pressure (“single-ended” pressures). Electromechanical transducers

(or aneroid manometers), which convert pressure to electrical current, may be located in the patient’s ventilator circuit or esophagus. The most common site of pressure transduction is the wye connector (the connector that joins the inspiratory and expiratory limbs of the ventilator circuit), although the distal ETT can also be used. Pressure measured within the ventilator or ventilator circuit is referred to as “airway pressure,” Paw (or, more correctly, airway opening pressure, Pao ), while that measured at the tip of the ETT is referred to as “tracheal pressure,” Ptr . Pressure measured within the esophagus is referred to as “esophageal pressure,” Pes . Five different pressure measurements are commonly made during the respiratory cycle: (1) peak airway pressure (Ppeak ), (2) plateau pressure (Pplat ), (3) mean airway pressure (Pmean ), (4) positive end-expiratory pressure (PEEP), and (5) auto-PEEP (also called intrinsic PEEP). Measurement of tracheal pressure at the tip of the distal ETT provides an assessment of pressure in the native airway, as the effect of flow through the ETT is eliminated. Esophageal pressure provides an estimate of pleural pressure. Although not used routinely in clinical practice, esophageal pressure can be used to estimate transpulmonary pressure, which is a more accurate measure of alveolar distending pressure than is plateau pressure. Accurate measurement of airway resistance requires that airway pressures be determined using constant flow conditions (i.e., a square flow-wave profile) (Fig. 152-5). Most modern ventilators make the flow-wave profile adjustment automatically when the “mechanics function” of the device is selected. In addition, since airway pressures are altered by respiratory muscle contraction, patients must be fully relaxed and exert minimal breathing effort. These conditions may be accomplished by using ventilator settings designed to fully support the patient (e.g., by providing a level of ventilatory support that exceeds patient demand, or administration of sedation). For quality control, ventilator waveforms should

50 40 30 20 10 0 −10


PPEAK Airflow resistance PPLAT PEEP

Respiratory system compliance

lpm 50 25 0 −25 −50 −75 −100

Figure 152-5 Inspiratory hold maneuver during constant flow in a volume-controlled breath. Note the significant difference between the patient’s peak airway pressure (48 cm H2 O) and plateau pressure (26 cm H2 O), indicative of increased airways resistance.

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be assessed during the mechanics maneuver to ensure the conditions have been met. Ppeak represents the total pressure the ventilator must generate in order to overcome the impedance of the respiratory system, including airflow resistance, elastic load (lung and chest wall distention), and any threshold load due to dynamic hyperinflation (from auto-PEEP). When interpreting Ppeak , in addition to impedance, several other factors must be considered, including peak flow rate, waveform profile (square or decelerating), and tidal volume. This is a very important point in clinical practice, since Ppeak may erroneously be considered as the primary determinant of barotrauma. When a high Ppeak is observed (as commonly seen in obstructive lung diseases), an attempt to lower Ppeak by reducing inspiratory flow rate may achieve the opposite effect. The risk of barotrauma may be increased by the resulting increment in plateau pressure that occurs as a consequence of reduced expiratory time and increased auto-PEEP. Pplat reflects the pressure within the alveoli at endinhalation and is the most important pressure to monitor in preventing barotrauma. The goal is less than or equal to 30 mmHg in all cases of ARF, including those due to obstructive airway disease. Pplat is measured at end-inspiration during a period of zero flow, which is achieved by applying an inspiratory “hold” during volume-controlled ventilation (see Fig. 152-5). Pplat is always lower than Ppeak by an amount equal to the pressure required to drive inspiratory flow through the ventilator circuit, ETT, and airways. For the patient with a high Paw , the clinician can determine rapidly whether the problem is resistive (airway) or elastic (lung or chest wall) in nature by assessing the pressure gradient between Ppeak and Pplat and between Pplat and total PEEP (set PEEP plus auto-PEEP) (see Fig. 152-5). For instance, if the differential between Ppeak and Pplat increases, airflow resistance must have increased; potential causes include bronchospasm, a kink in the ETT, and increased airway secretions. In contrast, if the rise in Paw is unaccompanied by an increase in the Ppeak –Pplat pressure gradient (i.e., both Ppeak and Pplat increase relative to total PEEP), the elastic load must have increased; causes include loss of lung volume (e.g., right main bronchus intubation; lobar atelectasis; or an alveolar filling process, such as pneumonia or CHF) or a stiffer chest wall apparatus (e.g., pleural effusion or intra-abdominal hypertension). These routinely measured airway pressures are also used to calculate additional important measures of respiratory mechanics, including airway resistance and respiratory compliance. Dividing the Ppeak –Pplat pressure gradient by inspiratory flow rate yields airway resistance. The normal value depends on the size of the ETT, but it is typically about 5 to 15 cm H2 O/L/s. Respiratory system compliance, expressed as ml/cm H2 O, is calculated as tidal volume divided by the difference between Pplat and total PEEP. Failure to consider autoPEEP in the calculation results in overestimation of compli-

ance. Normal respiratory system compliance is greater than 60 ml/cm H2 O. Auto-PEEP Auto-PEEP (also known as “intrinsic” PEEP) refers to the positive pressure within alveoli at end-expiration that has not been generated by a ventilator. A form of naturally occurring auto-PEEP may be observed with forced exhalation that occurs during heavy exercise. In this case, lung mechanics may be normal, and expiratory muscle force maintains positive intrathoracic and airway pressures throughout expiration; functional residual capacity (FRC) may be normal or decreased. In contrast, two other types of auto-PEEP are associated with dynamic hyperinflation. In one, auto-PEEP results from a high minute ventilatory requirement, as occurs in ARDS, where insufficient expiratory time promotes incomplete expiration before delivery of the next breath. In the other, more common variety, auto-PEEP results primarily from delayed emptying of alveoli due to airflow obstruction, as most commonly seen in status asthmaticus or an acute exacerbation of chronic obstructive pulmonary disease. The development of auto-PEEP is determined by three factors: tidal volume, expiratory time, and the respiratory system expiratory time constant (the product of resistance and compliance). Auto-PEEP poses significant problems in pressure-targeted mechanical ventilation, where the additional PEEP reduces ventilator driving pressure, and consequently, tidal volume. In contrast, in volume-targeted ventilation, auto-PEEP causes Paw and Pplat to increase, which, in turn, increase end-inspiratory lung volumes and alveolar “stretch.” In a mechanically ventilated patient, auto-PEEP is most easily identified by examining the ventilator flow waveform and observing that expiratory flow does not return to zero before initiation of the next breath (Fig. 152-6). Quantification of the magnitude of auto-PEEP is achieved by implementing a prolonged “expiratory hold” maneuver, during which equilibration of pressure throughout the ventilatory circuit is achieved (Fig. 152-7). A mechanically ventilated patient who is generating spontaneous breaths presents a challenge for measurement of auto-PEEP, as airway occlusion usually incites increased respiratory drive. Under these circumstances, an esophageal balloon catheter may be used to estimate pleural pressure, and auto-PEEP calculated by measuring the magnitude of the negative deflection in esophageal pressure from the start of inspiratory effort to onset of inspiratory flow. This method underestimates auto-PEEP in patients with significant airway obstruction. If auto-PEEP arises as a result of hyperinflation due to expiratory flow limitation in a spontaneously breathing, ventilated patient, external PEEP upto, but not exceeding, the level of auto-PEEP can be applied to offset the increased work of breathing associated with the additional inspiratory threshold load. The applied PEEP does not impact expiratory flow or lung volume. The applied PEEP should be no greater than 85 percent of the measured auto-PEEP.

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Volume Normal lung



ARDS lung

Figure 152-6 The presence of auto-PEEP is identified from the flow waveform. The next breath commences before expiratory flow returns to zero.


Pressure-Volume Curves In the normal lung, compliance is greatest at FRC, decreasing progressively as lung volume increases (Fig. 152-8). In patients with diffuse parenchymal lung disease (e.g., ARDS) FRC declines, and pressure application at low lung volume yields little increase in volume. With increasing levels of inflation pressure, a point is reached (the lower inflection point, or LIP) beyond which compliance improves dramatically. With further increments in inflation pressure, another point is reached beyond which the pressure-volume curve flattens, defining the upper inflection point (UIP). A significant reduction in mortality has been demonstrated in patients with ARF using PEEP levels greater than LIP as part of a ventilator protocol based on pressure-control, inverse-ratio, and pressure-limited techniques. The findings may relate to a reduction in the lung injury thought to be related to phasic opening and closing of lung units (“atelectrauma”) and resulting epithelial disruption, local inflammation, cytokine release, and tissue destruction. Therefore, some have advocated as an optimal ventilation strategy for minimizing ventilator-induced lung injury (VILI) application of

Valve closed Auto PEEP level



Valve closed

Exp Figure 152-7 Expiratory hold technique to quantify auto-PEEP. The expiratory valve is closed during an expiratory ‘‘hold” at the end of a set expiratory time. When flow equals zero, airway pressure rises to the auto-PEEP level.

LIP Pressure

Figure 152-8 Pressure-volume curves of normal and diseased lungs. In the curve in acute respiratory distress syndrome (ARDS), two inflection points have been identified: a lower inflection point (LIP) and an upper inflection point (UIP).

a PEEP level 2 cm H2 O above the LIP and maintenance of Pplat just below the UIP. However, although many believe that the LIP represents the critical opening pressure of the majority of atelectatic alveoli, alveolar recruitment has been shown to continue for the duration of inspiration. In addition, investigators have found no such inflection point in patients with obvious alveolar recruitment demonstrated by computed tomography (CT). Esophageal Pressure Measurement of respiratory system compliance includes the mechanical properties of the lung and chest wall. By measuring pleural pressure, the transmural distending pressure of the lung can be calculated. Although regional variation in pleural pressure exists, measurement of lung compliance is based on the change in pleural pressure, rather than its absolute value. Pleural pressure is usually estimated from esophageal pressure, which is recorded using an esophageal catheter. The typical device consists of a latex balloon which is 10 cm long and has several holes. The catheter is inserted into the lower esophagus (usually to a depth of about 40 cm). At this level, artifact from the beating heart is minimized. The adequacy of esophageal balloon positioning is confirmed by having the patient perform inspiratory attempts against an occluded airway. The esophageal pressure changes should be equal (±10 percent) to airway pressure changes. In the paralyzed patient, external chest compressions are used to create pressure fluctuations.

