14 Critical Care by Urvi Trivedi

SECTION 14

Critical Care 117.

ABG Analysis in Clinical Setting Rajesh Mahajan, Suman Sethi

553

118.

Electrolytes in ICU TH Trivedi

558

119.

Glycemic Control in I.C.U. Ramesh Kumar Goenka

562

120.

Approach to Sepsis Gurinder Mohan, AP Singh, Ranjeet Kaur

568

121.

Sepsis - Old Wine in New Bottle? Puneet Saxena, Madabhushi Shyam

572

122.

Septic Shock: How Do I Manage? Pravat Kumar Thatoi

576

123.

AKI in ICU â&#x20AC;&#x201C; Diagnosis and Management Georgi Abraham, Neethu Venkitakrishnan

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C H A P T E R

117

ABG Analysis in Clinical Setting

INTRODUCTION

Acid-Base balance is an intricate concept which requires an intimate and detailed knowledge of the body’s metabolic pathways used to eliminate the H+ ion. Accurately interpreting acid-base balance requires simultaneous measurements of arterial pH and plasma electrolytes, as well as knowledge of compensatory physiologic mechanisms. In this article, we’ll review normal acid-base physiology, acid-base disturbances, and lab techniques and mathematical calculations used to identify the cause of acid-base derangements.

Rajesh Mahajan, Suman Sethi

defined by the ratio of PCO2 to HCO3 and not by absolute value of either one alone.5,6

Overview of Fundamentals of Acid-Base Disorder

Normal metabolism of proteins and nucleotides generates about 100 mmol H+ per day in the form of sulphuric and phosphoric acids. By comparison, hydration of CO2 to form H2CO3 generates 12,500 mmol H+ per day.

Carbon dioxide transport 1.

Transport of carbon dioxide in the blood is considerably more complex. A small portion of carbon dioxide, about 5 percent, remains unchanged and is transported dissolved in blood.

The remainder is found in reversible chemical combinations in red blood cells or plasma. Some carbon dioxide binds to blood proteins, principally hemoglobin, to form a compound known as carbamate.

3.,

About 88 percent of carbon dioxide in the blood is in the form of bicarbonate ion.

BASIC PHYSIOLOGY

Acid-base Chemistry pH

The concept of pH was put forward by the Danish chemist, Soren Peter Sorensen in 1909 to refer to the negative logarithm of hydrogen ion (H+) concentration. An increase in the pH indicates a proportionate decrease in the [H+] and a decrease in the pH indicates a proportionate increase in the [H+].1 pH = – log [H+] The new generation of blood gas machines will report the H+ as well as the pH. Acid is an H+ donor andbase is H+ acceptor.2 The intra and extracellular buffer systems minimize the changes in H+ that occur as a result of addition of an acid or alkali load to the extracellular fluid (ECF), 60% of the acid load is buffered in the intracellular fluid (ICF). The most important buffer is the imidazole ring of the histidine in the hemoglobin molecule. The bicarbonate/carbonic acid is a weak buffer.3 However the presence of carbonic anhydrase, the high solubility of CO2 and the ability of kidney to synthesize new bicarbonate and above all the efficient removal of CO2 by lungs make it a powerful buffer. All buffers in a common solution are in equilibrium with the same H+ ion concentration. Therefore, whenever there is a change in the H+ ion concentration in the CSF, the balance of all the buffer system changes at the same time – the isohydric principle. It is therefore enough to study one buffer system in order to evaluate the acid base status of ECF.4 The Henderson-Hasselbalch equation, with its reliance on logarithms and antilogarithms is long andcumbersome and when attempting to deal with clinical situations. Kassirer and Bliech have rearranged the Henderson equation that relates H+ (instead of pH) to PCO2 and HCO3– and have derived an expression, which has great clinical utility. H+ = 24 x PCO2/HCO3It is important to emphasize that H+ ionconcentration is

Carbon dioxide enters blood in the tissues because its local partial pressure is greater than its partial pressure in blood flowing through the tissues. As carbon dioxide enters the blood, it combines with water to form carbonic acid (H2CO3), a relatively weak acid, which dissociates into hydrogen ions (H+) and bicarbonate ions (HCO3-). Blood acidity is minimally affected by the released hydrogen ions because blood proteins, especially hemoglobin, are effective buffering agents.7 The natural conversion of carbon dioxide to carbonic acid is a relatively slow process; however, carbonic anhydrase, a protein enzyme present inside the red blood cell, catalyzes this reaction with sufficient rapidity that it is accomplished in only a fraction of a second. Because the enzyme is present only inside the red blood cell, bicarbonate accumulates to a much greater extent within the red cell than in the plasma. The capacity of blood to carry carbon dioxide as bicarbonate is enhanced by an ion transport system inside the red blood cell membrane that simultaneously moves a bicarbonate ion out of the cell and into the plasma in exchange for a chloride ion. The simultaneous exchange of these two ions, known as the chloride shift, permits the plasma to be used as a storage site for bicarbonate without changing the electrical charge of either the plasma or the red blood cell.8 Hemoglobin acts in another way to facilitate the transport of carbon dioxide. Amino groups of the hemoglobin molecule react reversibly with carbon dioxide in solution to yield carbamates. A few amino sites on hemoglobin are

554

labile that is, their ability to bind carbon dioxide depends on the state of oxygenation of the hemoglobin molecule. 9

CRITICAL CARE

Only 5 percent of carbon dioxide in the blood is transported free in physical solution without chemical change or binding, yet this pool is important, because only free carbon dioxide easily crosses biologic membranes. Virtually every molecule of carbon dioxide produced by metabolism must exist in the free form as it enters blood in the tissues and leaves capillaries in the lung. Between these two events, most carbon dioxide is transported as bicarbonate or carbamate.10

Bicarbonate

Bicarbonate is a weak base that is regulated by the kidneys as part of acid–base homeostasis. The HCO3ˉ measured in arterial blood reflects the metabolic component of arterial blood. Together, CO2 and HCO3- act as metabolic and respiratory buffers respectively. They are related via the equation: H2O + CO2  H2CO3  HCO3- + H+

Compensatory changes

For any disturbance of gas tensions in arterial blood, a compensatory system exists to maintain homeostasis. In a metabolic disorder, where HCO3ˉ may be retained or excreted by the kidneys, respiratory compensation can occur almost immediately to alter the rate and depth of ventilation to retain or remove CO2. This occurs due to the exquisite sensitivity of chemoreceptors in the medulla to carbonic acid (H2CO3) or H+. Renal compensation in response to a respiratory disorder takes much longer, sometimes between three and five days, to retain or remove HCO3- as required.9 As a general rule, when compensation is present the arterial blood gas result shows two imbalances – derangement of both HCO3ˉ and PaCO2. A clue to which imbalance is the primary disturbance is obtained from the pH.If pH is leaning toward acidosis or alkalosis, then the parameter that matches the pH trend (that is, is increased or decreased corresponding to pH) is the primary problem and the other is due to compensation.10

Oxygenation

A PaO2 that is less than expected indicates hypoxemia. This can result from hypoventilation or a mismatch of ventilation and perfusion. If alveolar ventilation is adequate (that is, PaCO2 is normal), then the hypoxemia is almost certainly caused by a ventilation-perfusion disturbance. The nature of the hypoxemia can be further assessed by the difference between the alveolar and arterial oxygen tensions.

The alveolar–arterial oxygen tension difference

If an arterial blood gas result shows hypoxemia (low PaO2) and inadequate alveolar ventilation (high PaCO2), it must be determined whether the hypoxemia is related to hypoventilation, or is secondary to a disturbance in ventilation-perfusion, or both. This is assessed by calculating the difference between the alveolar (PAO2) and arterial (PaO2) oxygen tensions. The alveolar–arterial difference, or gradient, can be estimated only if the oxygen fraction of inspired air

(FiO2,usually 0.21 on room air), barometric pressure and water vapor pressure are known. A normal reference range is 5–15 mmHg. The difference, expressed as P (A–a) O2, increases with age, cigarette smoking and increasing FiO2. An expected P (A–a) O2 can be calculated using the formula P (A–a) O2 = 3 + (0.21 x patient’s age). All causes of hypoxemia, apart from hypoventilation, increase the alveolar-arterial difference. In a patient breathing room air, a P (A–a) O2 greater than 15 mmHg suggests a ventilation-perfusion mismatch related to disease of the airways, lung parenchyma or pulmonary vasculature. However, the result is non-specific in defining the actual pathology and again the patient’s clinical features are essential for diagnosis.

NOMENCLATURE FOR CLINICAL INTERPRETATION OF ARTERIAL BLOOD GAS MEASUREMENTS

Acid base disorders

Several definitions that are used to describe disturbances in acid base status are useful in understanding acid base disorders Acidemia – A H+ ion above the normal range of 36-44 nmolL–1, pH less than 7.36 Acidosis – A process that would cause acidemia, if not compensated Alkalemia– A H+ below the range of 36-44 nmolL–1, pH greater than 7.44 Alkalosis – A process that would cause alkalemia if not compensated There are mainly two types of disorders, respiratory and metabolic. They may be compensatory or noncompensatory. Changes in pH that are primarily a result of changes in PCO2 are termed respiratory disorders. On the other hand changes in pH brought about by changes in bicarbonate and other buffer bases are termed primary metabolic disorders. Basically there are four primary acid-base disorders viz. respiratory acidosis, metabolic acidosis, respiratory alkalosis and metabolic alkalosis.13 Compensation usually occurs in a primary acid base disturbance with an appropriate change in other components, e.g. a primary metabolic acidosis is compensated for by secondary respiratory alkalosis (by hyperventilation). On the other hand primary respiratory acidosis as it occurs in chronic obstructive airway disease (COPD) is secondarily compensated for by metabolic alkalosis brought about by H+ secretion and HCO3– absorption by the kidneys. While the former takes a few minutes to achieve the result, the latter may take days to weeks to be fully established.14

Respiratory acidosis

In respiratory acidosis, the patient’s pH is less than 7.35 and his PaCO2 is above 45 mm Hg (the upper limit of normal). Alveolar hypoventilation is the only mechanism that causes hypercarbia, or a PaCO2 above the upper limit of normal. The amount of alveolar ventilation necessary to maintain normal PaCO2 varies depending upon CO2 produced. The relationship between PaCO2 and plasma HCO3 - determines arterial pH. Generally, acute increases in PaCO2 are accompanied by only minimal changes in

serum HCO3. However, over a period of 1 to 3 days, renal conservation of HCO3 - results in an increase in pH.15 Chronic respiratory acidosis occurs secondary to a chronic reduction in alveolar ventilation—for example, in chronic lung diseases such as chronic obstructive pulmonary disease COPD, other main causes are: sedation, coma, neuromuscular disorders, severe kyphoscoliosis or obesity, pulmonary Fibrosis, sarcoidosis, pneumothorax or effusion, chronic obstructive airway disease, airway obstruction, severe pulmonary parenchymal disease etc.16

Respiratory alkalosis

Metabolic acidosis

Metabolic acidosis is an increase in the amount of absolute body acid, either from excess production of acids or excessive loss of bicarbonate, sodium, and potassium. Causes of metabolic acidosis include lactic acidosis, diabetic ketoacidosis, and loss of bicarbonate through severe diarrhea or bicarbonate wasting through the kidneys or gastrointestinal (GI) tract.18 In general, the kidneys attempt to preserve sodium by exchanging it for excreted H+ or potassium. In the presence of an H+ load, H+ ions move from the extracellular fluid into the intracellular fluid. For this process to occur, potassium moves outside the cell into the extracellular fluid to maintain electro neutrality. In severe acidosis, significant overall depletion of total body potassium stores can occur despite serum hyperkalemia. This is why I.V. potassium is given to patients with diabetic ketoacidosis early in treatment, despite the often-elevated serum potassium level. External and internal potassium balances are regulated to maintain an extracellular fluid concentration of 3.5 to 5.5 mEq/L and a total body content of about 50 mEq/kg (40mEq/kg in females).Main causesare:hypovolemia, cardiogenic or septic shock, severe hypoxia, diabetic ketoacidosis, renal failure, diarrhea, pancreatic fistula.19

Metabolic alkalosis

Metabolic alkalosis occurs when HCO3 - is increased, usually as the result of excessive loss of metabolic acids. Causes of metabolic alkalosis include diuretics, secretory adenoma of the colon, emesis, hyperaldosteronism, Cushing’s syndrome, and exogenous steroids. Some

ABG

Respiratory Acidosis

PaCO2

HCO3





Normal

Respiratory Alkalosis





Normal

Metabolic Acidosis



Normal



Metabolic Alkalosis



Normal



Estimate of Base Excess/Deficit

The metabolic component of the acid–base balance is reflected in the base excess. This is a calculated value derived from blood pH and PaCO2. It is defined as the amount of acid required to restore a liter of blood to its normal pH at a PaCO2 of 40 mmHg. The base excess increases in metabolic alkalosis and decreases (or becomes more negative) in metabolic acidosis, but its utility in interpreting blood gas results is controversial. While the base excess may give some idea of the metabolic nature of a disorder, it may also confuse the interpretation. The alkalaemia or acidaemia may be primary or secondary to respiratory acidosis or alkalosis. The base excess does not take into account the appropriateness of the metabolic response for any given disorder, thus limiting its utility when interpreting results.12

Anion Gap

Anion gap (AG) represents the concentration of all the unmeasured anions in the plasma and is measured by the following formula: AG = [Na+] - [Cl–] + [HCO3–] Normal AG is 12 ± 4mEq/l. Conditions resulting in metabolic acidosis other than hydrochloric acidosis usually lead to a decrease in the serum bicarbonate concentration without a concomitant rise in serum chloride thereby increasing the AG.11

Delta Ratio

Delta ratio is related to the AG and buffering, and is defined as: Delta ratio = [increase in AG/decrease in bicarbonate] A high delta ratio can occur when the bicarbonate levels are already elevated at the onset of the metabolic acidosis either due to a pre-existing metabolic alkalosis, or as a compensation for pre-existing respiratory acidosis. A low delta ratio occurs with hyperchloremic normalanion gap acidosis.18

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CHAPTER 117

Common in critical care, respiratory alkalosis occurs when PaCO2 is reduced, causing an increase in pH. The most common cause of respiratory alkalosis is increased alveolar ventilation, which can happen in hyperventilation, mechanical overventilation, hepaticdisease, pregnancy, and septicemia. Determining appropriate compensatory changes in HCO3- is key to determining if the patient also has a concomitant metabolic disorder. In chronic respiratory alkalosis, the compensatory mechanisms result in mild reduction in plasma HCO3- levels to maintain a near normal or normal pH. This causes a mixed acid-base disorder. Treatment of respiratory alkalosis is directed at discovering and correcting the underlying etiology. For example, if a patient is hyperventilating from anxiety, have him breathe into a paper bag. In mechanically ventilated patients with mechanical overventilation, reducing the minute ventilation or tidal volume will increase PaCO2 and reduce pH.17

causes of metabolic alkalosis respond to treatment with 0.9% sodium chloride solution. If the patient’s urine chloride concentration is less than 15 mmol/L, his metabolic alkalosis is saline-responsive; urine chloride levels above 25 mmol/L indicate non-saline-responsive metabolic alkalosis. The mechanisms resulting in saline-responsive metabolic alkalosis include GI loss, diuresis, or renal compensation from hypercapnia. Non-saline responsive metabolic alkalosis results from mineralocorticoid excess or potassium depletion. Fluid administration is the foundation for treatment for saline-responsive metabolic alkalosis. In cases of extreme alkalosis, the patient may be given dilute hydrochloric acid. Saline-resistant alkalosis is treated by addressing the underlying etiology.19

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Table 1: Comparing Acid-base imbalances Condition

CRITICAL CARE

Fig. 1: Allen's Test

INTERPRETATION OF THE ABG REPORT

Clinical Assessment

Patients with acid-base disturbances may present with symptoms due to the etiological cause that resulted in the disturbance. They may also present with manifestations that develop as a consequence of the disturbance as well as with symptoms that have nothing to do with the acidbase disturbance. Therefore, a carefully obtained history and a thorough physical examination are essential for the interpretation of ABG report.The following sequence may be followed to interpret the ABG report.11

Sampling and analysis

Blood is usually withdrawn from the radial artery (Figure 1) as it is easy to palpate and has a good collateral supply. The patient’s arm is placed palm-up on a flat surface, with the wrist dorsiflexed at 45°. A towel may be placed under the wrist for support. The puncture site should be cleaned with alcohol or iodine, and a local anesthetic (such as 2% lignocaine) should be infiltrated. Local anesthetic makes arterial puncture less painful for the patient and does not increase the difficulty of the procedure.1 The radial artery should be palpated for a pulse, and a preheparinized syringe with a 23 or 25 gauge needle should be inserted at an angle just distal to the palpated pulse to ensure accuracy, it is important to deliver the sample for analysis promptly. If there is any delay in processing the sample, the blood can be stored on ice for approximately 30 minutes with little effect on the accuracy of the results.

Validity of the ABG Report

Firstly, whether pH, PaCO2 and HCO3- are compatible should be confirmed using the Henderson- Hassel Bach equation or acid-base nomograms.16

Arterial pH

Net deviation in the arterial pH will indicate whetheran acidosis or an alkalosis is present. If pH is normal, either no acid-base disorder is present or compensating disorders are present.18

PaCO2 and HCO3–

Simple acid-base disorders result in a predictable change in the PaCO2 and HCO3-. Low PaCO2 and HCO3 - indicate respiratory alkalosis or metabolic acidosis; but a mixed disorder cannot be excluded.19 Elevated PaCO2 and HCO3– indicate respiratory acidosis or metabolic alkalosis; but a mixed disorder cannot be excluded. If PaCO2 and HCO3- show a change in opposite directions, it is indicative of a mixed disorder.

Pure respiratory alkalosis

High

Pure respiratory acidosis

Paco2

HCO3

Low

Normal

Low

High

Normal

Pure respiratory acidosis

Low

High

Normal

Pure metabolic alkalosis

High

Normal

High

Pure metabolic acidosis

Low

Normal

Low

Metabolic alkalosis with partial respiratory compensation

High

Metabolic acidosis with partial respiratory compensation

Low

Compensatory Response

The expected compensatory response for simple acidbase disorders is shown in Table 1 below. If the expected values and the actual values match, a mixed disorder is unlikely. If the expected values and the actual values differ, a mixed disorder is present.18

Calculating the Anion Gaps

The serum anion gap, calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration. This entity is used in the detection and analysis of acidbase disorders, assessment of quality control in the chemical laboratory, and detection of such disorders as multiple myeloma, bromide intoxication, and lithium intoxication.20 Low values most commonly indicate laboratory error or hypoalbuminemia but can denote the presence of a paraproteinemia or intoxication with lithium, bromide, or iodide. Elevated values most commonly indicate metabolic acidosis but can reflect laboratory error, metabolic alkalosis, hyperphosphatemia, or paraproteinemia. Metabolic acidosis can be divided into high anion and normal anion gap varieties, which can be present alone or concurrently (Table 2). The AG should be measured in all patients with metabolic acidosis.17 Causes of elevated AG metabolic acidosis can be remembered with the mnemonic MUDPILES [M = methanol; U = uremia; D = diabetic ketoacidosis (also alcoholic ketoacidosis and starvation); P = paraldehyde ingestion; I = isoniazid overdosage;L= lactic acidosis; E = ethylene glycol poisoning; S = salicylate poisoning]. Normal AG metabolic acidosis can be grouped as per the serum potassium levels. Normal AG acidosis with a normal to high potassium include hyperaldosteronism, type IV renal tubular acidosis, moderate degree of renal failure, administration of hydrochloric acid and posthypocapnia. Conditions causing normal AG acidosis include gastrointestinal losses of bicarbonate (diarrhea, ureteral diversion, biliary or pancreatic fistulas), carbonic anhydrase inhibitors, proximal and distal renal tubular acidosis. When {(Na++K+) - Cl-] can help in distinguishing renal from non-renal causes. A negative urinary anion gap indicates a non renal cause of acidosis.16

of arterial blood. When combined with a patient’s clinical features, blood gas analysis can facilitate diagnosis and management.

Table 2: Causes of Acidosis High anion gap • Renal failure (severe)

REFERENCES

• Lactic acidosis

- L: tissue hypoxia, tumors - D: short bowel syndrome, mental status changes; not measured by routine lab • Ketoacidosis: diabetic, alcoholic • Poisonings

- Ethylene glycol - Methanol 5

oxoprolinuria

Normal anion gap • Diarrhea (loss HCO3) • Renal tubular acidosis • Renal failure • Ureterosigmoidostomy • Carbonic anhydrase inhibitors (e.g. acetazolamide for glaucoma) • Dilution with hyperchloremic solutions (e.g. saline) • Pancreatic or biliary diversion • Administration of inorganic acid or acid equivalents • Ketoacidosis, well hydrated or excretion of Na+ ketones

OSMOLAR GAP

Osmolar gap is also useful in differentiating the causes of elevated AG metabolic acidosis. Osmolar gap is calculated by subtracting the calculated serum osmolality from measured osmolality using the formula shown below.15

Calculated osmolality =Glucose (mg/dl) +2[Na+ (mEq/l)]/18 + Blood urea nitrogen (mg/dl) /2.8

Osmolar gap = Measured osmolality - Calculated osmolality Osmolar gap >10 mOsm/l is considered abnormal when calculated using this formula. Conditions causing high AG metabolic acidosis include ethanol, ethyleneglycol, methanol, acetone, isopropyl ethanol and propylene glycol poisoning.17

CONCLUSIONS

Measuring arterial blood gases can be a useful adjunct to the assessment of patients with either acute or chronic diseases. The results show if the patient is acidaemic or alkalaemic and whether the cause is likely to have a respiratory or metabolic component. The PaCO2 reflects alveolar ventilation and the PaO2reflects the oxygenation

Hasten A, Berg B, Inerot S, Meth L. Importance of correct handling of samples for the results of blood gas analysis. Acta Anaesthesiol Scand 1988; 32:365-8. 2. Williams AJ. ABC of oxygen: assessing and interpreting arterial blood gases and acid-bas balance. BMJ 1998; 317:1213-6. 3. Burden and McMullan. BJA 1997; 78:479. 4. Guyton AC, Hall JE. Textbook of Medical Physiology 9th ed. 1996: 390. 5. Kassirer JP, Bleich HL. Rapid estimation of plasma CO2 from pH and total CO2 content. N Eng J Med 1965; 272:1067. 6. Shapiro BA, Peruzzi WT, Templin RK. Clinical application ofblood gases. 5th ed. 1994:230-31. 7. Hiramatsu T, et al. pH strategies and cerebral energetics before and after circulatory arrest. Thorac Cardiovasc Surg 1995; 109:948. 8. Burton David Rose. Clinical physiology of acid-base andelectrolyte disorders. 4th ed. 1994:508. 9. Mohan A, Sharma SK. An approach to interpret arterial bloodgases. In Agarwal AK, editor. Clinical medicine update - 2006.Vol. IX. A publication of Indian Association of Clinical Medicine. New Delhi: Jaypee Brothers Medical Publishers2006; 73-81. 10. Driscoll P, Brown T, Gwinnutt C, Wardle T. A simple guide toblood gas analysis. New Delhi: Jaypee Brothers Medical Publishers; 2002. 11. Sörenson SPL. Enzyme studies II. The measurement and meaning of hydrogen ion concentration in enzymatic processes. BiochemischeZeitschrift 1909; 21:131-200. Excerpts from pages 131-134 and 159-160 of the paper available at http://dbhs.wvusd.k12.ca.us/webdocs/ChemHistory/Sorensonn article.html. Accessed on 21 September 2006. 12. Shapiro BA, Harrison RA, Cane RD, Kozlowski-Templin R. Clinical application of blood gases. 4th ed. Chicago; Year Book Medical Publishers, Inc.; 1989. 13. Fall PJ. A stepwise approach to acid-base disorders. Practical patient evaluation for metabolic acidosis and other conditions. Postgrad Med 2000; 107:249-50, 253-4, 2578 passim. 14. Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical approach. Medicine (Baltimore) 1980; 59:161-87. 15. Williams AJ. ABC of oxygen: assessing and interpreting arterial blood gases and acid-base balance. BMJ 1998; 317:1213-6. 16. Beasley R, McNaughton A, Robinson G. New look at the oxyhemoglobin dissociation curve. Lancet 2006; 367:1124-6. 17. Ishihara K, Szerlip HM. Anion gap acidosis. Semi Nephrol 1998; 18:83-97. 18. Wrenn K. The delta (delta) gap: An approach to mixed acid-base disorders. Ann Emerg Med 1990; 19:1310-3. 11. 19. Ghosh AK. Diagnosing acid-base disorders. J Assoc Physicians India 2006; 54:720-4. 20. Kruse JA, CadnapaphornchaiP. The serum osmole gap. J Crit Care 1994; 9:185-97.