Ventilator Waveforms Most modern ventilators include a spirometer or flow monitor to measure the volume and flow of gas passing through the ventilator circuit with each breath. Data are analyzed by a microprocessor in the ventilator and are graphically represented

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as waveforms. The most commonly displayed waveforms include volume, pressure, and flow. Plots of flow versus volume (flow-volume loops) and pressure versus volume can be constructed electronically from the measurements. Monitoring of ventilator waveforms provides useful information about patient-ventilator synchrony, circuit leaks, patient-ventilator disconnection, development of auto-PEEP, and airway obstruction.

resulting electrical potential is measured, and the process is repeated for numerous configurations of applied current. Potential applications for the technique include titration of PEEP, evaluation of alveolar recruitment maneuvers, and investigation of phasic atelectasis. At present, EIT remains a research tool. The use of CT has dramatically changed the way in which clinicians view ARDS. Because of the diffuse, widespread distribution of abnormalities seen on conventional radiographs, ARDS was traditionally considered a homogeneous pathological process. However, application of CT imaging in ARDS has demonstrated that the disorder is quite heterogeneous. Furthermore, the advent of high-resolution, multidetector scanners will expand the number of applications of this technology—for example, in the diagnosis of the etiology of the lung injury (pulmonary versus extrapulmonary), nature of the injury (pneumonia versus lung contusion), or progression of injury from inflammation to fibrosis. In addition, the presence of complications (e.g., occult barotrauma or pleuropulmonary infection) and the response to interventions (e.g., adjustment of PEEP, implementation of alveolar recruitment maneuvers, incorporation of spontaneous breathing during mechanical ventilation, or determination of the need for insertion of chest drains) will be more readily discerned.

Inspiratory Muscle Strength Respiratory muscle strength may be assessed by measuring maximum inspiratory and expiratory pressures generated against an occluded airway. This is most easily measured using an aneroid manometer. Inspiratory strength is measured at FRC, where the length-tension relationship of the inspiratory muscles is optimal. The pressure determined by this maneuver is known as the negative inspiratory force (NIF) or maximal inspiratory pressure (MIP). Clearly, the measurement is dependent on the intensity of the inspiratory effort, which may be suboptimal in uncooperative or unconscious patients. The problem can be circumvented by performing the maneuver off the ventilator, using a one-way valve; the NIF is measured over 10 sequential breaths or 30 s. By measuring over time, progressively lower lung volumes are reached and the inspiratory drive increases progressively, promoting a maximal effort. Although the utility of the NIF as a predictor of weaning outcome has fallen out of favor, it remains a useful measurement in troubleshooting reasons for ventilator dependence. Maximal expiratory pressure (MEP) is measured at total lung capacity, where the expiratory muscle lengthtension relationship is optimal. Although not routinely employed in clinical practice, MEP may have use in predicting extubation outcome in selected patient populations.

Imaging in Acute Lung Injury A variety of imaging techniques may be useful in monitoring patients with ARF, including diaphragm ultrasound, electrical impedance activity (EIT), and CT. The thickness of the diaphragm changes dynamically between the relaxed phase and maximum inspiration. Ultrasound can be used to evaluate changes in diaphragm thickness in the so-called “zone of apposition,” where the lateral portions of the diaphragm lie adjacent and parallel to the lateral chest walls. The technique is noninvasive, inexpensive, and free of ionizing radiation. Diaphragm ultrasound has proved useful in the diagnosis of diaphragm paralysis in the context of ARF. EIT is a relatively new bedside imaging technique in which an image of gas distribution within the chest is constructed during different phases of respiration. Although the technique’s spatial resolution is limited in comparison with CT, its temporal resolution is better. With EIT, a series of eight pairs of electrodes are placed around the chest circumference and a current applied between electrode pairs. The

SUGGESTED READING Al-Kharrat T, Zarich S, Amoteng-Adjepong Y, et al: Analysis of observer variability in measurement of pulmonary artery occlusion pressures. Am J Respir Crit Care Med 160:415, 1999. Breen PH: Arterial blood gas and pH analysis. Clinical approach and interpretation. Anesth Clin North Am 19:885– 906, 2001 Caples SM, Hubmayr RD: Respiratory monitoring tools in the intensive care unit. Curr Opin Crit Care 9:230–235, 2003. Chaney J, Derdack S: Minimally invasive hemodynamic monitoring for the intensivist: Current and emergent technology. Crit Care Med 30:2338–2345, 2002. Chazal I, Hubmayr RD: Novel aspects of pulmonary mechanics in intensive care. Br J Anaesth 91:81–91, 2003. Connors AF Jr, Speroff T, Dawson NV, et al: The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators [comment]. JAMA 276:889, 1996. Dellinger RP, Carlet JM, Masur H, et al: Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858, 2004. Gattinoni L, Caironi P, Pelosi P, et al: What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 164:1701–1711, 2001.

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Georgopoulos D, Prinianakis G, Kondili E: Bedside waveforms interpretation as a tool to identify patient-ventilator asynchronies. Intensive Care Med 32:34–47, 2006. Harvey S, Harison DA, Singer M, et al: Assessment of the clinical effectiveness of PAC in management of patients in intensive care (PAC-MAN): A RCT. Lancet 366:472, 2005. Hoyt JD, Leatherman JW: Interpretation of the pulmonary artery occlusion pressure in mechanically ventilated patients with large respiratory excursions in intrathoracic pressure. Intensive Care Med 23:1125, 1997. Michard F, Teboul JL: Predicting fluid responsiveness in ICU patients: A critical analysis of the evidence. Chest 121:2000, 2002. Puybasset L, Gusman P, Muller JC, et al: Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the effects of positive end-expiratory pressure. CT Scan ARDS Study Group. Adult Respiratory Distress Syndrome. Intensive Care Med 26:1215–1227, 2000. Reinhart K, Bloos F: The value of venous oximetry. Curr Opin Crit Care 11:259, 2005.

Richard, C, Warszawski J, Anguel N, et al: Early use of the PAC and outcomes in patients with shock and acute respiratory distress syndrome. A randomized controlled trial. JAMA 290:2713, 2003. Rivers E, Nguyen B, Havstad S, et al: Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368, 2001. Rizvi K, deBoisblanc BP, Truwit JD, et al: The effect of airway pressure display on interobserver variability in the assessment of vascular pressures in patients with acute lung injury and ARDS. Crit Care Med 33:98, 2005. Schuster DP, Seeman MD: Temporary muscle paralysis for accurate measurement of pulmonary artery occlusion pressure. Chest 84:593, 1983. Stenqvist O: Practical assessment of respiratory mechanics. Br J Anaesth 91:92–105, 2003. Zakynthinos SG, Vassilakopoulos T, Zakynthinos E, et al: Contribution of expiratory muscle pressure to dynamic intrinsic positive end-expiratory pressure. Am J Respir Crit Care Med 162:1633, 2000.

153 Principles of Mechanical Ventilation Martin J. Tobin

I. OBJECTIVES AND INDICATIONS FOR MECHANICAL VENTILATION II. MODES OF MECHANICAL VENTILATION Controlled Mechanical Ventilation Assist-Control Ventilation Intermittent Mandatory Ventilation Pressure-Support Ventilation New Modes III. VENTILATOR SETTINGS Triggering Tidal Volume Respiratory Rate

The historical evolution of mechanical ventilation is rich and built on advances in many fields, including endeavors by anatomists, chemists, explorers, physiologists, and clinicians. In 1543, Vesalius demonstrated that positive-pressure ventilation could be used to resuscitate a dying animal. Bellows ventilation was advocated by various lay bodies in the resuscitation of near-drowning victims late in the eighteenth century. In 1827, however, Leroy demonstrated that overzealous bellows inflation could result in pneumothoraces. Official bodies condemned the technique, and, thus, early in its infancy, positive-pressure ventilation was banned from use. Around this time, negative-pressure ventilators were developed and later popularized as a panacea for a wide variety of ailments. The modern era of mechanical ventilation was ushered in by Bjorn Ibsen in response to epidemic of bulbar poliomyelitis in Copenhagen in 1952. In the first 3 weeks of the epidemic, 31 patients had been treated with negativepressure respirators, and 27 had died. Ibsen advised immediate tracheostomy and the use of positive-pressure ventilation with manual positive pressure from a rubber bag, as was then customary in the operating room. Hundreds of medical students worked in relays, delivering bag ventilation during

Inspiratory Flow Rate Fractional Inspired Oxygen Concentration Positive End-Expiratory Pressure IV. BRONCHODILATOR THERAPY V. MONITORING AND COMPLICATIONS VI. WEANING Causes of Weaning Failure Timing of the Weaning Process Weaning Trials Extubation

the epidemic; shortly thereafter, machines were introduced to deliver positive-pressure ventilation. Over the following 40 years, ventilators changed enormously in appearance, becoming more sophisticated and versatile and having enhanced capabilities for monitoring and alarming.

OBJECTIVES AND INDICATIONS FOR MECHANICAL VENTILATION The objectives of mechanical ventilation are listed in Table 153-1. In isolation, hypoxemia of mild to moderate severity can be managed by administration of oxygen (O2 ) through a face mask. With more severe hypoxemia secondary ˙ mismatching, it is to shunt or ventilation-perfusion (V˙ a /Q) difficult to guarantee the delivery of a high fractional inspired oxygen concentration (Fio2 ) through a face mask. Moreover, these patients are commonly in considerable distress. Thus, intubation helps by ensuring delivery of the required Fio2 , and positive-pressure ventilation helps by recruiting collapsed lung units, leading to improved matching of ventilation and perfusion.

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Table 153-1 Objectives of Mechanical Ventilation Improve pulmonary gas exchange Reverse hypoxemia Relieve acute respiratory acidosis Relieve respiratory distress Decrease oxygen cost of breathing Reverse respiratory muscle fatigue Alter pressure-volume relationships Prevent or reverse atelectasis Improve lung compliance Prevent further lung injury Permit lung and airway healing Avoid complications

with atelectasis or acute lung injury because breathing occurs on the low, flat portion of the pressure-volume curve. By shifting tidal ventilation to the steep, compliant portion of the curve, mechanical ventilation can decrease respiratory work. Commonly listed indications for mechanical ventilation include acute respiratory failure, exacerbation of chronic respiratory failure (e.g., secondary to infection, bronchoconstriction, or heart failure), coma, and neuromuscular disease. Many patients with these same conditions, however, do not require ventilator assistance. Indeed, the most common, and honest, reason that mechanical ventilation is instituted is a tautology: A physician thinks that “the patient looks like he (or she) needs to be placed on the ventilator.” Mechanical ventilation is most commonly instituted based on a physician’s clinical gestalt, formed through assessing a patient’s signs and symptoms, rather than because a patient satisfies a certain set of criteria on a checklist. It is important to ground this decision on solid knowledge of pulmonary pathophysiology.

source: From: Tobin MJ: Mechanical ventilation. N Engl J Med 330:1056–1061, 1994, with permission.