CHAPTER 117

- Salicylate (usually associated with respiratory alkalosis)

- Acetaminophen - induced (pyroglutamic aciduria)

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Electrolytes in ICU

C H A P T E R

118 INTRODUCTION

Electrolyte disturbances are common clinical problems encountered in the intensive care unit (ICU) and are associated with increased morbidity and mortality among critically ill patients. Unless suspected they can be missed and inappropriate therapy can lead to irreversible damage. For management of hyponatremia in ICU identifying stimuli for vasopressin secretion, judicious use of hypertonic saline, and close monitoring are essential components. Hypernatremia is associated with cellular dehydration and central nervous system dysfunction. Water deficit should be corrected with hypotonic fluid, taking into account ongoing water losses. Cardiac manifestations should be identified and treated before initiating stepwise diagnostic evaluation of potassium disturbances. Disturbances of calcium phosphorous and magnesium metabolism are also frequently encountered in some critically ill patient with trauma, burns, sepsis, pancreatitis and renal failure. Early recognition and prompt correction of these abnormalities are necessary to avoid catastrophes. A brief description electrolyte disturbance pertaining to ICU patients follows.

HYPONATREMIA

Hyponatremia may be present on ICU admission or can develop later. In either case it is associated with poor prognosis. A recent study of 151,486 adult patients from 77 intensive care units over a period of 10 years demonstrated that severity of dysnatremia is associated with poor outcome in a graded fashion. Another study reported that both ICU-acquired hyponatremia and ICU-acquired hypernatremia were associated with increased mortality. It should be noted that patients with hyponatremia may also have manifestations of concurrent volume depletion and possible underlying neurologic diseases that predispose to development of hyponatremia due to SIADH or cerebral salt wasting. Hyponatremia-induced cerebral edema occurs with sudden fall in the serum sodium concentration, usually within 24 hours. Causes of hyponatremia are mentioned in Table 1. Clinically, hyponatremia manifests with primarily neurologic symptoms. Their severity depends on rapidity of the change in the serum sodium concentration in addition to level of sodium. When serum sodium falls acutely below 120 meq/L, patients become symptomatic with lethargy, apathy, confusion, seizures and coma. Premenopausal women and young children with acute postoperative hyponatremia have high risk of brain herniation suggesting a possible hormonallymediated decrease in the degree of osmotic adaptation.

TH Trivedi

Patients with chronic hyponatremia usually do not have neurological symptoms and manifest with muscle cramps, anorexia, nausea and weakness. In most of the cases cause of hyponatremia becomes apparent by detail clinical evaluation including medication history. Measurement of serum osmolality, urinary sodium, cortisol, thyroid hormone and relevant radiological investigations are needed in selected cases. Low uric acid levels and BUN are found in patients with SIADH, thiazide induced hyponatremia, hypopitutarism and hypervolemia. Concurrent metabolic alkalosis is seen in patients with diuretic use, vomiting and hypopitutarism while metabolic acidosis is seen in cases of diarrhea and primary adrenalin insufficiency.

Treatment

Acute hyponatemia is generally symptomatic and needs rapid correction. Treatment is recommended with 3% NaCl by giving a bolus of 100ml IV over 10 min, repeated upto maximum 3 doses, or till acute symptoms subsides. The goal is to provide an urgent correction by 4 to 6 mmol/L to prevent brain herniation. For patients with mild to moderate symptoms, 3% NaCl is infused at lower rate of 0.5-2 mL/kg/h. In chronic hyponatremia the brain undergoes gradual adaptation and there is less cerebral edema, and very rapid correction can lead to osmotic demyelination syndrome (ODS). Hence, chronic hyponatremia generally needs gradual correction. High risk of ODS is seen with serum sodium < 120meq/L

Table 1: Causes of Hyponatremia Pseudohyponatremia (normo-osmolar)

Hyperlipidemia Hyperproteinemia

Redistributive Hyponatremia (hyperosmolar)

Hyperglycemia Mannitol therapy

Hypovolemic Hyponatremia

GI losses Third space losses Diuretic therapy Cerebral salt wasting Mineralocorticoid deficiency

Euvolemic hyponatremia

SIADH Hypothyroidism Glucocorticoid deficiency Polydipsia

Hypervolemic Hyponatremia

Congestive heart failure Cirrhosis of liver Nephrotic syndrome Renal failure

or if there are comorbidities such as alcoholism, liver disease, malnutrition, or severe hypokalemia are present. However, if chronic hyponatremia is symptomatic with neurological features or is severe, aggressive therapy is indicated as for acute hyponatremia and Initial administration of 3% NaCl is needed to raise the serum sodium by 4-6 mmol above baseline.

hypernatremia can complicate traumatic brain injury. The clinical manifestations of acute hypernatremia begin with lethargy, weakness, and irritability, and can progress to convulsions and coma if serum sodium is >160meq/L. Patients may have intense thirst initially, however most ICU patients cannot communicate same.

Estimated change in plasma [Na+] following the administration of 1 L of an intravenous fluid regimen can be calculated by equations proposed by Madias and Adrogue:

Acute (<48 hours) hypernatremia is rare, occurring in patients with diabetes insipidus or is iatrogenic. The initial regimen in such patients is fluid therapy with D5-5 percent dextrose in water, intravenously, at a rate of 3 to 6 mL/kg per hour with close monitoring of serum sodium and blood glucose until the serum sodium is lowered below 145 meq/L, followed by infusion at 0.5-1 mL/kg/ hour till normonatremia is restored over 24 hours.

There is a tendency to underestimate the achieved plasma [Na+] using this formula. Also ongoing losses have to be accounted for and close clinical and laboratory monitoring is needed. In hypovolemic hyponatremia, the initial intravenous fluid of choice should be 0.9% sodium chloride, unless the patient is symptomatic or hyponatremia is documented to have developed acutely (< 48 hours). Euvolemic asymptomatic hyponatremia does not require urgent therapy. Identification and removal of reversible causes should be done followed by fluid restriction in patients with chronic SIADH. Loop diuretics concurrently used are beneficial in patients with SIADH who have a high urine to serum electrolyte ratio (>1). Vaptans are useful for chronic hyponatremia in addition to fluid restriction and sodium chloride administration. Many cases of hypervolemic hyponatremia are associated with significant dysfunction of the heart, liver, or kidney. Treatment includes restriction of water and sodium intake, administration of loop diuretics and treatment of cause. Treatment of severe hyponatremia in patients with decompensated heart failure may require extracorporeal ultrafiltration, which has been shown to improve congestion, lower diuretic requirements, and correct hyponatremias. Vaptans can be used in cirrhotic patients for management of fluid overload with hyponatremia if water restriction and diuretics do not help.

HYPERNATREMIA

Predisposing factors for hypernatremia in ICU include the administration of sodium bicarbonate solutions for acidosis correction; selective renal water loss, use of diuretics; gastrointestinal fluid losses through nasogastric suction, and selective water losses through fever, drainage tubes, and open wounds. Acute diabetes insipidus with

Treatment

Chronic (>48 hours) hypernatremia is more common, even in those who present with acute changes in mentation. The initial regimen in such patients is D5 infusion, intravenously, at a rate of (1.35 x patient’s weight in kg ml/hour) to lower the serum sodium by a maximum of 10 meq/L in a 24-hour period (0.4 meq/L/hour). It is likely that this regimen will lower the serum sodium by less than 10 meq/L in 24 hours, as many patients have ongoing free water losses (osmotic diuresis, diarrhea, nasogastric suction) slowing the rate of correction. Potassium can be added to the intravenous fluid in patients with concomitant hypokalemia. A potential complication of rapid administration of dextrose-containing intravenous fluids is the development of hyperglycemia, more so in patients with diabetes. Hyperglycemia can lead to an osmotic diuresis, which creates electrolyte-free water losses further limiting the reduction in serum sodium. Lower concentration e.g. 2.5% dextrose in water- solution can be used in such patients. Hypervolemic hypernatremia is usually an iatrogenic complication that develops in patients with renal failure. Renal replacement therapy is the only effective treatment in them. Composition of hemodialysis solution should be adjusted to lower sodium concentration in such patients.

HYPOKALEMIA

This is a common electrolyte disturbance in ICU patients resulting from GI losses (diarrhea, vomiting, nasogastric suction), renal losses (diuretics, diuretic phase of renal failure, RTA), trans-cellular shifts or drugs (beta stimulants, insulin, aminoglycosides, amphotericin B). Clinical manifestations of hypo and hperkalemia are enumerated in Table 2. The most dreaded complications

Table 2: Clinical manifestations of Hypokalemia and Hyperkalemia Manifestations of Hypokalemia

Manifestations of Hyperkalemia

GI manifestations

Anorexia, nausea, vomiting, paralytic ileus

Nausea, vomiting, diarrhea, intestinal cramps

Neuromuscular Manifestations

Muscle cramps, weakness, paraesthesia, paralysis

Paraesthesia, weakness, muscle cramps, dizziness

Cardiovascular Manifestations

Postural hypotension, ECG changes, cardiac dysrhymias

ECG changes, risk of cardiac arrest

Associated Acid Base Disorders

Metabolic alkalosis

Metabolic acidosis

CHAPTER 118

Change in plasma [Na+] =Infusate [Na+] – plasma [Na+]/ Total body water + 1

559

CRITICAL CARE

560

of hypokalemia are cardiac arrhythmias, especially in patients with hypertension and IHD, heart failure and neuromuscular paralysis. ECG changes seen in patients with hypokalemia include ST-segment depression, T-wave flattening followed by inversion, and the presence of U waves. In presence of life threatening symptoms like respiratory muscle paralysis or changes in ECG, therapy should precede investigations. In cases where cause is not obvious clinically, urinary potassium excretion should be measured. If it is appropriately low (urine K+ < 20 mEq/ day then trans-cellular shift or extrarenal K+ loss should be suspected. If urinary K+ excretion is high, trans-tubular potassium gradient (TTKG), acid-base status, and the presence or absence of hypertension help in identifying cause of hypokalemia.

Treatment

Parentral therapy is reserved for patients with severe symptoms and ECG changes. Infusion of > 10–20 mEq/ hr of potassium requires a central venous catheter, as infusion via peripheral line causes phlebitis. Total amount of daily K+ replacement should be less than 240–300 mEq with close monitoring. Parenteral K+ replacement should be given in dextrose-free vehicle. Hypocalcemia and hypomagnesemia should be suspected and corrected if hypokalemia persists despite adequate potassium supplementation. Milder hypokalemia should be corrected with oral therapy.

HYPERKALEMIA

It is seen in 1-2% of hospitalized patients. Increased intake, impaired renal excretion, hypoaldosteronism, transcellular shifts (acidosis, drugs, periodic paralysis, exercise) and cellular injury are important causes. Pseudohyperkalemia due to hemolysis of sample, leukocytosis, thrombocytosis and laboratory error should be suspected in absence of obvious cause, symptoms and ECG changes. ECG changes include tall T waves, low p wave, prolongation of PR interval and widening of QRS complex. Table 2 enumerates clinical manifestations. Initial step after exclusion of pseudohyperkalemia is to identify the cause of trans-cellular potassium shift, and discontinuation of medications responsible for hyperkalemia. The next step is to assess urinary potassium excretion. If there is relatively low urinary K+ excretion, calculation of TTKG should follow. A low TTKG may warrant further tests to differentiate between aldosterone deficiency and resistance to aldosterone. If ECG abnormality of hyperkalemia is present, emergency management should be started before further investigations. Intravenous calcium gluconate is the first therapy to antagonize the depolarizing effect of hyperkalemia. Administration of Insulin with 50% glucose follows. It takes 30 minutes to produce effect that lasts for 4-6 hours. Nebulization with beta stimulants lower potassium levels for at least 2 hours. Sodium bicarbonate should be avoided in patients with extracellular fluid volume overload. Infusion of 44 meq over 5-15 minutes lowers serum potassium for approximately 2 hours. In case of emergency and in presence of renal failure or rhabdomyolysis, hemodialysis

is most effective therapy. Exchange resins are advocated in long term management in chronic cases.

MAGNESIUM IMBALANCE

It is second most abundant intracellular cation but only 1% of body’s Mg is present in ECF. Hypomagnesemia is common finding in hospitalised patients (10-20%) especially in emergency department and ICU patients (as high as 50%). It may result from impaired intake (alcoholism, starvation, malabsorption, TPN), increased losses (diuretics, DKA, hyperaldosteronism, magnesium losing kidney disease). Drugs like aminoglycosides, amphotericin, beta agonists, diuretics and PPIs predispose to hypomagnesemia. Severe hypomagnesemia can result in ECG changes, arrhythmias including torsades de pointes, seizures, coma, and death. Neuromuscular manifestations are muscle weakness, tremors and hyperreflexia. Hypomagnesemia can also lead to refractory hypokalemia and hypocalcemia. Severe hypomagnesemia(serum Mg < 1mg/dl) is treated with IV infusion of 1.5 meq/Kg MgSO4 over 12-24 hours with monitoring of serum Mg level and renal function. Hypermagnesemia is rare but can be seen in ICU patients following administration of IV MgSO4 for eclampsia, Mg containing laxatives and in patients with renal failure. It manifests with lethargy, hyporeflexia, hypotension, confusion and coma and respiratory paralysis. Treatment of hypermagnesemia includes stopping Mg supplementation, IV Calcium infusion in severe cases, hydration, loop diuretics and dialysis for patients with life threatening manifestations.

CALCIUM IMBALANCE

Hypocalcemia is a frequent electrolyte abnormality encountered in the ICU. Prevalence of hypocalcemia measured as ionized calcium is estimated to be about 15–20%. Hypocalcemia is also associated with increased mortality in ICU patients. Spuriously low concentration of calcium can be seen following the administration of gadolinium based contrast, as gadolinium interferes with calorimetric calcium assays. Common causes of hypocalcemia in ICU patients are trauma, renal failure, sepsis, pancreatitis, massive transfusion, post parathyroidectomy, associated hypomagnesemia and vitamin D deficiency. The symptoms and signs of severe acute hypocalcemia include tetany, seizures, cardiovascular manifestations such as prolonged QT interval and ventricular arrhythmias. Calcium chloride should be preferred over calcium gluconate for urgent situations, since it contains three times more elemental calcium. Hypomagnesemia should be suspected and corrected if hypocalcemia is not getting corrected by repeated calcium administration. If metabolic acidosis is present concomitantly, hypocalcemia should be corrected first as the treatment of acidosis with bicarbonates further decreases level of ionized calcium, precipitating tetany or cardiac arrest. Hypercalcemia is seen in ICU patients with hyperparathyroidism, prolonged immobilization, malignancies, use of thiazide diuretics and milk alkali syndrome. Clinical manifestations are vomiting, constipation, hypertension, renal dysfunction and CNS

disturbances including coma. Management is with saline hydration, followed by loop diuretics. Biphosphonates, calcitonin, steroids and plicamycin have role in chronic and severe cases. Dialysis is required in patients with renal failure or fluid overload.

PHOSPHOROUS IMBALANCE

Hyperphosphatemia can result from increased phosphate intake, decreased phosphate excretion, or shift of intracellular phosphate to extracellular space. It is an independent risk factor for mortality in ICU patients. Rhabdoomyolysis, acidosis, tumor lysis and acute hemolysis can cause hyperphosphatemia due to cellular shifts. Renal failure and hypoparathyroidism are common causes of hyperphosphatemia due to decreased loss. Most patients are asymptomatic but occasionally have symptoms of hypocalcemia, such as muscle cramps, tetany, and perioral numbness or tingling. Bone and joint pain, pruritus, and rash are other symptoms. Carpopedal spasms and seizures can develop in patients

561

CONCLUSION

Various types of electrolyte imbalances are found in critically ill patients along with fluid and acid base disturbances. In majority of cases there are no symptoms and even if present are non-specific. Thus high index of suspicion is needed to identify these disorders depending on predisposing conditions in these patients. Their prompt recognition and appropriate treatment are of utmost importance as some of these can be fatal if left untreated. Treatment is simple for most of disturbances but patients fluid status, renal function, pre-existing conditions have to be considered and close monitoring is required to avoid complications of too rapid correction with long term sequel.

REFERENCES

1. Funk GC, Lindner G, Druml W, et al. Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med 2010; 36:304-311. 2.

Stelfox HT, Ahmed SB, Khandwala F, Zygun D, Shahpori R, Laupland K: The epidemiology of intensive care unitacquired hyponatraemia and hypernatraemia in medicalsurgical intensive care units. Crit Care 2008; 12:R162.

Sahay M, Sahay R. Hyponatremia: A practical approach. Indian J Endocr Metab 2014;18:760-71.

4. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, evaluation and treatment of hyponatremia: Expert panel recommendations. Am J Med. 2013; 126:S1–42. 5.

Liamis G, Kalogirou M, Saugos V, Elisaf M: Therapeutic approach in patients with dysnatraemias. Nephrol Dial Transplant 2006; 21:1564-1569.

Lee JW. Fluid and Electrolyte Disturbances in Critically Ill Patients. Electrolyte Blood Press 2010; 8:72-81.

7. Pandey CK, Singh RB. Fluid and electrolyte disorders. Indian J Anaesth 2003; 47:380-87. 8. Gibbs R, Macnaughton P. Electrolyte and metabolic disturbances in critically ill patients. Anaesthesia & Intensive Care Medicine 2007; 8:529 -533.

CHAPTER 118

Hypophosphatemia is a frequent disorder in critically ill patients with Gram-negative sepsis, DKA, malnutrition, alcoholism, diuretic therapy and cardiac surgery (2025%). Hypophosphatemia may result from decreased intestinal phosphate absorption, increased renal loss, and trans-cellular shift of phosphate to intracellular space. Rapid infusion of glucose containing solution to chronically malnourished patients can precipitate hypophosphatemia by causing trans-cellular shift know as re-feeding syndrome. It may manifest with leukocyte, erythrocyte, and platelet dysfunction. Clinical features are muscular weakness, confusion, ataxia, convulsions and coma; respiratory failure and cardiac arrhythmias. Hypotension and ventilator dependence are frequent problems encountered in ICU due to hypophoaphatemia. Symptomatic or severe hypophosphatemia (< 1.0 mg/dL) should be treated with intravenous sodium or potassium phosphate with initial intravenous infusion of 2–5 mg/kg of inorganic phosphate dissolved in 0.45% saline given over 6–12 hours and repeated as needed. Monitoring for hypocalcemia is required during IV phosphate infusion. Patients on CRRT need higher dose. Milder hypophosphatemia is treated with oral supplementations such as potassium phosphate.

with acute hyperphophatemia. Treatment is by restricting supplementation, hydration, infusion of glucose with insulin and dialysis in severe cases. Aluminium or calcium containing phosphate binders are commonly used to retard absorption. Sevelamer is a non calcium/aluminium containing binder with additional effect on lipid profile.

Glycemic Control in I.C.U.

C H A P T E R

119

Ramesh Kumar Goenka

INTRODUCTION

Hyperglycemia in ICU setting has been a common finding in critically ill patients. Although Diabetes is sometimes the reason for admission to ICU, it is more commonly a co morbid condition complicating the patient management by increasing the severity of primary illness. Also a nondiabetic patient admitted to ICU for a critical illness can have hyperglycemia (also called Stress Hyperglycemia) as a consequence of many factors. Attempts at controlling glycemia have met with conflicting results, probably reflecting an association rather than causality of this marker of stress. The glycemic control in different ICUs whether medical, surgical, or cardiac have different impact in diabetics vs non-diabetics. Hyperglycemia in ICU is associated with increased morbidity, mortality and longer hospital stay regardless of reason for admission (e.g. AMI, Status Post Cardiovascular Surgery, Stroke, Sepsis and Trauma). Stress hyperglycemia is defined as blood sugar level >140 mg% without a previous history of DM or HbA1C >6.5%.

EPIDEMIOLOGY

The incidence of acute hyperglycemia is difficult to define and may vary from 40-90% depending upon threshold used to define abnormal blood glucose. Hyperglycemia in ICU is associated with poor prognosis in patient with no history of DM. This association is well documented for both admission and mean glucose level during the Acute Illness

↑↑↑ Glucagon ↑↑ Cortisol ↑ Epinephrine

↑ GLUT-4 ↓ Postreceptor insulin signalling

↑↑↑ Gluconeogenesis ↑ Lipolysis

↑ Cytokines (Such as TNF-α)

Insulin resistance ↓ Muscle glycogen

Glucocorticoid therapy Parenteral nutrition Continuous enteral nutrition Decreased level of activity

↓ Insulin resistance ↑ Glucagon

Stress hyperglycemia

Eﬀect Circulatory and electrolytes eﬀects • Volume depletion • Hypoperfusion • Electrolyte loss • Acid base disturbances

Tissue eﬀects • Reduced nitric oxide • Endothelial dysfunction • Platelet activation • Immune dysregulation • Mitochondrial injury • Multiorgan dysfunction

Fig. 1: Pathogenesis of Stress induced Hyperglycemia

hospital stay. A review by Deane et al reported 30-40% of patients admitted to ICU suffer from hyperglycemia of whom 10-15% have previously undiagnosed DM. In NICE Sugar Study at least one blood sugar of >180 mg% was recorded in 60% patients without a prior history of diabetes. It is estimated that 15-20% of adult admission to ICU has prior DM and there was suboptimal glycemic control prior to onset of acute illness as shown in a retrospective study that found an HbA1C<6% in only 20% of known diabetic patients. Gornik et al assessed diabetes prevalence 4-6 weeks after discharge from ICU and reported approximately 17% of patients who suffered hyperglycemia during ICU stay actually had unrecognised T2DM. A retrospective review of 614 patients who underwent cardiothoracic surgery hyperglycemia was seen in 80% of patients after surgery. From India Bajwa et al in 2011 reported 38.73% of patients had hyperglycemia (BS >140mg%) on admission to ICU out of which 13.95% had prior history of DM and 4.99% detected diabetic after admission. In a recent prospective study by Godinjak et al 100 patients were followed in a MICU and overall prevalence of hyperglycemia was found to be 54% (35% with DM and 19% with stress hyperglycemia) and 46% were normoglycemic. Patients with stress hyperglycemia had higher mortality (52.6%) compare to patients with previously diagnosed diabetes (48.6%) or normoglycemia (36.9%). Glycemic variability was the strongest predictor of adverse outcome. There was a statistically significant difference in glycemic variability between patients with stress hyperglycemia and normoglycemia. There was no statistically significant difference in length of mechanical ventilation and hospital stay among three group. Patients with stress hyperglycemia had higher mortality than patients with previously diagnosed diabetes or nondiabetics.

PATHOGENESIS

Hyperglycemia may be an independent determinant of prognosis of a critically ill patient or only a marker of dieses severity. The mechanism of development of hyperglycemia in critical illness includes a release of counter-regulatory stress hormones (Corticosteroids, Glucagon, Catecholamine and GH) and pro-inflammatory mediators (TNFα, IL1, IL6). Increased counter-regulatory hormones contribute to alteration in glucose metabolism including increased hepatic glucose production and impaired peripheral utilisation. Catecholamine inhibit insulin release and Cortisol increases hepatic glucose production and stimulates protein catabolism. Proinflammatory cytokines not only increase insulin resistance

but also increase hepatic glucose production through Gluconeogenesis. The whole picture is complicated by administration of exogenous corticosteroids, Vasopressors and parenteral solution containing dextrose. The most important contributor to stress hyperglycemia seems to be gluconeogenesis mediated primarily by glucagon and supplemented by cortisol and epinephrine (Figure 1).

BENEFITS OF GLYCEMIC CONTROL (INTENSIVE VS CONVENTIONAL) IN ICU

563

GLUCOSE MONITERING IN CRITICALLY ILL PATIENTS

Till date capillary blood sugar estimation is the only means available in most of the ICUs in India. In patients receiving IV insulin, hourly blood sugar estimation is done till blood sugar is stable followed by testing every 2 hourly. Patients with or without history of diabetes receiving enteral or parenteral nutrition support should undergo glucose testing every 4 to 6 hours. The testing can be discontinued in a non diabetic patients if glucose values are <140 mg% without insulin therapy for 24 to 48 hours, following achievement of desired caloric intake. Patients on oral feed are measured 4 times a day, before meals and at bed time. More frequent measurements are indicated after a medication change e.g. corticosteroid use, abrupt discontinuation of enteral or parenteral nutrition or in patients with frequent episodes of hypoglycemia. Since critically ill patients have poor peripheral perfusion, the proportion of glucose reaching periphery is lower. On the contrary there is increased capillary recruitment, increasing the efficiency of capillary glucose uptake. Hence capillary glucose measurements are less representative of arterial and central compartment glucose level. CGMS is based on a sensor placed in subcutaneous tissue, and is the preferred method for blood glucose measurement in critically ill patients. This method may provide important additional information on trends and fluctuations in glucose control and may predict progression to hyperglycemia or hypoglycaemia.