Acute progressive respiratory acidosis is a major indication for mechanical ventilation, although simpler measures can sometimes reverse the process. For example, among patients with acute severe asthma and hypercapnia, hypercapnia resolves with standard bronchodilator therapy, without the need for mechanical ventilation, in more than 90 percent of patients. If a patient has severe respiratory depression that is expected to be slow in resolving (e.g., certain drug overdoses), intubation and mechanical ventilation should be instituted without delay. A substantial proportion of patients who require (and benefit from) mechanical ventilation have relatively normal arterial blood gases but have clinical signs of increased work of breathing: nasal flaring; vigorous activity of the sternomastoid muscles; tracheal tug; recession of the suprasternal, supraclavicular, and intercostal spaces; paradoxical motion of the abdomen; and pulsus paradoxus. This picture of a patient “tiring out” is the most common reason for instituting mechanical ventilation. The increase in work of breathing may be the result of increased airway resistance, increased stiffness of the lungs or chest wall, or the presence of a threshold inspiratory load secondary to auto- or intrinsic positive end-expiratory pressure (PEEPi ). Increased respiratory work increases the O2 cost of breathing to as much as 50 percent of total O2 consumption. By decreasing respiratory work, mechanical ventilation allows precious O2 stores to be rerouted to other vulnerable tissue beds. To substantially reduce patient effort, the ventilator must cycle in unison with the patient’s central respiratory rhythm (Fig. 153-1). For perfect synchronization, the period of mechanical inflation must match the period of neural inspiratory time (the duration of inspiratory effort), and the period of mechanical inactivity must match the neural expiratory time. Work of breathing is increased in patients

MODES OF MECHANICAL VENTILATION The term mode refers to the relationship among various breath types (mandatory, assisted, supported, and spontaneous), as well as inspiratory phase variables.

Controlled Mechanical Ventilation In controlled mechanical ventilation, the ventilator delivers all breaths at a preset rate, and the patient cannot trigger the machine. In the volume-targeted mode, the breaths have a preset volume—so-called volume-controlled ventilation. When the breaths are pressure limited and time cycled, the mode is termed pressure-controlled ventilation. Use of volume-controlled ventilation is largely restricted to patients who are apneic as a result of brain damage, sedation, or paralysis.

Assist-Control Ventilation In the assist-control mode, the ventilator delivers a breath either when triggered by the patient’s inspiratory effort (pressure- or flow-triggered) or, independently, if such an effort does not occur within a preselected time period. All breaths are delivered under positive pressure by the machine, but unlike controlled mechanical ventilation, the patient’s triggering effort can exceed the preset rate. If the patient’s spontaneous rate drops below the preset back-up rate, controlled ventilation is provided. The pressure to achieve the set tidal volume may be provided solely by the machine or, in part, by the patient. By design, delivered tidal volume is not influenced by patient effort. The more the patient contributes, the less pressure is provided by the machine, and ventilator-generated pressure bears an inverse relationship to patient-generated pressure.

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Figure 153-1 Flow, airway pressure, and inspiratory and expiratory muscle activity in a patient with chronic obstructive pulmonary disease who received pressure-support ventilation at an airway pressure of 20 cm H2 O. The electromyograms in the lower portion of the figure show inspiratory muscle activity in the patient’s diaphragm and expiratory muscle activity in the transversus abdominis. The patient’s increased inspiratory effort caused the airway pressure to fall below the set sensitivity (−2 cm H2 O), and inadequate delivery of flow by the ventilator resulted in a scooped contour on the airway-pressure curve during inspiration. While the ventilator was still pumping gas into the patient, his expiratory muscles were recruited, causing a bump in the airway-pressure curve. That the flow never returned to zero throughout expiration reflected the presence of PEEPi . The broken red line shows airway pressure in another patient, who generated just enough effort to trigger the ventilator and in whom there was adequate delivery of gas by the ventilator. (Data are from Jubran A, Van de Graaff WB, Tobin MJ: Variability of patient-ventilator interaction with pressure support ventilation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:129– 136, 1995; Parthasarathy S, Jubran A, Tobin MJ: Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation. Am J Respir Crit Care Med 158:1471–1478, 1998. Reproduced with permission from Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001.)

The ventilator cycles off when the preset tidal volume is reached, and machine inspiratory time may be shorter or longer than the patient’s intrinsic (neural) inspiratory time. If the set tidal volume is reached before the end of neural inspiratory time, the machine cycles off while the patient’s inspiratory effort continues. If the patient’s inspiratory effort ceases before the set tidal volume is reached, the machine increases pressure to provide continued inspiratory flow. The amount of active work performed by a patient ventilated in the assist-control mode is critically dependent on the trig-

ger sensitivity and inspiratory flow settings. Even when these settings are selected appropriately, patients actively perform about one-third of the work performed by the ventilator during passive conditions.

Intermittent Mandatory Ventilation With intermittent mandatory ventilation (IMV), the patient receives periodic positive-pressure breaths from the ventilator at a preset volume and rate, but the patient can also breathe

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Figure 153-2 Electromyograms of the diaphragm (EMGdi) and sternocleidomastoid muscles (EMGscm) in a patient receiving synchronized intermittent mandatory ventilation. Similar intensity and duration of electrical activity during assisted (A) and spontaneous (S) cycles are demonstrated. Paw = airway pressure; Pes = esophageal pressure. (From Imsand C, Feihl F, Perret C, et al: Regulation of inspiratory neuromuscular output during synchronized intermittent mechanical ventilation. Anesthesiology 80:13– 22, 1994, with permission.)

spontaneously between these mandatory breaths. A problem unforeseen at the time IMV was introduced is the difficulty that patients encounter in trying to adapt to the intermittent nature of ventilator assistance. It had been assumed that the degree of respiratory muscle rest achieved by IMV would be proportional to the number of mandatory breaths delivered. Studies, however, have demonstrated that inspiratory effort is equivalent for spontaneous and assisted breaths during IMV (Fig. 153-2). Indeed, the tension-time index for both spontaneous and assisted breaths is above the threshold associated with respiratory muscle fatigue at IMV rates of 14 breaths per minute or less. At a moderate level of machine assistance (at which the ventilator accounts for 20 to 50 percent of total ventilation), electromyographic activity of the diaphragm and sternocleidomastoid muscles is equivalent for assisted and spontaneous breaths. These findings suggest that respiratory center output is preprogrammed and does not adjust to breath-to-breath changes in load, as occur during IMV. As a result, IMV may contribute to development of respiratory muscle fatigue or prevent its recovery.

Pressure-Support Ventilation Pressure-support ventilation is patient triggered, like assistcontrol ventilation and IMV, but differs in that it is pressure targeted and flow cycled. The physician sets a level of pressure that augments every spontaneous effort, and the patient can alter respiratory frequency, inspiratory time, and tidal

volume. Tidal volume is determined by the pressure setting, the patient’s effort, and pulmonary mechanics, in contrast to assist-control ventilation and IMV, in which a guaranteed volume is delivered. With volume-targeted ventilation, the inspiratory flow setting is a crucial determinant of patient work. There is no flow setting with pressure-support ventilation, although the initial peak flow determines the speed of pressurization and the initial pressure ramp profile. The level of pressure delivered by the ventilator is usually adjusted in accordance with changes in the patient’s respiratory frequency. However, the frequency that signals a satisfactory level of respiratory muscle rest has never been well defined, and recommendations range from 16 to 30 breaths per minute. Several investigators have shown that pressure support is very effective in decreasing the work of inspiration. The degree of inspiratory muscle unloading, however, is variable, with a coefficient of variation of up to 96 percent among patients. Pressure-support does not decrease PEEPi in patients with chronic obstructive pulmonary disease (COPD). Thus, at a pressure support of 20 cm H2 O, PEEPi may account for two-thirds of total inspiratory effort. Cycling to exhalation is triggered by a decrease in inspiratory flow to a preset level, such as 5 L/min or 25 percent of peak inspiratory flow, depending on the manufacturer’s algorithm (Fig. 153-3). The algorithm for “cyclingoff ” of mechanical inflation causes problems in patients with COPD, because increases in resistance and compliance produce a slow time constant (of the respiratory system). The longer time needed for flow to fall to the threshold value can cause mechanical inflation to persist into neural expiration.

Figure 153-3 Airway pressure (Paw ) and inspiratory (Insp) and expiratory (Exp) flow during pressure support ventilation in patients with normal and obstructed airways. Patient effort triggers the ventilator to deliver a preset pressure, and inspiratory assistance continues until the flow rate falls to 25 percent of the peak inspiratory flow. In patients with airway obstruction who have a prolonged time constant, more time is required for flow to decrease to this threshold value, so that neural expiration commences before the termination of mechanical inflation. The resulting activation of the expiratory muscles hastens the fall in flow, but it also results in dyssynchrony between the patient’s neuromuscular activity and the mechanical phase of the ventilator–-socalled ‘‘fighting the ventilator.”

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In 12 patients with COPD receiving pressure support of 20 cm H2 O, investigators found that five recruited their expiratory muscles while the machine was still inflating the thorax. Interestingly, the patients who recruited their expiratory muscles during mechanical inflation had an average time constant of 0.54 seconds, as compared with an average of 0.38 seconds in the patients who did not exhibit expiratory muscle activity. The persistence of mechanical inflation into neural expiration is very uncomfortable, as well recognized with use of inverse-ratio ventilation.

New Modes New modes of mechanical ventilation are frequently introduced. Each has an acronym, and the jargon is inhibiting to those unfamiliar with it. Yet each new mode involves nothing more than a modification of the manner in which positive pressure is delivered to the airway and of the interplay between mechanical assistance and the patient’s respiratory effort. The purpose of a new mode may be to enhance respiratory muscle rest, prevent deconditioning, improve gas exchange, prevent lung damage, enhance coordination between ventilator assistance and patient respiratory effort, and foster lung healing; the priority given to each goal varies.