GLYCEMIC TARGETS

A series of trial conducted to ascertain impact of glycemic control in deferent ICU setting and are summarised in Table 1.

Based on the recent trials, AACE and ADA task force on inpatient glycemic control recommended a blood glucose level between 140-180mg/dl for majority of ICU patients and a lower target between 110-140mg/ dl in selected ICU patients (i.e. centres with extensive experience and appropriate nursing support, cardiac surgical patients, patients with stable glycemic control without hypoglycemia). Glucose targets of >180mg/dl and <110mg/dl are not recommended in ICU patients. Based on these recommendations and by adopting a grading systems a consensus recommendation was published in API journal in July 2014. The recommendations by various associations are summarised in Table 2.

When we compare the control between diabetes vs non diabetic hyperglycemia, the later is met with worse outcomes . In a retrospective cohort study, a “U” shaped curve was noted for ICU mortality and mean blood glucose in non diabetics, where as no such relationship was noted for diabetics. All the three domains of sugar control i.e. Hyperglycemia, hypoglycaemia and glycemic variability are affected by premorbid diabetic status of patients. Hyperglycemia was strongly associated with increased mortality in critically ill patients without diabetics than with diabetics. Hypoglycaemia was

Indian consensus guideline as well as most of other guideline recommends IV insulin administration as a preferred modality for critically ill patients, because of its rapid onset of action, quicker doses adjustment, better safety profile and predictable glucose lowering effect. Subcutaneous insulin administration (SC insulin) is best avoided in critical care setting, because of its unreliable absorption, unpredictable effects and the “Stacking Effect” causing delayed hypoglycemia. The patient can be shifted to SC insulin once he is stable and started to accept

INSULIN ADMINISTRATION (IV VS SC)

CHAPTER 119

Till 2006 several randomised controlled trails intensified glucose control with administration of IV insulin both in medical and surgical ICU patients and reported a reduction in multi-organ failure, systemic infection as well as short and long term mortality. In Belgian clinical trial by Vendenberghe et.al, achievement of strict glycemic control (B.S 80-110mg %) by IV insulin therapy in a surgical ICU led to 32% reduction in mortality compared to more flexible glucose control(B.S 180- 215mg%).The same investigators in 2006 conducted a similar trial in a medical ICU and found a reduction in mortality only among patients who stayed in ICU for more than 3days. However, there was no difference in overall mortality in this study and in a sub group of patients staying in ICU for less than 3days mortality was highter in intensive treatment group(H.R:1.09,P=0.05). The NICE sugar trial, the largest randomised controlled trial conducted till date compared two insulin based glucose control strategies (target B,S <180mg% in control group verses a target range of 81-108 mg% in intervention group )in a sample of 6104 patients. In this trial intensive sugar control was associated with increased CV mortality with an absolute difference of 5.8%.A series of meta-analysis, were conducted after NICE sugar trial and found no benefit for intensive control and confirmed that this strategy was associated with increased risk of hypoglycemia. This difference between Vendenberghe and NICE sugar trial is proposed to be due to the amount of energy provided by parenteral nutrition, which was very high in Belgian study indicating greater calorie intake. A meta-regression analysis found that there is a significant relationship between the treatment effect (28 days mortality)and the proportion of calories provided parenterally, suggesting beneficial effect of strict glucose control when parenteral nutrition is energy rich.

independently associated with increased mortality in both these population. Increasing glycemic variability may have a stronger association with mortality in nondiabetics than in diabetics.

Study population, N

Single observational

Single central observational

Furnary et al 2006 Surgical ICU, N=3554

Furnary et al 2006 Surgical ICU, N=5534

Multicentre, prospective randomised, open label

Single central observational

Diabetic patients with suspected AMI, N=12534

DIGAMI 2, Malmberg et al 2005

Multicentre, randomised

Design

Furnary et al 2003 Surgical ICU, N-=2467

Diabetic patients with suspected AMI, N=620

DIGAMI 1, Malmberg et al 1995

Trials showing Benefits of IIT vs CG

Trial, author

177 +/- 30 mg

IIT group BG 150- Data not provided 200 mg/dl firther down to 70-110 mg/dl vs BG >200 mg/dl

IIT group, BG 150-200 mg/dl firther down to 100-150 mg/dl vs BG >200 mg/dl

IIT group BG 150- Daily 178 200 mg/dl vs CG BG >200

213 +/- 41 mg/dl

Daily 188

65% â Mortality

57% â mortality

69% â Deep Sternal Wound Infection

Group 1 (23.4%); Group 2 (22.6%); Group 3 (19.3%)

Group 3: 180 ± 64.8 (P=0.0001)

Group 1: 163.8 Group 1 GI ± 54.0 Group 2: infusion + 163.8 ± 50.4 insulin – based glucose control (n=474, BG: 126-180); Group 2, GI Infusion + Standard Glucose Control (N=473, BG:126-198); Group 3. Usual care (n=306, BG: not specified

P=0.001

Group 1 and 2: P=0.831; Group 2 and 3: P=0.203

P=0.027

Mortality (IIT vs. P-value CG)

210.6 ± 73.8 mg/dl Infusion group (P<0.0001) vs CG (18.6% vs 26.1%)

IIT

Glucose level at endpoint, mg/dl (Mean ± SD)

Group 1: GI 172.8 ± 59.4 infusion followed by multi dose SC insulin (n=306, BG:126-198) vs group 2 : ususal care (n=314, BG; not specified)

Intervention (N. target BG [mg/ dl])

Table 1: Trils showing Impact of glycemic Control in ICU Hypoglycemia (%)

Patients in study group 1 did not reach the protocol-outlined glucose levels

Data not provided

Contd...

Administration of 1.5% vs 0% in 1st 24 h addition insulin dose to control group patients; small sample size

Limitations

CRITICAL CARE 564

Surgical ICU patients on mechanical ventilation, N=1548

Medical ICU, N=767

Leuven 1, Van den Berghe etal 2001

Leuven 2, Van den Berghe et al 2006

117 (IQR 108-130) 144 (IQR 128-162) ICU mortality (P<0.0001) (17.2% vs 15.3%): In-hospital mortaltiy (23.3% vs 19.4%); 28 days mortality (18.7% vs 15.3%)

IIT group (n=536, BG: 80-110) vs CG (n=542, BG: 140-180)

Prospective randomised multicentr controlled

Glucontrol, Preiser et al. 2009

ICU mortality: P=0.41; Hospital mortality: P=0.11; 28 days mortality P=0.14

P=0.02

28 mortality: P=0.74; 90 days mortality P=0.31

ICU mortality P=0.05; Hospital mortality:P=0.009 90 days mortality: P=0.06

ICU mortality P<0.04 (adjusted); Hospital mortality P=0.01

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Hypoglycemia (%)

17.0% vs 4.1%, P<0.001

6.8% vs 0.5%, P<0.001

8.7% vs. 2.79%, p<0.0001

IIT group did not achieve target; stopped study early for hypoglycemia risk; underpowered IIT group did not achieve target

Stopped study early for hypoglycemia, many protocol violation

Single centre, 18.1 in IG versus high use of 3.1 in CG parenteral dextrose (in TPN)

Single centre, 5 in IG VERSUS high use of 0.8 IN cg parenteral dextrose (in TPN)

Limitations

Abbreviations: ICU: Intensive care unit; IIT Intensive Insulin Therapy; BG: Blood glucose; CG: Conventional Group; GI: Glucose Insulin; TPN: Total Parenteral Nutrition; VISEP: Volume Substitution and Insulin Therapy in Severe Sepsis; DIGAMI: Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction; AMI: Acute Myocardial Infarction; SC: Subcutaneous

Medical-surgical ICU patients, N=6104

90 days mortality (27.5% vs 24.9%)

144±23 (P<0.001)

115±18

28 days mortality (24.7% vs 26.0%); 90 days mortality (39.7% vs 35.4%)

ICU mortality (31.3% vs 38.1%): In-hospital mortality (43.0% vs 52.5%); 90 days mortality (42.2% vs 49.1%)

ICU mortality (4.6% vs 8.0-%); In-hospital mortality (7.2% vs 10.9%)

IIT group (n=3054, BG:81108) vs CG (nb=3050, BG: 144-180)

Daily 156±25 (P<0.001)

Daily 153 ± 33 (P<0.001)

Mortality (IIT vs. P-value CG)

138 (QR 111-184) (P=0.05)

Parallel-group randomised, controlled, computerised treatment algorithm

Patients with sepsis, N=537

Medical surgical NICE-SUGAR, The NICEICU patients, N=6104 SUGAR innestigators 2009

VISEP, Brunokhost et al 2008

Daily 108±26

Daily 103± 19

Glucose level at endpoint, mg/dl (Mean ± SD)

130 (IQAR 108167)

IIT group (n=386, BG: 80-110) vs. CG (n=381, BG: 180-200)

IIT group (n=765, BG: 80-100) vs. conventional (n=783, BG: 1802000

Intervention (N. target BG [mg/ dl])

IIT group (n=247, BG: 80-110) vs CG (n=290, BG:180-200)

Prospective randomised controlled

Design

Multi centre, randomised open-label

Trials showing no Benefits of IIT vs CG

Study population, N

Trial, author

Table 1: Trils showing Impact of glycemic Control in ICU

565

Consensus

140-180 mg/dl, <110 mg/dl, is not recommended, 110-140 mg/dl in post-CABG, uncomplicated surgical patients

Initiate IIT (continuous IV insulin infusion when BG level >180 mg/dl; Shortacting regular insulin, preferably with infusion pump; recheck BG before starting IIT in patients without diabetes, start insulin infusion at BG/100U/hour

Monitor capillary BG every 1 hour; If BG <70 mg/dl every 20-30 mins till hypoglycemia resolves, restart IIT in modified doses as necessary once BG rises

Criteria

Glycemic target

Initiating insulin therapy

Monitoring of blood glucose

Table 2: Recommendations by Associations 144-180 mg/ dl (MICU/ SICU patients), Intraoperative: 99-180 mg/ dl (patients with diabetes undergoing CABG) and Perioperative : 90180 mg/dl for most other surgical patients Initiate IIT (continuous IV insulin infusion) when BG level >180 mg/dl, other recommendations same as consensus

Do not use IIT to strickly control or normalize BG in MICU/SICU patients with or without diabetes

Initiate IIT (continuous IV insulin infusion) when BG>180 mg/dl

Initial monitoring should be done on hourly basis, 2 hourly once BG is stable

Initiate IIT (Continuous IV insulin infusion when BG>180 mg/dl

Frequent glucose monitoring in patients with IV insulin therapy, to minimize the risk of hypoglycemia

CDA

140-200 mg/dl, (MICU/SICU patients on insulin therapy)

ACP

140-180 mg/dl in patients with medical morbidity and 110-140 mg/dl for patients with surgical morbidity

API

140-180 tmg/dl, <110 mg/dl is not recommended

AACE-ADA

Frequent monitoring required in IIT patients

<180 mg/dl in patients with hyperglycemia with AMI or acute thrombotic stroke

ADS

Initiate IIT (continuous IV insulin infusion) when BG level >180 mg/dl

Close monitoring of BG in ICU patients with ACS

Initiate IIT (continuous IV insulin infusion when BG level >180 mg/dl

Every 1-2 hrs until BG values and insulin infusion rates are stable, Every 4 hrs thereafter

Contd...

90-140 mg/dl in ICU patients with ACS.

AHA

<180 mg/dl in ICU patients with severe sepsis

SSC

CRITICAL CARE 566

Starts SC insulin atleast 1-2 hr before discontinuing IV insulin or 15-30 min if rapid – acting analoges are used Once patient is stable and taking enteral / oral feeds, start transition, SC basal 1-2 hr prior to discontinuing IV insuloin Transition from IV Once patient is to SC insulin stable and taking enterl / oral feeds, start transition wherever needed, start SC insulin therapy at least 1 hour prior to discontinuing IV insulin therapy

Abbreviations: AACE-ADA: American Association of clinical endocrinologiss and American diabetes Associaiton; API: Association of Physicians of India; ACP: American College of Physicians; CDA: Canadian Diabetes Associaiton; ADS: Australian Diabetes Society; SSC: Surviving Sepsis Campaign; AHA: American Heart Association; CABG: Coronary Artery Bypass Grafting; MICU: Medical Intensive Care Unit; SICU: Surgical Intensive Care Unit; AMI: Acute Myocardial Infarction; IIT; Intensive Insulin Therapy; IV: Intravenous; ACS: Acute Coronary Syndrome; SC: Subcutaneous

AHA SSC ADS CDA ACP API AACE-ADA Consensus Criteria

567

REFERENCES

1. Godinjak A, Iglica A, Burekovic A, Jusufovic S, Ajanovic A, Tancica I, Kukuljac A.; Hyperglycemia in Critically Ill Patients: Management and Prognosis Med Arch 2015; 69:15760. 2.

Marina Verçoza Viana, Rafael Barberena Moraes, Amanda Rodrigues Fabbrin, Manoella Freitas Santos, Fernando Gerchman. Assessment and treatment of hyperglycemia in critically ill patients. Rev Bras Ter Intensiva 2014; 26:71–76.

Farnoosh Farrokhi, Dawn Smiley, Guillermo E. Umpierrez. Glycemic control in non-diabetic critically ill patients, Best Pract Res. Clin Endocrinol Metab 2011; 25:813–824.

4. Mala Dharmalingam : Glycemic control in Intensive Care Unit. Indian J Endocrinol Metab 2016; 20:415–417. 5. SK Todi. Glucose control in critically ill diabetic: Not so sweet. Indian J Crit Care Med 2016; 20:65-6. 6. JJ Mukherjee, PS Chatterjee, M Saikia, A Muruganathan, Ashok Kumar Das : Consensus Recommendations for the Management of Hyperglycaemia in Critically Ill Patients in the Indian Setting. JAPI 2014; 62:16-25. 7. Sukhminder Jit Singh Bajwa : Intensive care management of critically sick diabetic patients. Indian J Endocrinol Metab 2011; 15:349–350. 8. Sukhminderjit Singh Bajwa, Manash P Baruah, Sanjay Kalra, Mukul Chandra Kapoor: Guidelines on Inpatient Management of Hyperglycemia. medicine_update_2013/ chap35, apiindia: 164-169 9. Andrew John Gardner : The benefits of tight glycemic control in critical illness: Sweeter than assumed?. Indian J Crit Care Med 2014; 18:807–813. 10. ACE/ADA Task Force on Inpatient Diabetes. American College of Endocrinology and American Diabetes Association consensus statement on inpatient diabetes and glycemic control. Endocr Pract 2006; 12:458–68.

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Table 2: Recommendations by Associations

calories orally. It is recommended to start SC insulin therapy at least 1hr prior to discontinuing IV insulin therapy. When changing from IV to SC insulin it is better to start basal-bolus regimen and dose of insulin should be individualised.

Approach to Sepsis

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120

Gurinder Mohan, AP Singh, Ranjeet Kaur

•

INTRODUCTION

Sepsis is a clinical syndrome characterized by systemic inflammation due to infection. There is a continuum of severity ranging from sepsis to septic shock. Over 1,665,000 cases of sepsis occur in the United States each year, with a mortality rate up to 50 percent. Even with optimal treatment, mortality due to septic shock is approximately 40 percent and can exceed 50 percent in the sickest patients. Currently sepsis is diagnosed by clinical identification of an infection in a patient who meets the clinical criteria for systemic inflammatory response syndrome (SIRS). According to the international consensus definition published in 1991 (and reviewed in 2001) SIRS is defined by the presence of 2 or more criteria from a collection of clinical signs and laboratory investigations as follows:

Hepatic (bilirubin level).

At present, the SIRS criteria remain the current standard for identifying sepsis. In the 1991/2001 international consensus definitions, severe sepsis is defined as sepsis that leads to dysfunction of 1 or more organ systems, and includes the subset septic shock. Organ dysfunction variables are: •

Arterial hypoxaemia (PaO2/FiO2 ratio <300) with new pulmonary infiltrates

•

A new or increased oxygen requirement to maintain SpO2 >90%

•

Acute oliguria (urine output <0.5 mL/kg/hour for at least 2 hours)

•

Serum creatinine>176.8 micromol/L (2.0 mg/dL)

•

Coagulation abnormalities (INR >1.5 or aPTT>60 seconds) Thrombocytopenia (platelets [100,000/microlitre])

•

Temperature >38.3°C (101°F) or <36.0°C (96.8°F)

•

Tachycardia >90 bpm

•

Tachypnoea>20 breaths/minute or PaCO2 <4.3 kPa (32 mmHg)

•

Hyperglycaemia (blood glucose >7.7 mmol/L [>140 mg/dL]) in the absence of diabetes mellitus

• Hyperbilirubinaemia (total micromol/L [4 mg/dL])

•

Acutely altered mental status

•

Leukocytosis (WBC count >12x10^9/L [12,000/ microlitre])

Arterial hypotension (systolic BP <90 mmHg, mean BP < 65 mmHg, or reduction in systolic BP >40 mmHg from baseline)

•

Serum lactate >2 mmol/L (>18 mg/dL).

• Leukopenia microlitre]) •

(WBC

count

<4x10^9/L

[4000/

Normal WBC count with >10% immature forms.

The international consensus definitions have been updated in 2016 (Sepsis-3), and the Sequential (Sepsisrelated) Organ Failure Assessment (SOFA) criteria and ‘quick’ (q)SOFA criteria have been proposed to replace the SIRS criteria. The SOFA score is calculated based on the assessment of the following systems in the ICU setting: •

Respiratory (PaO2/FiO2 ratio)

•

Neurological (as assessed by the Glasgow coma scale)

•

Cardiovascular (mean arterial pressure [MAP] or administration of vasopressors)

•

Coagulation (platelet count)

•

Renal (creatinine level and urine output)

<100

10^9/L

bilirubin

>68.42

In the 1991/2001 international consensus definitions, septic shock is defined as: •

Arterial hypotension (systolic BP <90 mmHg, mean BP < 65 mmHg, or reduction in systolic BP >40 mmHg from baseline) persisting for at least 1 hour, despite adequate fluid resuscitation, or

•

Serum lactate >4 mmol/L (>36 mg/dL) after adequate fluid resuscitation.

The use of vasopressor agents to correct hypotension does not exclude shock. According to the 2016 international consensus definitions, septic shock is defined as sepsis with the following: •

Persistent hypotension requiring vasopressors to maintain mean MAP ≥65 mmHg, and

•

Serum lactate >2 mmol/L (>18 mg/dL) despite adequate volume resuscitation.

The 2016 international consensus definitions state that

and regularly until the patient improves.Elevated serum lactate highlights tissue hypoperfusion, and is most reliably assessed using an arterial blood gas (ABG) sample. Markers of inflammation including CRP and procalcitonin, are of use in determining clinical progress and response to therapy. The combination of procalcitonin, TREM-1 and CD64 expression appears to be superior to the use of any of these markers alone.

this group is associated with hospital mortality rates greater than 40%.

INITIAL EVALUATION

Investigations to identify the source of the infection: The source of infection may be immediately evident; for example, with classical signs and symptoms of pneumonia (purulent sputum, dyspnoea, tachypnoea, cyanosis) or peritonism (abdominal pain, guarding, distension, tenderness, absent bowel sounds). However, in many patients the origin must be actively sought. Diagnostic studies may identify a source of infection that requires removal of a foreign body or drainage to maximise the likelihood of a satisfactory response to therapy. Chest x-rays and ultrasound scans can be performed at the bedside..In patients at risk of, or with symptoms compatible with, bacterial endocarditis, a transthoracic or transoesophageal echocardiogram is useful.

To prognosticate and in selection of an appropriate level of care: Certain investigations carry prognostic value and can help determine the need for critical care. Lactate measurement is a useful assessment of perfusion once a diagnosis of sepsis has been established. High lactate carries adverse prognostic value if elevated to >2 mmol/L (>18 mg/ dL), and still worse outcomes are associated with levels >4 mmol/L (>36 mg/dL). Studies with trauma patients have evaluated lactate levels against Acute Physiology and Chronic Health Evaluation (APACHE) scores and lactate clearance rates and found lactate levels to be inferior. However, an APACHE score takes 24 hours to calculate. An alternative measure is serum procalcitonin levels. Some experts recommend the use of shock index (heart rate divided by systolic BP) as a predictor of requirement for critical care, with one group finding an index of >0.9 to be predictive. More recently, non-invasive impedance echocardiography has been shown, if a cardiac index of <2 is identified, to predict poor outcome.

INVESTIGATIONS

Initial investigations cover 4 purposes: 1.

Investigations to identify causative organisms: Identification of pathogens permits early broadening of spectrum in patients whose initial antimicrobial cover is inadequate, and narrowing of spectrum in those with sensitive organisms. Blood cultures should be taken immediately and preferably before antibiotics are started, provided their sampling will not delay administration of antibiotics. Ideally, at least one set should be taken percutaneously, and one set from any vascular access device that has been in situ for more than 24 hours. Other cultures (e.g. sputum, stool, and urine) should be taken as clinically indicated. Imaging studies performed promptly to confirm a potential source of infection. If no localizing signs are present, examination and culture of all potential sites of infection including wounds, catheters, prosthetic implants, epidural sites, and pleural or peritoneal fluid, as indicated by the clinical presentation and history, is required.If meningitis is suspected , a lumbar puncture (LP) for CSF microscopy and culture should be performed. If an enclosed collection such as an abscess or empyema is suspected, it is recommended that this be drained and cultured early in the course of the illness (within 6 hours following identification). Intubated patients in whom there is a suspicion of pneumonia should have tracheal aspirates, broncho-alveolar lavage, or protected brush specimens taken. Evaluation for organ dysfunction: This demands baseline assessment of liver function tests, an CBC, coagulation profile, serum creatinine, and blood urea. Serum electrolytes and glucose are frequently deranged, and should be measured at baseline

MANAGEMENT

Initial Resuscitation

Protocolized, quantitative resuscitation of patients with sepsis induced tissue hypoperfusion (defined as hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L) (grade 1C). Goals during the first 6 hrs of resuscitation (Early Goal Directed Therapy): a.

Central venous pressure (CVP) 8–12 mm Hg,

Mean arterial pressure (MAP) ≥ 65 mm Hg,

CHAPTER 120

As for all acutely ill patients, initial evaluation should follow the ABCDE format, to include assessment of the airway, respiratory, and circulatory sufficiency, and conscious level (Glasgow Coma Scale or AVPU [Alert, responds to Voice, responds to Pain, Unresponsive). Attention should be paid to seeking other signs of organ dysfunction (jaundice, purpura fulminans, cyanosis), and signs of circulatory insufficiency including oliguria, mottling of the skin, and prolonged capillary refill times. Oxygen saturation, respiratory rate, heart rate, BP, temperature, and accurate hourly fluid balance (including urine output) should be monitored. It is important to seek clinical evidence for the source of infection. This will aid diagnosis and provide vital information as to the patient’s risk factors for sepsis. Risk factors strongly associated with sepsis include: underlying malignancy, age >65 years, pregnancy, haemodialysis, history of alcoholism and diabetes mellitus.

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570

Urine output ≥ 0.5 mL/kg/hr,

Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively.

In patients with elevated lactate levels, targeting resuscitation to normalize lactate (grade 2C).

Antimicrobial Therapy

CRITICAL CARE

Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) as the goal of therapy. a.

Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B)

Antimicrobial regimen should be reassessed daily for potential de-escalation (grade 1B).

Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics (grade 2C).

Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp. (grade 2B).

Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known (grade 2B)

Duration of therapy is typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia (grade 2C).

Source Control

A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C). If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established (UG).

Infection Prevention

Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilatorassociated pneumonia (grade 2B).

HEMODYNAMIC SUPPORT AND ADJUNCTIVE THERAPY

Fluid Therapy of Severe Sepsis

Crystalloids should be used as the initial fluid of choice in

the resuscitation of severe sepsis and septic shock (grade 1B)..Albumin should be added to fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids (grade 2C). Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables (UG).

Vasopressors

Vasopressor therapy is initially to target a mean arterial pressure (MAP) of 65 mm Hg (grade 1C). Norepinephrine is used as the first choice vasopressor (grade 1B). Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure (grade 2B). Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage (UG). Dopamine is used as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia) (grade 2C).Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target (grade 1C). Low dose dopamine should not be used for renal protection (grade 1A). All patients requiring vasopressors have an arterial catheter placed as a trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP (grade 1C).

Corticosteroids

Intravenous hydrocortisone should not be used to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. In case this is not achievable, intravenous hydrocortisone should be used at a dose of 200 mg per day (grade 2C). In treated patients hydrocortisone should be tapered when vasopressors are no longer required (grade 2D). Corticosteroids should not be administered for the treatment of sepsis in the absence of shock (grade 1D).