VENTILATOR SETTINGS Ventilator settings are based on the patient’s size and clinical condition. Determination of the settings is a dynamic

Principles of Mechanical Ventilation

process, based on a patient’s physiological response, rather than on a fixed set of numbers. The settings require repeated readjustment over the period of ventilator dependency. Such an iterative process requires careful respiratory monitoring.

Triggering Many ventilators employ pressure triggering, whereby a decrease in circuit pressure is required to initiate ventilator assistance. Patients reach the set sensitivity by activating their inspiratory muscles. When the threshold is reached, however, inspiratory neurons do not simply switch off. Consequently, the patient may expend considerable inspiratory effort throughout a machine-cycled inflation. The level of patient effort during this post-trigger phase is closely related to a patient’s respiratory drive at the point of triggering. As such, measures that decrease respiratory drive may enhance respiratory muscle rest during mechanical ventilation. If respiratory drive at the point of triggering is important, one might expect that effort during the time of triggering would determine patient effort during the remainder of inspiration. To elucidate this issue, investigators applied graded levels of pressure support in eleven critically ill patients. They achieved a fourfold reduction in overall patient effort. Yet patient effort during the time of triggering did not change. The constancy of effort during the trigger phase was probably secondary to different factors becoming operational as the level of ventilator assistance was varied (Fig. 1534). Thus, increases in the level of ventilator assistance do

Figure 153-4 Graded increases in pressure support produced a decrease in total pressure-time product (PTP) per breath (closed symbols), although PTP during the trigger phase (open symbols) did not change (left panel). The constancy of PTP during triggering probably resulted from different factors becoming operational at different levels of assistance (right panel). At low levels of pressure support, respiratory drive (dP/dt) and PEEPi were high, but triggering time was short, resulting in a large change in pleural pressure over a brief interval. At high levels of pressure support, dP/dt and PEEPi were low, but triggering time was long, resulting in a smaller change in pleural pressure over a longer time. (Based on data from Leung P, Jubran A, Tobin MJ: Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med 155:1940–1948, 1997; Tobin MJ, Jubran A, Laghi F: Patient-ventilator interaction. Am J Respir Crit Care Med 163:1059–1063, 2001, with permission.)

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to counterbalance the elastic recoil; it then must reach the set sensitivity. The time at which a patient initiates an expiratory effort (in relation to the cycling of the ventilator) partly determines the success of the ensuing inspiratory effort in triggering the machine. The relationship between the onset of expiratory muscle activity and termination of mechanical inflation by the ventilator has been quantified. At a pressure support of 20 cm H2 O, mechanical inflation continues for a longer time into neural expiration in the breaths preceding nontriggering attempts. Continuation of mechanical inflation into neural expiration counters expiratory flow, and also decreases the time available for unopposed exhalation. Consequently, elastic recoil increases. In turn, a greater inspiratory effort will be needed to achieve effective triggering. In this way, the time at which a patient commences an expiratory effort (in relation to cycling-off of mechanical inflation) partly determines the success of the ensuing inspiratory effort in triggering the ventilator.

Tidal Volume Figure 153-5 Recordings of tidal volume, inspiratory (I) and expiratory (E) flow, airway pressure (Paw ), and esophageal pressure (Pes ) in a patient with COPD receiving pressure-support ventilation. Approximately half of the patient’s inspiratory efforts do not succeed in triggering the ventilator. Triggering occurs only when the patient generates Pes more negative than −8 cm H2 O (indicated by the interrupted horizontal line), a pressure equal in magnitude to the opposing elastic recoil pressure. Expiratory flow exhibits a biphasic pattern, with momentary braking signaling ineffective inspiratory effort. Thus, monitoring of expiratory flow provides a more accurate measurement of the patient’s intrinsic respiratory rate than does the number of machine cycles displayed on the bedside monitor. (From Tobin MJ, Jubran A: Pathophysiology of failure to wean from mechanical ventilation. Schweiz Med Wochenschr 124:2138–2145, 1994, with permission.)

not substantially decrease patient effort during the time of triggering. The display of airway pressure and flow tracings on ventilator screens has increased awareness that inspiratory effort is frequently insufficient to trigger the ventilator. At high levels of mechanical assistance, up to one-third of a patient’s inspiratory efforts may fail to trigger the machine (Fig. 153-5).The number of ineffective triggering attempts increases in direct proportion to the level of ventilator assistance. Surprisingly, unsuccessful triggering is not the result of poor inspiratory effort. In a study of factors contributing to ineffective triggering, effort was noted to be more than one-third greater when the threshold for triggering the ventilator was not reached than when it was. Breaths that do not reach the threshold for triggering the ventilator have higher tidal volumes and shorter expiratory times than do breaths that do trigger the ventilator. Consequently, elasticrecoil pressure builds up within the thorax in the form of PEEPi . To trigger the ventilator, the patient’s inspiratory effort has to first generate a negative intrathoracic pressure in order

In the past, use of a tidal volume setting of 10 to 15 ml/kg had been the standard recommendation. This setting is still used by many anesthesiologists for patients without lung disease who are undergoing surgery. Since the early 1990s, however, lower tidal volumes have been used when ventilating patients in medical intensive care units (ICUs). The change in practice was precipitated by research in experimental animals that provided convincing evidence of severe lung injury induced by alveolar overdistension. A 1990 retrospective study of patients with the acute respiratory distress syndrome (ARDS) revealed a 60 percent decrease in the expected mortality rate with use of lower tidal volumes. Subsequent randomized trials, including that conducted by the ARDS Network investigators, revealed a significantly lower mortality with a tidal volume of 6 ml/kg compared with a tidal volume of 12 ml/kg. Three other controlled trials, however, did not reveal a lower mortality using the lower tidal volume. To understand the discrepant findings among the five randomized trials, a meta-analysis was undertaken. The analysis focused on plateau pressure, which is the airway pressure during an end-inspiratory pause. The low tidal volume arms of the three negative studies had plateau pressures that were at least as low as in the two positive studies. Thus, authors of the meta-analysis concluded that use of low tidal volumes did not lower mortality. The control arms of the three negative studies had plateau pressures that were comparable to those of usual practice (as reflected by plateau pressures before randomization). The control arms of the two positive studies, however, had plateau pressures higher than those used in usual practice (plateaus above 35 cm H2 O versus plateaus of 29 to 31 cm H2 O). Thus, the conclusion from the meta-analysis was that the control arms of the two positive studies were associated with increased mortality. A subsequent analysis of the data from the ARDS Network study revealed that respiratory compliance had a major

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influence on the response to the setting of tidal volume. If compliance was low before randomization, lowering of tidal volume decreased mortality from 42 to 29 percent. If compliance was high, however, lowering of tidal volume increased mortality from 21 to 37 percent. Thus, a low tidal volume is not appropriate for every patient with ARDS. Instead, it is essential to characterize each patient’s pathophysiology and to customize the ventilator settings accordingly.

Respiratory Rate Correct setting of the ventilator rate depends on the mode of ventilation employed. With assist-control ventilation, the ventilator supplies a breath in response to each patient effort. With this mode, physicians commonly pay little attention to the machine rate, which may be set much lower than the patient’s spontaneous rate. This gap results in two problems: (a) If the patient has a sudden decrease in respiratory center output, a low machine rate results in serious hypoventilation. (b) A large discrepancy between the patient’s spontaneous rate and the machine’s back-up rate results in a respiratory cycle with an inverse inspiratory-to-expiratory time (I:E) ratio. Development of an inverse I:E ratio arises because inspiratory time (Ti) on the machine remains fixed at the initial setting and does not change in response to increases in the patient’s spontaneous rate (Fig. 153-6). For example, if the machine rate is initially set at 12 breaths per minute (Ttot of 5 seconds) and Ti set at 1.65 seconds (either set directly or indirectly as a consequence of the volume and flow settings), then Te will be 3.35 seconds. The I:E ratio will be 1:2. If the patient’s spontaneous respiratory rate is increased to 25 breaths per minute, TTOT will be 2.4 seconds. Because Ti remains fixed at 1.65 seconds, Te will be 0.75 s, and the I:E ratio will be 2:1. Such inverse-ratio ventilation is very uncomfortable and may lead to increased sedative use, or even to use of neuromuscular blockade, simply because of inappropriate

Figure 153-6 Effect of interaction between a patient’s respiratory rate and the ventilator back-up rate on inspiratory time– expiratory time ratio (I:E) during assist-control ventilation. Ventilator back-up rate is 12 breaths per minute and inspiratory time (TI) 1.65 seconds. Left panel. If the patient’s intrinsic respiratory (fpt ) rate is also 12 breaths per minute, the total respiratory cycle time (TTOT ) is 5.0 seconds, the expiratory time (TE) is 3.35 seconds, and the I:E ratio is 1:2. Right panel. If the patient’s respiratory rate increases to 25 breaths per minute, the new TTOT is 2.4 seconds, TE is 0.75 seconds, and I:E is 1:0.45 (or, as more conventionally noted, 2.2:1).

Principles of Mechanical Ventilation

setting of the back-up rate. Based on these considerations, the back-up rate during assist-control ventilation should be set at approximately four breaths less than the patient’s spontaneous rate. With IMV, the ventilator (or mandatory) rate is initially set high and then gradually reduced according to patient tolerance. Unfortunately, titration is often based on data from arterial blood gases, and even a small number of ventilator breaths can result in acceptable values for Pao2 and Paco2 but achieve little or no respiratory muscle rest in patients with increased work of breathing. In ventilator-dependent patients, work of breathing at IMV rates of 14 breaths per minute or less may be sufficient to induce respiratory muscle fatigue. With PS ventilation, the ventilator rate is not set.