OTHER SUPPORTIVE THERAPY OF SEVERE SEPSIS

Blood Product Administration

Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or

ischemic heart disease, red blood cell transfusion should be done only when hemoglobin concentration decreases to <7.0 g/dl to target a hemoglobin concentration of 7.0 –9.0 g/dL in adults (grade 1B). Erythropoietin should not be used as a specific treatment of anemia associated with severe sepsis (grade 1B). Fresh frozen plasma should not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures (grade 2D). In patients with severe sepsis, administer platelets prophylactically when counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures (grade 2D).

Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who have bleeding risk factors (grade 1B).

Mechanical Ventilation of Sepsis-Induced ARDS

Nutrition

Sedation, Analgesia, and Neuromuscular Blockade in Sepsis

Continuous or intermittent sedation should be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints (grade 1B).Neuromuscular blocking agents (NMBAs) should be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation (grade 1C).

Glucose Control

Insulin dosing should be commenced when 2 consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target a blood glucose of 140 – 180 mg/ dL. Blood glucose values should be monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter (grade 1C).

Renal Replacement Therapy

Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure (grade 2B).

Bicarbonate Therapy

Sodium bicarbonate therapy should not be used for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusioninduced lactic acidemia with pH ≥7.15 (grade 2B).

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Patients with severe sepsis should receive daily pharmacoprophylaxis against venous thromboembolism (VTE) (grade 1B). Septic patients who have a contraindication for heparin use should receive mechanical prophylactic treatment, such as graduated compression stockings or intermittent compression devices(grade 2C), unless contraindicated. When the risk decreases, start with pharmacoprophylaxis (grade 2C).

Stress Ulcer Prophylaxis

Oral or enteral (if necessary) feedings, should be administered rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C).

REFERENCES

1. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis.The Ibuprofen in Sepsis Study Group. N Engl J Med 1997; 336:912. 2. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-1256. 3. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 201623; 315:801-810. 4.

Coburn B, Morris AM, Tomlinson G, et al. Does this adult patient with suspected bacteremia require bloodcultures? JAMA 2012; 308:502-511.

Jimenez MF, Marshall JC. Source control in the management of sepsis. Intensive Care Med 2001; 27(suppl1):S49-S62.

6. Trzeciak S, Chansky ME, Dellinger PR, et al. Operationalizing the use of serum lactate measurement for identifying high risk of death in a clinical practice algorithm for suspected severe sepsis. A Cad Emerg Med 2006; 13:150-151. 7.

Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637-1642.

Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy :a randomized clinical trial. JAMA 2010; 303:739746.

9. Phua J, Koay ES, Lee KH. Lactate, procalcitonin and amino-terminal pro-B type natriuretic peptide versus cytokine measurements and clinical severity scores for prognostication in septic shock. Shock 2008; 29:328-333. 10. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms for antibiotic therapy decisions : a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011; 171:1322-1331.

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Tidal volume of 6 mL/kg predicted body weight should be kept in patients with sepsis-induced ARDS (grade 1A) vs. 12 mL/kg. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma) (grade 1B).Prone positioning should be used in sepsis-induced ARDS patients with a PaO 2/FiO 2 ratio ≤ 100 mm Hg in facilities that have experience with such practices (grade 2B). A weaning protocol should be in place and mechanically ventilated patients with severe sepsis should undergo spontaneous breathing trials regularly. If the spontaneous breathing trial is successful, consideration should be given for extubation (grade 1A). A conservative rather than liberal fluid strategy should be used for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion (grade 1C). In the absence of specific indications such as bronchospasm, beta 2-agonists should not be used for treatment of sepsis-induced ARDS (grade 1B).

Deep Vein Thrombosis Prophylaxis

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121

Sepsis - Old Wine in New Bottle?

INTRODUCTION

“Nothing endures but change” – eternal words by Heraclitus echo around, as the medical community endeavours to imbibe the revised definitions and diagnostic algorithms of “Sepsis-3”, the Third International Consensus Definitions for Sepsis and Septic Shock released by European Society of Intensive Care Medicine (ESICM) and the Society of Critical Care Medicine (SCCM) in 2016. Despite advances in intensive care and antimicrobial therapy, in last two decades, Sepsis continues to be the leading cause of death from infection. Sepsis, as a syndrome, refers to the complex interplay of pathogen’s virulence and host’s immune response leading to multifaceted changes in the host’s physiology and biochemical milieu that ultimately lead to organ dysfunction. The details of pathophysiology behind this complicated phenomenon remain poorly understood and the heterogeneity of presentation, course and outcome make it a daunting task to arrive at a precise consensus definition and diagnostic criterion.

BACKGROUND

The first definition of sepsis originated in 1992, and was defined as presence of at least two out of the four Systemic Inflammatory Response Syndrome (SIRS) criteria (Table 1). The definition lacked specificity and was revised in 2002, wherein a revised set of laboratory and clinical parameters were added to the criteria to define sepsis and organ dysfunction. In this revision organ dysfunction during sepsis was labeled as ‘Severe Sepsis’ and persistent hypotension despite fluid resuscitation was called ‘Septic Shock’. However, in the last decade the epidemiological as well as clinical utility of these definitions were questioned leading to formulation of a 19-member-Task Force commissioned under the aegis of ESICM and SCCM, in the year 2014. The Task-Force came out with the new definitions and the classification criteria

Puneet Saxena, Madabhushi Shyam

in 2016, now called “Sepsis-3”. This nomenclature and the authors of Sepsis-3 also emphasise that this is “a work in progress”. With the existing knowledge, understanding and evidence, it is impossible to work-out the “perfect definition” and classification criteria with acceptable sensitivity and specificity in all settings. With continued research and experience, as new evidence and information surfaces, it is hoped that the future generations of “sepsis definitions” will be closer to perfection than the existing one. This article will dwell upon these new changes, their basis and the concerns.

WHY WAS THE CHANGE REQUIRED?

An acceptable criteria for “sepsis” should have multiple characteristics, namely - reliability (valid for all kinds of settings, at all times without significant intra-observer and inter-observer variations), content validity (measure represents every single facet of the condition), construct validity (should be able to measure what they purport to measure), criterion validity (should improve upon the existing standards), measurement burden (economic, pragmatic and safe), and timeliness (should not delay the clinical care). The existing standards of defining and diagnosing sepsis, severe sepsis and septic shock had several pitfalls leading to conceptual misinterpretations as well as heterogeneity in surveillance studies and clinical trials. 1.

Problems with existing definition and SIRS criteria: The earlier proposition of defining sepsis with “the presence (probable or documented) of infection together with systemic manifestations of infection” and the qualifying criteria of presence of “at least two SIRS features” were deceptive because even uncomplicated infections may have systemic manifestations and SIRS features (as an appropriate host adaptive response). This created an illusory increase in the number of sepsis cases reported in epidemiological and statistical surveys and downplayed the severity of the condition. The SIRS criteria were found to be lacking both sensitivity and specificity.

A large number of patients in acute medical and surgical wards with infective illnesses would satisfy SIRS criteria without really being septic. These (fever, leukocytosis, tachycardia or tachypnoea) may represent appropriate host responses rather than a “dysregulated” one that can cause organdysfunction. Studies conducted in the West have shown that 68-93% patients admitted to acute and

Table 1: SIRS Systemic inflammatory response syndrome (SIRS) in adults requires 2 or more of the following : 1. Temperature >38 C or <36 C 2. Pulse >90/min 3. RR >20/min or PaCO2 <32 mmHg 4. WBC count >12,000/cmm or < 4000/cmm or >10% immature band forms

critical care wards may have 2 or more SIRS criteria positive, at some point during their stay in the hospital. Similarly, a considerable number of septic patients may not have 2 or more SIRS criteria positive. It has been shown that 1 in 8 ICU patients with infection and organ dysfunction do not have 2 or more SIRS criteria.

Also, the effect of pre-existing co-morbidities on SIRS parameters had not been addressed.

Limitations of “Septic shock” definition: The existing definition of “septic shock” focussed only on circulatory failure without taking into account the role of cellular metabolism dysfunction in sepsis. The existing criteria do not satisfactorily differentiate mere cardiovascular dysfunction from the more complicated and sinister “septic shock”.

Absence of screening tool: The importance of early suspicion of sepsis in the pre-hospital and emergency room setting cannot be over-emphasised as it has been unequivocally shown that early and appropriateness of treatment has significant bearing on outcomes. It was vital to formulate a screening tool that can assist the practitioners in the non-ICU environment to suspect sepsis early. Such a tool should be based on point-of-care assessment and thus SIRS did not fit the requirement.

SEPSIS 3: NEW DEFINITIONS AND CRITERIA

Aim of the New Definition and Criteria

The aims of the new definition and criteria are to assist medical practitioners to recognize septic patients early in the pre-hospital, emergency department as well as inhospital setting and equally important to aid researchers in designing clinical trials and reporting epidemiological analyses. The endpoint for formulating the new criteria was increased specificity for predicting mortality or ICU stay of > 3 days.

Definition of Sepsis

“A ‘life-threatening organ dysfunction dysregulated host response to infection”.

due

The earlier “SIRS criteria” in the definition of sepsis has been removed. More importantly, the new definition emphasizes that in septic patients the normal immunepathological host response becomes maladaptive creating disturbance in the homeostatic milieu, which will ultimately cause life-threatening organ dysfunction. It is this stormy host response that the future trials are likely to be focused on.

Diagnosis of Sepsis

The organ dysfunction in sepsis is recommended to be identified by ‘an acute change in total SOFA score (Sequential or Sepsis-related Organ Failure Assessment) ≥ 2 points consequent to infection’. Such a criterion reflects an overall mortality rate of approximately 10%.

Screening Tool

The Task Force also gave a screening tool for the prehospital or emergency room setting, for early identification of “potential septic” patients using an abridged SOFA score called qSOFA (for Quick SOFA). The qSOFA score (Table 3) eliminates the laboratory parameters of the detailed SOFA score and focuses on only three clinical variables - hypotension (systolic blood pressure ≤100mmHg), altered mental status and tachypnea (respiratory rate > 22/min): the presence of at least two of these criteria strongly predicts the likelihood of poor outcome in patients with clinical suspicion of sepsis in the non-ICU environment. It is reiterated that the role of qSOFA is only to raise suspicion of Sepsis. It is not a part of the definition of Sepsis. A patient with infection may have positive qSOFA but not fulfill the definition of sepsis because the parameters in qSOFA are different from the SOFA score (compare tables 2 and 3). Also, patient may have sepsis without fulfilling qSOFA because all organ dysfunctions (like coagulation/renal function) are not represented in qSOFA. Thus, qSOFA, although still unvalidated, appears to be a robust sepsis-screening tool in the pre-ICU setting but is not to be used to define sepsis or to rule it out. Its role is to encourage early suspicion of sepsis and prompt further action.

Septic Shock

Sepsis-3 has defined septic shock as a ‘subset of sepsis where underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality’. For making the diagnosis of septic shock the patient with sepsis should have the need for vasopressors to obtain a MAP≥ 65mmHg and an increase in lactate concentration > 2 mmol/L, despite adequate fluid resuscitation. This new definition differentiates septic shock from other forms of circulatory shock and reiterates the devastating impact of sepsis-induced cellular metabolism abnormalities. With these criteria, the in-hospital mortality of septic shock exceeds 40%. To increase the awareness about this life threatening condition and to encourage its early identification and treatment, the Task Force also endorsed a lay definition of sepsis as ‘a life-threatening condition that arises when the body’s response to infection injures its own tissue’.

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The baseline (SOFA) score (Table 2) is assumed zero unless the patient has a previously known co-morbidity (e.g. cirrhosis, chronic kidney disease, etc.) In ICU patients with suspected infection, SOFA was found to be a superior predictor of mortality in sepsis patients compared to SIRS, Logistic Organ Dysfunction System (LODS) score and other scores. The term “severe sepsis” which was earlier defined as “sepsis with evidence of organ definition” has now been removed because firstly, it is a misnomer considering that all septic patients are “severe” considering the high mortality and morbidity in “true sepsis” and secondly, because organ dysfunction as evidenced by SOFA score is now essential to label “sepsis”.