Inspiratory Flow Rate Clinicians initially set the inspiratory flow rate at a default value, such as 60 L/min. Many critically ill patients, however, have an elevated respiratory drive, and the initial flow setting may be insufficient to meet flow demands. As a result, patients will struggle against their own respiratory impedance and that of the ventilator. Consequently, work of breathing increases. Clinicians sometimes increase flow in order to shorten the inspiratory time and increase the expiratory time. However, an increase in flow causes immediate and persistent tachypnea; as a result, expiratory time may be shortened. In a study of healthy subjects, increases in inspiratory flow from 30 L/min to 60 and 90 L/min caused increases in respiratory rate of 20 and 41 percent, respectively. One of the main reasons that clinicians increase inspiratory flow is to decrease inspiratory time, in hope of allowing more time for expiration and, thereby, decreasing PEEPi , especially in patients with COPD. Because increased flow usually leads to an increase in respiratory rate, the expected shortening of expiratory time might actually increase PEEPi . An investigation of this phenomenon was conducted in 10 patients with COPD (Fig. 153-7). As with healthy subjects, an increase in flow from 30 to 90 L/min caused respiratory rate to increase from 16 to 21 breaths per minute. Despite the increase in rate, PEEPi fell from 7.0 to 6.4 cm H2 O. The decrease in PEEPi arose because of an increase in expiratory time (from 2.1 to 2.3 seconds), which allowed more time for lung deflation. Why did expiratory time increase? An increase in inspiratory flow is usually achieved by shortening of mechanical inspiratory time. The shortened inspiratory time combined with time-constant inhomogeneity of COPD causes overinflation of some lung units to persist into neural expiration. Continued inflation during neural expiration causes stimulation of the vagus nerve, which prolongs expiratory time. When adjusting the flow rate and trigger sensitivity, examination of the contour of the airway pressure waveform is helpful (Fig. 153-8). Ideally, the waveform should show a smooth rise and convex appearance during inspiration. In

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Figure 153-7 Continuous recordings of flow, esophageal pressure (Pes), and the sum of rib cage and abdominal motion, in a patient with chronic obstructive pulmonary disease receiving assist-control ventilation at a constant tidal volume. As flow increased from 30 to 60 and 90 L/min (from right to left), frequency increased (from 18 to 23 and 26 breaths/min, respectively), PEEPi decreased (from 15.6 to 14.4 and 13.3 cm H2 O, respectively), and end-expiratory lung volume also fell. Increases in flow from 30 L/min to 60 and 90 L/min also led to decreases in the swings in Pes from 21.5 to 19.5 and 16.8 cm H2 O, respectively. (Reproduced from Laghi F, Segal J, Choe WK, et al: Effect of imposed inflation time on respiratory frequency and hyperinflation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:1365–1370, 2001.)

contrast, a prolonged negative phase, with excessive scalloping of the tracing, indicates unsatisfactory settings of sensitivity or flow.

Fractional Inspired Oxygen Concentration Correction of hypoxemia and its prevention are major goals in mechanically ventilated patients. Many predictive equations have been published to aid in selecting an appropriate

Figure 153-8 Airway-pressure waveforms recorded during assist-control ventilation. The tracings represent changes in airway pressure during inspiration in a completely relaxed patient, and in patients making slight (center tracing) and strenuous efforts (tracing on right) to breathe. The distance between the dashed line (representing controlled ventilation) and the solid line (representing spontaneous breathing) is proportional to the patient’s work of breathing. (From Tobin MJ: Mechanical ventilation. N Engl J Med 330:1056–1061, 1994, with permission.)

Fio2 , but none is sufficiently accurate to substitute for a trialand-error approach. Initially, Fio2 is set at a high value (often 1.0) to ensure adequate oxygenation. Thereafter, the lowest Fio2 that achieves satisfactory arterial oxygenation should be selected. The usual target is a Pao2 of 60 mmHg or an arterial saturation (Sao2 ) of 90 percent; higher values do not substantially enhance tissue oxygenation. Although it is customary to wait 30 min to assess the response to a change in Fio2 , the effect is usually well defined within 10 min. When using arterial blood samples to assess oxygenation, a target of 90 percent for Sao2 is appropriate. If pulse oximetry is employed, a Spo2 target may result in values for Pao2 as low as 41 mmHg. In white patients, a target of 92 percent for Spo2 indicates satisfactory oxygenation. In black patients, however, this target may still result in significant hypoxemia. In experimental animals, hyperoxia produces diffuse alveolar damage, with histologic changes that are indistinguishable from ARDS resulting from any other cause. No diagnostic tests distinguish O2 -induced injury from progression of the underlying disease. Thus, the possibility of O2 toxicity should be considered in any patient receiving an Fio2 of more than 0.50 to 0.60 for 24 to 48 hours or longer. Healthy human subjects who inhale 100 percent O2 develop acute tracheobronchitis, manifested as substernal discomfort, cough, sore throat, nasal congestion, eye and ear discomfort, paresthesias, and fatigue. Symptoms begin within 4 hours; bronchoscopic features of tracheal inflammation are evident after

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6 hours. Retrosternal discomfort also occurs with an Fio2 of 0.75 but not with an Fio2 of 0.50. Hyperoxia causes absorption atelectasis in lung units with low V˙ a /Q˙ ratios, because the rate of absorption of O2 from the alveoli into the bloodstream is faster than the rate of replenishment from inspired gas. Such atelectasis results in a small shunt (approximately 3 percent) in healthy elderly subjects and requires only about 6 minutes to develop. A decrease in vital capacity is probably the best indicator of O2 toxicity. In several studies of healthy volunteers breathing 50 percent O2 over 7 to 28 days, little, if any, change in vital capacity was observed. When healthy subjects breathed 100 percent O2 , a decrease in static lung compliance was observed within 3 hours. This decrease resolved readily with deep breathing, suggesting that the decreased compliance was caused by absorption atelectasis, rather than direct toxicity. Exposure of healthy subjects to 100 percent O2 for as long as 4 days resulted in only modest reductions in vital capacity, and gas exchange function returned to normal with air breathing. Overall, studies in human subjects reveal much less parenchymal injury than has been observed in animals. It has been suggested the risk of O2 toxicity might be greater in patients who have coexisting lung injury, but ironically, indirect data suggest that patients with ARDS have a reduced risk of O2 toxicity. Exuded plasma proteins and intra-alveolar hemorrhage provide a medium that is rich in antioxidant enzyme capacity and helps to protect against O2 toxicity. Death in experimental animals exposed to prolonged hyperoxia is usually attributed to acute lung injury. Several investigators, however, have reported a terminal course characterized by severe cardiac embarrassment associated with focal areas of myocardial necrosis on microscopy. In the face of potential O2 toxicity, the only possible strategy is to reduce the Fio2 to the lowest level compatible with adequate systemic oxygenation. Thus, excess O2 demand should be minimized, and measures to enhance systemic oxygenation optimized. Although excessive O2 administration should be avoided, there is more to fear from severe hypoxemia than from the potential damage that might result from hyperoxia.

Positive End-Expiratory Pressure The beneficial effects of positive end-expiratory pressure (PEEP) include improvement in arterial oxygenation, improvement in lung compliance, alleviation of excessive respiratory work secondary to PEEPi in patients with airflow limitation, and, possibly, a decrease in lung injury resulting from repeated alveolar collapse and reopening. The principal beneficial effect of PEEP is an increase in Pao2 , which permits a decrease in Fio2 and a reduction in the risk of O2 toxicity. The major mechanism for the increase in Pao2 with PEEP is an increase in end-expiratory lung volume (Table 153-2). Patients with ARDS develop alveolar instability and collapse (see Chapters 144 and 145). Consequently, functional residual capacity falls below closing volume, and small air-

Principles of Mechanical Ventilation

Table 153-2 Mechanisms of Increased Pao2 with PEEP Increase in end-expiratory lung volume Distention of patent lung units Recruitment of collapsed lung units Redistribution of fluid within the lung Decrease in shunt Increase in end-expiratory lung volume Decrease in cardiac output

ways close during tidal breathing, leading to intrapulmonary shunt and hypoxemia. PEEP increases end-inspiratory lung volume by distending lung units that are already open, preventing collapse of unstable alveoli at end-expiration, recruiting collapsed lung units, and redistributing liquid within the lung. The decrease in venous admixture with PEEP is proportional to alveolar recruitment. It had been thought that the decrease in venous admixture with PEEP resulted largely from a decrease in cardiac output. This view has been shown to be erroneous. At one time PEEP was thought to decrease extravascular lung water by “pushing” alveolar fluid back into the circulation. On the contrary, PEEP can actually increase lung water. As alveoli expand with application of PEEP, interstitial pressure in the extra-alveolar space decreases, leading to an increase in transmural pressure across the vessel wall. If intravascular pressures remain the same or increase, the filtration of fluid across the vessel wall increases, causing an increase in pulmonary edema; if PEEP causes a decrease in cardiac output and vascular pressures, lung water does not change. The beneficial action of PEEP in pulmonary edema is produced by redistribution of edema fluid from the alveolar space into the perivascular cuffs. This redistribution of lung water, in association with an increase in end-expiratory lung volume, is the major mechanism underlying the increase in Pao2 with PEEP. In patients with acute respiratory distress syndrome, PEEP is often used for the purpose of recruiting previously nonfunctioning lung tissue (see Chapter 145). Selecting the right level of PEEP for a given patient is difficult, however, because the severity of injury varies throughout the lungs. PEEP can recruit atelectatic areas, but it may also overdistend normally aerated areas. In one study involving six patients with acute lung injury, the use of PEEP at 13 cm H2 O resulted in recruitment of nonaerated portions of lung, with a gain of 320 ml in lung volume; however, three patients had overdistention of already aerated portions of lung, with an excess volume of 238 ml. Overall, about 30 percent of patients with acute lung injury either do not benefit from PEEP or experience a fall in Pao2 . With the patient in the supine posture, PEEP generally

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Figure 153-9 Respiratory pressure-volume curve and the effects of traditional versus protective ventilation in a 70-kg patient with acute respiratory distress syndrome. The lower and upper inflection points of the inspiratory pressure-volume curve (center panel) are at 14 and 26 cm H2 O, respectively. With conventional ventilation at a tidal volume of 12 ml/kg and zero end-expiratory pressure (left panel), alveoli collapse at the end of expiration. The generation of shear forces during the subsequent mechanical inflation may tear the alveolar lining, and attaining an endinspiratory volume higher than the upper inflection point causes alveolar over-distention. With protective ventilation at a tidal volume of 6 ml/kg (right panel), the end-inspiratory volume remains below the upper inflection point; the addition of PEEP at 2 cm H2 O above the lower inflection point may prevent alveolar collapse at the end of expiration and provide protection against the development of shear forces during mechanical inflation. (Reproduced Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986â&#x20AC;&#x201C;1996, 2001, with permission.)

recruits the regions of the lung closest to the apex and sternum. Conversely, PEEP can increase the amount of nonaerated tissue in the regions close to the spine and diaphragm. Among patients in the early stages of ARDS, those with pulmonary causes, such as pneumonia, are less likely to benefit from PEEP than are patients with nonpulmonary causes, such as intra-abdominal sepsis or extrathoracic trauma. This distinction may be related to the type of morphologic involvement: Pulmonary causes of ARDS are characterized by alveolar filling, whereas nonpulmonary causes are characterized by interstitial edema and alveolar collapse. In the later stages of ARDS, remodeling and fibrosis may eliminate this distinction between pulmonary and nonpulmonary causes. Even if a pressure-volume curve is not performed at the bedside, it is useful to select the PEEP level according to this conceptual framework (Fig. 153-9). A level above the lower bend in the pressure-volume curve is thought to keep alveoli open at the end of expiration, thereby preventing injury that can result from shear forces created by the opening

and closing of alveoli. This level of PEEP may also prevent an increase in the amount of nonaerated tissue and, thus, atelectasis. However, the notion that the lower bend of the pressure-volume curve signals the level of PEEP necessary to prevent end-expiratory collapse, and that pressure above the upper bend signal alveolar overdistention, is a gross oversimplification. The relation between the shape of the pressurevolume curve and events at the alveolar level is confounded by numerous factors and is the subject of ongoing research and debate. An understanding of this relation is also impeded by the difficulty in distinguishing collapsed lung units from fluid-filled units on computed tomography scans.

BRONCHODILATOR THERAPY Several obstacles are encountered when inhaled drugs are administered to ventilated patients. As a result, drug deposition to the lower respiratory tract is less than that in

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ambulatory patients. Determinants of aerosol deposition include the configuration of the endotracheal tube and ventilator circuit, ventilator mode and settings, and patient-related factors. Nebulizers have been used traditionally for the delivery of bronchodilators, but they have a number of disadvantages. Nebulizer contamination causes aerosolization of bacteria, and lack of attention to this matter by health care providers has led to epidemics of nosocomial pneumonia. Tidal volume and inspiratory flow must be adjusted to compensate for nebulizer flow. This factor is inconsequential in most adults, but instances of hypoventilation have occurred in patients who are unable to trigger the ventilator. Another shortcoming of nebulizers is the considerable variation in efficiency of different commercial brands, as well as among various batches of the same brand. In contrast, metered-dose inhalers (MDIs) are easy to administer, involve less personnel time, and provide reliable dosing. Moreover, when MDIs are used with a collapsible cylindrical spacer, it is not necessary to disconnect the ventilator circuit for each treatment. Thus, risk of ventilatorassociated pneumonia is decreased. Using MDIs instead of nebulizers results in substantial cost savings. The combination of an MDI and a chamber device achieves a four- to sixfold greater delivery of aerosol than MDI actuation into a connector attached directly to the endotracheal tube or into an in-line device that lacks a chamber. Aerosol delivery is increased with use of a higher tidal volume and longer fractional inspiratory time (TI /TTOT ). Aerosol delivery is decreased by a high inspiratory flow rate; heating and humidification of inhaled gas reduce aerosol deposition by about 40 percent. When an aerosol is carried by a low-density gas, such as an 80:20 helium-oxygen mixture, aerosol delivery from a MDI is increased by more than 50 percent. A dose-response study of four, eight, and 16 puffs of albuterol (administered with an MDI and cylindrical spacer) conducted in ventilated patients with COPD (Fig. 153-10) demonstrated a decrease in airway resistance after four puffs of albuterol; no additional effects were noted after cumulative doses of 12 and 28 puffs. In another study in ventilated patients with COPD, the bronchodilator effect of a single dose of four puffs of albuterol was sustained for at least 60 minutes. The bronchodilator effect obtained with four puffs of albuterol from an MDI was comparable to that obtained with six to 12 times the same dose given by a nebulizer. Based on research conducted over the past decade, it is possible to formulate specific steps to achieve maximum bronchodilator effect with use of MDIs in ventilated patients (Table 153-3). Therapy can be given in combination with either controlled or assisted ventilation, provided aerosol administration is synchronized with inspiratory flow. Based on the recommended technique for use of an MDI in ambulatory patients, some authors recommend use of a postinspiratory breath hold; with optimal technique, however, this maneuver does not influence bronchodilator response in ventilated patients. Although humidification of the circuit re-

Principles of Mechanical Ventilation

Figure 153-10 Effect of albuterol on minimal inspiratory resistance (Rrsmin ) in 12 stable mechanically ventilated patients with chronic obstructive pulmonary disease. Significant decreases in resistance occurred within 5 minutes of administration of four puffs of albuterol. The addition of eight and 16 puffs (cumulative doses of 12 and 28 puffs, respectively) did not achieve a significantly greater effect than that with four puffs ( p > 0.05). Bars represent SE. ∗∗p < 0.001. (Modified from Dhand R, Duarte AG, Jubran A, et al: Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients. Am J Respir Crit Care Med 154:388–393, 1996, with permission)

duces aerosol deposition, it is advisable not to bypass the humidifier. Even with a humidified circuit, significant bronchodilation can be achieved with as few as four puffs of a bronchodilator aerosol when the MDI technique is carefully executed.

MONITORING AND COMPLICATIONS Several devices can be used to monitor pulmonary gas exchange, respiratory neuromuscular function, respiratory mechanics, and patient-ventilator interaction. Use of the derived information permits the physician to better tailor ventilator settings to an individual patient’s requirements, with the promise of enhancing patient comfort. Monitoring of key variables helps to minimize the risk of iatrogenic complications and alerts the physician to the likelihood of an impending catastrophe, allowing sufficient time for the institution of lifesaving measures. A detailed discussion of techniques used for monitoring of ventilator-supported patients can be found in Chapter 152 and in other textbooks. Patients receiving mechanical ventilation are at risk for numerous complications, including O2 toxicity, volutrauma and air leaks, decreased cardiac output, and endotracheal tube–related issues. These problems are discussed elsewhere in this volume.

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Table 153-3 Technique for Using Metered-Dose Inhalers in Mechanically Ventilated Patients 1. Assure VT > 500 ml (in adults) during assisted ventilation. 2. Aim for an inspiratory time (excluding the inspiratory pause) >0.30 of total breath duration. 3. Ensure that the ventilator breath is synchronized with the patient’s inspiration. 4. Shake the metered-dose inhalers vigorously. 5. Place canister in actuator of a cylindrical spacer situated in inspiratory limb of ventilator circuit.∗ 6. Actuate metered-dose inhalers to synchronize with precise onset of inspiration by the ventilator.† 7. Allow a breath hold at end-inspiration for 3–5 s. 8. Allow passive exhalation. 9. Repeat actuations after 20–30 s until total dose is delivered.‡ ∗ With metered-dose inhalers, it is preferable to use a spacer that remains in

the ventilator circuit to avoid disconnecting the ventilator circuit for each bronchodilator treatment. Although bypassing the humidifier can increase aerosol delivery, it prolongs each treatment and requires disconnecting the ventilator circuit. † In ambulatory patients with metered-dose inhalers placed inside the mouth, actuation is recommended briefly after initiation of inspiratory airflow. In mechanically ventilated patients using a metered-dose inhaler and spacer combination, actuation should be synchronized with onset of inspiration. ‡ The manufacturer recommends repeating the dose after 1 min. Metered-dose inhalers’ actuation within 20–30 s after the previous dose does not compromise drug delivery. source: Modified from Dhand R, Tobin MJ: Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 156:3–10, 1997.

WEANING The term weaning literally means a slow, gradual decrease in the amount of ventilator support. However, the term is used more commonly to refer to all methods of discontinuing mechanical ventilation.

Causes of Weaning Failure After discontinuation of mechanical ventilation, up to 25 percent of patients experience respiratory distress severe enough to necessitate the reinstitution of ventilator support. Our understanding of the basis for weaning failure in patients has advanced considerably in recent years. Among patients who cannot be weaned, disconnection from the ventilator is followed almost immediately by an increase in respiratory frequency and fall in tidal volume; that is, rapid, shallow breathing (Fig. 153-11). As a trial of spontaneous breathing is continued over the next 30 to 60 minutes, respiratory ef-

Figure 153-11 A time-series, breath-by-breath plot of respiratory frequency and tidal volume in a patient who failed a weaning trial. The arrow indicates the point of resuming spontaneous breathing. Rapid, shallow breathing developed almost immediately after discontinuation of the ventilator. (From Tobin MJ, Perez W, Guenther SM, et al: The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134:1111–1118, 1986, with permission.)

fort increases considerably, reaching more than four times the normal value at the end of this period (Fig. 153-12). The increased effort is caused mainly by worsening respiratory mechanics. Respiratory resistance increases progressively, reaching about seven times the normal value at the end of a failed weaning trial; lung stiffness also increases, reaching five times the normal value; and gas trapping, measured as PEEPi , more than doubles over the course of the trial. Before weaning is started, however, respiratory mechanics in such patients are similar to patients in whom subsequent weaning is successful. Thus, unknown mechanisms associated with the act of spontaneous breathing cause the worsening of respiratory mechanics in patients who are weaning failures. In addition to the increase in respiratory effort, an unsuccessful attempt at spontaneous breathing causes considerable cardiovascular stress. Patients can experience substantial increases in right- and left-ventricular afterload during a trial of spontaneous breathing, with increases of 39 and 27 percent in pulmonary and systemic arterial pressures, respectively. The changes are most likely attributable to the extreme negative swings in intrathoracic pressure. At the completion of a weaning trial, the level of O2 consumption is equivalent in patients who can be weaned and in those who cannot. How the cardiovascular system meets the O2 demand differs in the two groups of patients.

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Figure 153-12 Tidal volume, pleural pressure, and pulmonary-artery pressure during assist-control ventilation and at the start and end of a failed weaning trial. During mechanical ventilation, the patient’s inspiratory effort is in the normal range, and the pulmonary-artery pressure is 45/22 mmHg. At the start of the weaning trial, tidal volume falls to 200 ml, respiratory frequency increases to 33 breaths per minute, and a swing of 11 cm H2 O in pleural pressure is noted; the pulmonary-artery pressure at the end of expiration is 60/28 mmHg. At the end of the trial, 45 minutes later, the tidal volume and respiratory frequency are unchanged, a swing in pleural pressure of 19 cm H2 O is evident, and PEEPi is 4 cm H2 O; pulmonary artery pressure is 60/31 mmHg. The values in a healthy subject are tidal volume, 380 ml; respiratory frequency, 17 breaths per minute; pleural-pressure swing, 3 cm H2 O; and pulmonary artery pressure, 18/8 mmHg. (Data are from Tobin MJ, Perez W, Guenther SM, et al: The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134:1111–1118, 1986; Jubran A, Mathru M, Dries D, et al: Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 158:1763–1769, 1998; Jubran A, Tobin MJ: Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 155:906–915, 1997. Reproduced from Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001, with permission.)

In patients who are successfully weaned, O2 demand is met through an increase in O2 delivery, mediated by the expected increase in cardiac output on discontinuation of positive-pressure ventilation. In patients who cannot be weaned, O2 demand is met through an increase in O2 extraction; these patients have a relative decrease in O2 delivery. The greater O2 extraction causes a substantial decrease in mixed venous O2 saturation, contributing to the arterial hypoxemia that occurs in some patients. Over the course of a trial of spontaneous breathing, about half of patients in whom the trial fails have an increase in Paco2 of 10 mm Hg or more. The hypercapnia is not usually a consequence of a decrease in minute ventilation. Instead, hypercapnia results from rapid, shallow breathing, which causes an increase in dead-space ventilation. In a

small proportion of patients who cannot be weaned, primary depression of respiratory drive may be responsible for the hypercapnia.

Timing of the Weaning Process One of the major challenges in the management of ventilatorsupported patients is deciding on the right time to discontinue mechanical ventilation. If the physician is too conservative and postpones weaning onset, the patient is placed at an increased risk of life-threatening, ventilator-induced complications. Conversely, if weaning is begun prematurely, the patient may suffer cardiopulmonary or psychological decompensation of sufficient severity to set back a patient’s clinical course.

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In randomized trials of different weaning techniques, most patients who had received mechanical ventilation for a week or longer were able to tolerate ventilator discontinuation on the first day that weaning-predictor tests were measured. It is likely that many of these patients would have tolerated extubation a day or so earlier. As such, one of the main sources of weaning delay is the failure of the physician to think that the patient just might come off the ventilator. It is possible to speed up the weaning process by undertaking physiological assessment early in the patient’s clinical course. A cardinal precept of diagnostic testing is to begin with a screening test and follow with a confirmatory test. The characteristics of these test types differ. A single diagnostic test rarely fulfills both functions. The fundamental job of a weaning-predictor test is screening. Because the goal is to not miss anyone with the condition under consideration, a good screening test has a very low rate of false-negative results; to achieve this goal, a higher false-positive rate is acceptable. Thus, an ideal screening test has a very high sensitivity. The ratio of respiratory frequency to tidal volume (f/VT ) meets this requirement; numerous studies have documented that its sensitivity is 0.90 or higher. The f/VT ratio must be calculated during spontaneous breathing. Measurements of f/VT in the presence of pressure support or CPAP will result in inaccurate predictions of weaning outcome. The higher is the f/VT ratio, the more rapid and shallow the breathing and the greater the likelihood of unsuccessful weaning. A ratio of 100 discriminates between successful (less than 100) and unsuccessful (greater than 100) attempts at weaning. Because the results of screening tests are often negative, an ideal screening test should be simple, expeditious, and safe. Measurement of f/VT takes a minute or so to perform. In contrast, a trial of spontaneous breathing takes one-half to 2 hours to perform, during which time attendants commonly leave the patient’s room. Accordingly, a spontaneous breathing trial does not satisfy the criteria for a desirable screening test, and commencing weaning with such a trial is likely to prolong the weaning process. If clinicians obtain weaning-predictor tests at the earliest point that a patient might tolerate extubation, the results will be negative at least half the time. In studies of weaningpredictor tests, however, positive results have been obtained at least 75 percent of time. Such a high rate of positive test results indicates that clinicians were being too slow in initiating the weaning process. When a screening test is positive, the diagnostician proceeds to a confirmatory test. A positive confirmatory test result essentially rules in a condition: The likelihood of a patient tolerating a trial of extubation is very high. An ideal confirmatory test has a very low rate of false-positive results, i.e., a high specificity. The specificity of a weaning trial is not known and will never be known, since its determination would require an unethical experiment—extubating all patients who fail a weaning trial and noting how many require reintubation.

Weaning Trials Four methods can be used for conducting a weaning trial. The oldest is to perform trials of spontaneous breathing several times a day, using a T-tube circuit that contains an enriched supply of O2 . Initially 5 to 10 minutes in duration, T-tube trials are extended and repeated several times a day until the patient can sustain spontaneous ventilation for several hours. This approach has become unpopular because it requires considerable time on the part of ICU staff. For many years, IMV was the most popular methods of weaning. With IMV, the mandatory rate from the ventilator is reduced in steps of one to three breaths per minute, and an arterial blood gas is obtained about 30 minutes after each rate change. Unfortunately, titrating the number of breaths from the ventilator in accordance with the results of arterial blood gases can produce a false sense of security. As few as two to three positive-pressure breaths per minute can achieve acceptable blood gases, but these values provide no information regarding the patient’s work of breathing (which may be excessive). As noted previously, at IMV rates of 14 breaths per minute or less, patient inspiratory efforts are increased to a level likely to cause respiratory muscle fatigue. Moreover, this occurs not only with the intervening spontaneous breaths, but also with ventilator-assisted breaths. Consequently, use of IMV may actually contribute to the development of respiratory muscle fatigue or prevent its recovery. When pressure support is used for weaning, the level of pressure is reduced gradually (decrements of 3 to 6 cm H2 O) and titrated on the basis of the patient’s respiratory frequency. When the patient tolerates a minimal level of pressure support, he or she is extubated. What exactly constitutes a “minimal level of pressure support” has never been defined. For example, pressure support of 6 to 8 cm H2 O is widely used to compensate for the resistance imposed by the endotracheal tube and ventilator circuit. It is reasoned that a patient who can breathe comfortably at this level of pressure support will be able to tolerate extubation. However, if the upper airways are swollen because an endotracheal tube has been in place for several days, the work engendered by breathing through the swollen airways is about the same as that caused by breathing through an endotracheal tube. Accordingly, any amount of pressure support overcompensates and may give misleading information about the likelihood that a patient can tolerate extubation. The fourth method of weaning is to perform a single daily T-tube trial, lasting for 30 to 120 minutes. If this trial is successful, the patient is extubated. If the trial is unsuccessful, the patient is given at least 24 hours of respiratory muscle rest with full ventilator support before another trial is performed. Until the early 1990s, it was widely believed that all weaning methods were equally effective, and the physician’s judgment was regarded as the critical determinant. However, the results of randomized, controlled trials clearly indicate that the period of weaning is as much as three times as long with IMV as with trials of spontaneous breathing. In a study involving patients with respiratory difficulties on weaning,

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trials of spontaneous breathing halved the weaning time as compared with pressure support; in another study, the weaning time was similar with the two methods. Performing trials of spontaneous breathing once a day is as effective as performing such trials several times a day but is much simpler. In a recent study, half-hour trials of spontaneous breathing were as effective as 2-hour trials. This study, however, involved all patients being considered for weaning, not just those for whom there were difficulties with weaning. In conclusion, to minimize the likelihood of either delayed weaning or premature extubation, a two-step diagnostic strategy is recommended: measurement of weaning predictors followed by a weaning trial. The critical step is for the physician to contemplate the possibility that a patient just might be able to tolerate weaning. Such diagnostic triggering is facilitated through use of a screening test, which is the rationale for measurement of weaning-predictor tests. It is important not to postpone this first step by waiting for a more complex diagnostic test, such as a T-tube trial.

Extubation Decisions about weaning and extubation are commonly conflated. When a patient tolerates a weaning trial without distress, a clinician feels reasonably confident that the patient will be able to sustain spontaneous ventilation after extubation. Before removing the endotracheal tube, however, the clinician also has to judge whether or not the patient will be able to maintain a patent upper airway after extubation. Of patients who are expected to tolerate extubation without difficulty, about 10 to 20 percent fail and require reintubation. Mortality among patients who require reintubation is more than six times as high as mortality among patients who can tolerate extubation. The reason for the higher mortality is unknown. It might be related to the development of new problems after extubation or complications associated with reinsertion of a new tube. A more likely explanation is that the need for reintubation reflects greater severity of the underlying illness. Because of the high mortality associated with reintubation, clinicians are eager to avoid this problem. The major diagnostic test used to predict the success of an extubation attempt is a weaning trial. In contrast to the many studies that have evaluated the reliability of diagnostic tests that predict the outcome of a trial of weaning, the diagnostic accuracy of weaning trials in predicting the outcome of a trial of extubation is unknown. Moreover, the accuracy is impossible to determine, because the experiments necessary to measure the sensitivity and specificity of a weaning trial (for predicting extubation outcome) are unethical.

CONCLUSION Since the previous edition of this textbook, we have gained a better understanding of the pathophysiology associated with

Principles of Mechanical Ventilation

unsuccessful weaning and have learned how to wean patients more efficiently. We have also learned how ventilator settings influence survival in patients with ARDS. Less progress has been made in determining how the ventilator can best be used to achieve maximal respiratory muscle rest, which is the most common reason for providing mechanical ventilation.

SUGGESTED READING The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000. Amato MB, Barbas CS, Medeiros DM, et al: Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347–354, 1998. Brochard L, Rauss A, Benito S, et al: Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 150:896–903, 1994. Brochard L, Roudot-Thoraval F, Roupie E, et al: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 158:1831–1838, 1998. Brower RG, Shanholtz CB, Fessler HE, et al: Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 27:1492– 1498, 1999. Deans KJ, Minneci PC, Cui X, et al: Mechanical ventilation in ARDS: One size does not fit all. Crit Care Med 33:1141– 1143, 2005. Dhand R, Duarte AG, Jubran A, et al: Dose-response to bronchodilator delivered by metered-dose inhaler in ventilatorsupported patients. Am J Respir Crit Care Med 154:388– 393, 1996. Dhand R, Tobin MJ: Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 156:3–10, 1997. Eichacker PQ, Gerstenberger EP, Banks SM, et al: Metaanalysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 166:1510–1514, 2002. Esteban A, Alia I, Tobin MJ, et al: Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 159:512–518, 1999. Esteban A, Frutos F, Tobin MJ, et al: A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N Engl J Med 332:345–350, 1995.

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Gattinoni L, Pelosi P, Suter PM, et al: Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 158:3–11, 1998. Imsand C, Feihl F, Perret C, et al: Regulation of inspiratory neuromuscular output during synchronized intermittent mechanical ventilation. Anesthesiology 80:13–22, 1994. Jubran A, Mathru M, Dries D, et al: Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 158:1763–1769, 1998. Jubran A, Tobin MJ: Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 155:906– 915, 1997. Jubran A, Van de Graaff WB, Tobin MJ: Variability of patientventilator interaction with pressure support ventilation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:129–136, 1995. Laghi F, Segal J, Choe WK, et al: Effect of imposed inflation time on respiratory frequency and hyperinflation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:1365–1370, 2001. Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 168:10–48, 2003. Leung P, Jubran A, Tobin MJ: Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med 155:1940–1948, 1997. Marini JJ, Capps JS, Culver BH: The inspiratory work of breathing during assisted mechanical ventilation. Chest 87:612–618, 1985. Marini JJ, Smith TC, Lamb VJ: External work output and force generation during synchronized intermittent mechanical ventilation. Effect of machine assistance on breathing effort. Am Rev Respir Dis 138:1169–1179, 1988.

Parthasarathy S, Jubran A, Tobin MJ: Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation. Am J Respir Crit Care Med 158:1471–1478, 1998. Rouby JJ, Lu Q, Goldstein I: Selecting the right level of positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 165:1182– 1186, 2002. Stewart TE, Meade MO, Cook DJ, et al: Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 338:355–361, 1998. Straus C, Louis B, Isabey D, et al: Contribution of the endotracheal tube and the upper airway to breathing workload. Am J Respir Crit Care Med 157:23–30, 1998. Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001. Tobin MJ: Mechanical ventilation. N Engl J Med 330:1056– 1061, 1994. Tobin MJ (ed): Principles and Practice of Intensive Care Monitoring. New York, McGraw-Hill, 1998. Tobin MJ (ed): Principles and Practice of Mechanical Ventilation, 2nd ed. New York, McGraw-Hill, 2006. Tobin MJ, Jubran A: Pathophysiology of failure to wean from mechanical ventilation. Schweiz Med Wochenschr 124:2138–2145, 1994. Tobin MJ, Jubran A, Laghi F: Patient-ventilator interaction. Am J Respir Crit Care Med 163:1059–1063, 2001. Tobin MJ, Perez W, Guenther SM, et al: The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134:1111– 1118, 1986. Yang KL, Tobin MJ: A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 324:1445–1450, 1991.

154 Nutrition in Acute Respiratory Failure Lisa M. Bellini

I. OVERVIEW OF MALNUTRITION Incidence of Malnutrition in the Intensive Care Unit Incidence of Malnutrition in Advanced Lung Disease II. EFFECTS OF MALNUTRITION Pathophysiology and Complications of Malnutrition Protein Calorie Malnutrition and Critical Illness Effects of Nutritional Supplementation in Acute Respiratory Failure III. ASSESSMENT OF NUTRITIONAL STATUS Functional Assessment Metabolic Assessment IV. INDICATIONS FOR NUTRITIONAL SUPPORT

VII. BASIC NUTRITIONAL PRESCRIPTION Energy Requirements Glucose Requirements Protein Requirements Fat Requirements Micronutrients Immunonutrition VIII. MONITORING Nitrogen Balance Glucose Control Other Monitoring IX. SPECIAL CONSIDERATIONS IN PATIENTS WITH ADVANCED LUNG DISEASE


OVERVIEW OF MALNUTRITION Malnutrition is a disorder of body composition in which nutritional intake is less than required, resulting in reduced organ function, abnormalities in blood chemistry, reduced body mass, and worsened clinical outcomes. Malnutrition in the setting of acute respiratory failure (ARF) may be a preexisting condition due to underlying advanced lung disease, such as chronic obstructive pulmonary disease (COPD) (see Chapters 41 and 42); alternatively, it may develop during the course of acute illnesses that promote hypermetabolism, as occurs in acute respiratory distress syndrome (ARDS) (see Chapter 145). Regardless of the starting point, ARF results in alterations in substrate metabolism that are manifest as nutritional deficiencies and altered body composition. As the body tries to conserve protein, fat is metabolized as a prin-

cipal source of energy. When fat stores are depleted, visceral and muscle protein catabolism and gluconeogenesis become the main processes for generating energy. Nutritional assessment in these settings is critical. Evaluation usually consists of determination of clinical, anthropometric, chemical, and immunologic parameters that reflect altered body composition. The assessment must be considered in light of the patientâ&#x20AC;&#x2122;s underlying condition, as no single test is diagnostic of malnutrition.

Incidence of Malnutrition in the Intensive Care Unit Physicians may contribute to malnutrition in the hospital setting by failing to recognize it as a complication of illness or injury and addressing it inadequately. Recognition of malnutrition does not insure that adequate nutrition repletion will

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occur. When enteral feeding is undertaken in the intensive care unit (ICU), inadequate nutrition is frequently delivered because of underestimation of patients’ nutritional needs and inappropriate cessation of feedings. A prospective study of patients requiring enteral feedings in an ICU found that physician prescriptions provided a mean of only 66 percent of goal caloric requirements; furthermore, a mean of only 78 percent of the ordered volume was actually infused. Cessation of enteral feeds was judged avoidable in 66 percent of cases, including circumstances when feeding was discontinued at midnight for a procedure on the following day, or was stopped for simple bedside tasks, such as bathing the patient or placement of intravenous lines. An additional study of patients with COPD presenting with ARF (with slightly over one-half requiring mechanical ventilation) revealed malnutrition in 60 percent. Malnutrition was more frequent in those that required mechanical ventilation (74 percent versus 43 percent). In 1997, the American College of Chest Physicians (ACCP) published a consensus statement on nutrition in the ICU, aimed at guiding patient selection, timing and route of administration, nutrient use, and monitoring of nutrition support. In a study of over 1500 critically ill medical patients who had an ICU length of stay greater than 96 h, cumulative caloric intake reached only about 50 percent of ACCPrecommended guidelines. Notably, patients receiving 33 to 65 percent of recommended caloric targets were more likely to achieve spontaneous ventilation prior to discharge from the ICU, while those receiving more than 65 percent of targets were less likely to be weaned or to be discharged alive from the hospital. The findings suggest that current caloric targets may overestimate patient needs, since moderate caloric intake was associated with a better outcome.

Incidence of Malnutrition in Advanced Lung Disease The finding that patients with advanced lung disease suffer from changes in body composition manifest by progressive weight loss has long been recognized. Thirty to seventy percent of patients with COPD have clinical evidence of malnutrition. Malnutrition associated with advanced lung disease, so-called “pulmonary cachexia syndrome,” has been associated with increased mortality and decline in functional status. Although COPD has been best studied, current thinking is that all advanced lung diseases are characterized by progressive reduction in lean body mass, which is a function of many variables, including aging, exercise, metabolism, tissue hypoxia, inflammation, and use of certain medications. Importantly, basal metabolism in patients with advanced lung disease does not follow the expected normal age-related decline. Many patients are hypermetabolic, presumably secondary to an increased work of breathing. In fact, patients with COPD have a 10-fold increase in daily energy expenditure over the normal baseline of 36 to 72 calories per day.

EFFECTS OF MALNUTRITION The effects of malnutrition may be considered with respect to the underlying pathophysiology, consequences of malnutrition during critical illness, and effects of nutritional supplementation.

Pathophysiology and Complications of Malnutrition A reduction in food intake results in loss of fat, muscle, skin, and, ultimately, bone and viscera. Body mass declines and extracellular fluid volume increases. Nutritional requirements fall as an individual’s body mass decreases, probably reflecting more efficient utilization of ingested food and a reduction in work capacity at the cellular level. However, the combination of decreased tissue mass and reduction in work capacity impedes homeostatic responses to stressors, such as acute respiratory failure. Malnutrition causes a number of deleterious consequences, including increased susceptibility to infection, poor wound healing, increased frequency of decubitus ulcers, overgrowth of bacteria in the gastrointestinal tract, and abnormal nutrient losses in stool. These alterations result in increased morbidity and mortality in malnourished, hospitalized patients. One study of over 2000 hospitalized veterans found a 30-day mortality rate of 62 percent among those whose serum albumin concentrations fell below 2.0 g/dl. A study of over 4300 patients in ICUs revealed that those with a low body mass index (BMI) on admission (due to preexisting malnutrition) were at increased risk of death during hospitalization and at 6 mo following BMI measurement. A BMI on admission below the 15th percentile was associated with a 23 percent increase in 6-mo mortality. Adequate nutrition is essential for reversing the physiological derangements described and for recovery from ARF. Supplemental nutrition has been demonstrated to improve morbidity and mortality in certain groups of patients, likely related to contraction of previously expanded extracellular fluid volume and repletion of protein reserves.

Protein Calorie Malnutrition and Critical Illness Metabolic derangements are amplified during periods of critical illness, including ARF; protein calorie malnutrition is particularly detrimental in this situation. The stress of critical illness inhibits the body’s natural conservation responses to malnutrition; aggressive nutritional support instituted early during a critical illness may be protective. Hypermetabolism associated with critical illness causes a redistribution of macronutrients (fat, protein, and glycogen) from the labile reserves of adipose tissue and skeletal muscle to more metabolically active tissues, such as bone, liver, and other viscera. Within a few days, this response may lead to the onset of protein calorie malnutrition, defined as

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a negative balance of 100 g of nitrogen and 10,000 kcal. The rate of development of malnutrition in critically ill patients is a function of preexisting nutritional status and degree of hypermetabolism. In the 1940s, Cuthbertson described two phases of the metabolic response to shock: (a) an initial “ebb” phase, and (b) a later, hypercatabolic “flow” phase. The initial “ebb” phase lasts 12 to 24 h and is characterized by fever, increased oxygen consumption, decreased body temperature, and vasoconstriction. These adaptive changes reflect activation of the sympathetic nervous system and pituitary-adrenal axis, reflected in rapid rises in plasma concentrations of epinephrine, norepinephrine, adrenocorticotropic hormone, growth hormone, cortisol, and other corticosteroids. The “flow” p