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Table 2: SOFA Score Organ System score

≥400 (53.3)

<400 (53.3)

<300(40)

<200 (26.7)with respiratory support

<100 (13.3) with respiratory support

Coagulation Platelets , x103/µL

≥150

>150

>100

>50

>20

Hepatic Bilirubin, mg/dL

<1.2

1.2-1.9

2.0-5.9

6.0-11.9

>12.0

13-14

10-12

6-9

MAP ≥70 mmHg

MAP <70 mmHg

Dopamine <5.0 or dobutamine (any dose) a

Dopamine 5.1-15 or epinephrine ≤0.1 or norepinephrine ≤0.1a

Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1a

<1.2

1.2-1.9

2.0-3.4

3.5-4.9

>5.0 or dialysis

Or <500 mL/24h

Or <200 mL/24h

Respiration PaO2/FiO2, mmHg(kPa)

CRITICAL CARE

CNS Glasgow Coma Scale Cardiovasc.

Renal Serum creatinine, µmol/l mg/dL Or urine output

Abbreviations: FIO2, fraction of inspired oxygen; MAP, mean arterial pressure; PaO2, partial pressure of oxygen. a

Catecholamine doses are given as μg/kg/min for at least 1 hour.

The PaO2/FiO2 ratio is calculated without reference to the use or mode of mechanical ventilation, and without reference to the use or level of PEEP. Glasgow Coma Score - For the patient receiving sedation or muscle relaxants, normal function is assumed unless there is evidence of intrinsically altered mentation).

from retrospective analysis of limited data. The evidence to support its usefulness as a sensitive tool to pick-up the diverse presentations of sepsis is lacking. A patient with isolated hypotension or altered mentation with underlying evidence of infection may be classified as uncomplicated infection (not having sepsis) which is potentially perilous. It is also unclear how to use qSOFA in patients with pre-existing illnesses that may affect the three parameters used (example - old stroke). Additionally, the qSOFA is recommended for nonICU settings. In the intubated and the mechanically ventilated patient, or in the patient with psychotropic substance abuse, an appropriate tool is still required. These patients are paradoxically at a higher risk for developing sepsis.

Table 3: qSOFA score 2 or more of: 1. Hypotension: SBP less than or equal to 100 mmHg 2. Altered mental status (any GCS less than 15) 3. Tachypnoea: Respiratory rate greater than or equal to 22

CONCERNS WITH “SEPSIS-3”

The Taskforce for Sepsis-3 admits that consensus could not be arrived at on all points, considering the complexity of syndrome, lacunae in knowledge and wide variations in clinical infrastructures and practices. Thus, few pragmatic compromises had to be made to facilitate generalizability and applicability. Following are the limitations of the new definitions/criteria which, though seemingly trivial, must be made note of before implementing the definitions in practice and research. 1.

The data utilized to formulate the sepsis-3 consensus definitions is primarily from Europe and United States. Data from the low-middle group nations is lacking. Though extrapolation seems intuitive, differences in the infection spectrum and the hospital infrastructure and set-up, poses questions on the validity of these definitions in the Indian setting. More validation studies, using Indian data are required to endorse the new definitions. The screening-tool qSOFA has been arrived at

The new criteria for defining sepsis may miss an evolving sepsis (when it is eminently treatable) and pick it up only at an advanced stage (after frank organ dysfunction has set in) and may thus delay the institution of prompt appropriate management. Since the endpoint of Sepsis-3 was predicting increased mortality and ICU stay beyond 3 days, this definition may encourage “waiting” rather than prompt aggressive management.

SOFA score needs to be revised in sync with existing practice guidelines. For example, in the cardiovascular score the order of introduction of

vasopressors is not in concordance with the existing guidelines. 5.

CONCLUSION

It is clear that the “Sepsis-3” does not address all the expected objectives of a “perfect” definition and “gold standard” criteria, which should ideally have unquestionable acceptability in clinical care, research, surveillance, and also quality improvement and audit. However, the adaptation of the new definitions will lay the foundation for further studies in the complex field of sepsis and will allow homogeneity in recruitment and pooling of data for generation of quality evidence. As of now, it is prudent to adapt to Sepsis-3 but hold strongly on to sound clinical judgment, in clinical care, which takes precedence over any guideline, scoring or criteria. With developments in genetics, genomics, immunology, and cellular biology, the understanding of sepsis syndrome

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REFERENCES

Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801–10.

Seymour CW, Liu VX, Iwashyna TJ. Assessment of Clinical Criteria for Sepsis For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:762–744.

3. Vincent J-L, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet 2013; 381:774-775. 4.

Kaukonen KM, BaileyM, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl JMed. 2015; 372:1629-1638.

Hernandez G, Castro R, Romero C, et al. Persistent sepsisinduced hypotension without hyperlactatemia. J Crit Care 2011; 26:435.e9-435.e14.

6. Thomas-Rueddel DO, Poidinger B,WeissM, et al. Hyperlactatemia is an independent predictor of mortality and denotes distinct subtypes of severe sepsis and septic shock. J Crit Care 2015; 30:439.e1-439.e6. 7. Kleinpell RM, Schorr CA, Balk RA. The New Sepsis Definitions: Implications for Critical Care Practitioners. American Journal of Critical Care 2016; 25:457-64. 8.

Kempker JA, Martin GS. The Changing Epidemiology and Definitions of Sepsis. Clinics in chest medicine 2016; 37:16579.

Shankar-Hari M, Deutschman CS, Singer M. Do we need a new definition of sepsis?. Intensive care medicine 2015; 41:909.

10. Drewry AM, Hotchkiss RS. Sepsis: Revising definitions of sepsis. Nature Reviews Nephrology 2015; 11:326-8.

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Septic shock has been defined by the presence of hypotension and hyperlactatemia. This approach may tend to miss cases of pre-shock or early shock that may have one of the two conditions and not both (hypotension with normal lactates or vice versa). Even with well-established shock pathology, it is well known that there is a subset of patients that do not develop hyperlactatemia. Additionally, serum lactate measurement may not be available in all care settings. The authors of sepsis-3 justify this concern by stating that presence of both the parameters significantly increases the mortality, compared to presence of only one of them. This does not imply that the energetic treatment will not be offered to patients with early or pre-shock. The definition will however have an important statistical role in designing clinical trials and studying epidemiological aspects of sepsis presentation and management outcomes.

is likely to improve and lead to sub-division into pathophysiologically distinct entities with targeted therapies. Thus, Sepsis-4 may incorporate specific biomarkers in its definition giving it a vital clinical role apart from being a mere epidemiological tool.

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Septic Shock: How Do I Manage? Pravat Kumar Thatoi

INTRODUCTION

Sepsis, the systemic maladaptive response to an infection manifested as complex immunological, metabolic and cardiovascular disorders that progress gradually. Increase in venous and arteriolar dilatation and cardiac depression lead to tissue hypo-perfusion. Organ dysfunction can be represented as an acute change in total qSOFA score â&#x2030;Ľ 2points consequent to the infection [quick SOFA= respiration rate > 22/min, altered mental status, systolic blood pressure < 100mmHg; each carries one point]. Septic shock is the state where vasopressor is required to maintain mean arterial pressure (MAP) > 65mmHg, and serum lactate level > 1.5 mmol/L in the absence of hypovolemia.

PATHOGENESIS

Sepsis is the culmination of complex interactions between the infecting microorganisms and the host immune, inflammatory, and coagulation responses. Both the host responses and the characteristics of the infecting organism influence the outcome of sepsis. The innate immune system responds rapidly by means of pattern-recognition receptors (e.g., toll-like receptors [TLRs]). Binding of TLRs to epitopes on microorganisms stimulates intracellular signalling, increasing transcription of pro-inflammatory molecules. Activated neutrophils release mediators that increase vascular permeability. Activated endothelial cells release nitric oxide, a potent vasodilator that acts as a key mediator of septic shock. These processes like intravascular volume depletion, peripheral vasodilatation, myocardial depression, and increased tissue metabolism lead to an imbalance between systemic oxygen delivery and oxygen demand, resulting in global tissue hypoxia or shock.

DIAGNOSIS

Diagnosis of septic shock is based on hemodynamic and biochemical changes. i.e.

clinical,

Clinical signs of tissue hypo-perfusion; cold and clammy skin, cyanosis, decreased urine output (less than 0.5ml/kg body weight per/hr) and altered mental status (obtundation, disorientation, and confusion).

Systemic arterial hypotension i.e. systolic blood pressure (SBP) < 90mmHg or MAP < 70mmHg, with associated tachycardia.

Increase in serum lactate level (more than 1.5mmol/L).

Early adequate hemodynamic support of patients in septic shock is crucial to prevent worsening organ dysfunction and failure. The investigations include: appropriate cultures (blood, urine etc.), routine investigations, serum lactate, serum procalcitonin, CRP, fungal antibody assay (1,3 beta-D-glucan assay, mannan & anti-mannan antibody assay, if available) where invasive candidiasis is in differential diagnosis of cause of infection. Imaging studies can be done to confirm the source of infection.

TREATMENT

Fluid resuscitation and early antibiotic therapy is the rule in treatment of septic shock. Aim is to administer antibiotics within one hour. In the mean time the patient has to be resuscitated, a diagnosis is made and microbiological specimens are taken. In emergency department (ED), patient to be resuscitated quickly according to VIP rule: ventilate (oxygen administration), infuse (fluid resuscitation) and pump (administration of vasoactive agents).

VENTILATION

Oxygen has to be given quickly, either by mask or if required endotracheal intubation and mechanical ventilation.

INFUSION

Patient is ideally given crystalloids (NS/RL) at the rate of 20-30 ml/kg in first hour and after that fluid to be infused accordingly. After each 250ml of fluid given, the patientâ&#x20AC;&#x2122;s chest has to be examined to avoid volume overload. Passive leg rising test may be done to ascertain the fluid requirement but this needs meticulous examination and sophisticated instruments like PICCO etc. Central venous pressure (CVP) has to be maintained between 8-12 cmH2O. In resource poor settings, thorough clinical examinations like heart rate, MAP, chest examinations and hourly urinary output can be done to judge fluid requirement.

PUMP

If still, MAP is not in optimal level vasopressors and inotropes are to be given. Nor-adrenalin is the vasopressor of choice followed by adrenalin, vasopressin, and dopamine at a dose given in the table 1. Dopamine has limited role as a vasopressor in septic shock, as there is risk of arrhythmias or if given, only in bradycardiac septic shock patients. The role of steroid is minimal in septic shock management. If given, it is hydrocortisone as continuous IV infusion totalling 200 mg/ 24 hours in patients where BP is poorly responsive to fluid

Table 1: Doses of commonly used Vasopressors and Inotropes Dose

Adrenalin

0.05-0.5 µg/kg/min

Nor-adrenalin

0.01-0.4 µg/kg/min

Vasopressin

0.04 units/min

Dopamine

5-20 µg/kg/min

Dobutamine

5-20 µg/kg/min

Levosimendan

6-12 µg/kg loading dose over 10 min followed by 0.05- 0.2 µg/kg/min as a continuous infusion.

resuscitation and vasopressor therapy. Ionotropic agents like dobutamine can be given by itself or in addition to vassopressors to the patients with cardiac dysfunction as evidenced by high-filling pressures and low cardiac output. Levosimendan, as an inotrope, is more expensive and acts primarily by binding to cardiac troponin C and increasing the calcium sensitivity of myocytes. However this agent is having a very long half-life, which limits the practicality of its use in acute shock states.

OTHERS

Antibiotics

With resuscitation of the patients, early appropriate antibiotics in the recommended doses to be given within first hour of arrival. Two or more antibiotics can be given according to micro-organism susceptibility patterns in the hospital or community. Once the culture or microbiologic identification is done, the antibiotic may be given according to the culture sensitivity report (De-escalation of antibiotic therapy). The care must be given to achieve the goals of therapy like; a.

CVP 8-12 cmH2O

Mixed venous oxygen saturation (Svo2) > 65%

MAP ≥ 65 mm Hg

Urine out-put > 0.5 ml/kg/hr

Normalization of serum lactate level i.e. less than 1.5 mmol/L where Svo2 measurement is not available.

In resource poor settings like distant peripheral hospitals, achieving MAP ≥ 65 mm Hg and urine output > 0.5 ml/kg/ hr justifies treatment.

Hand hygiene of the health care personnel, before and after touching the patients is very much crucial.

Nutrition

Early feeding is always beneficial, which prevents gut translocation of bacteria. Calorie requirement is 20-30 Kcal/kg/day, where carbohydrate source is 60%, proteins 20% and Lipids 20%. Electrolyte corrections, micro nutrients has definite role in sepsis management.

Organ Support

Organ support such as ventilator and renal replacement therapy often required at the time of respiratory failure and renal failure respectively.

Other Parameters

Other parameters to be optimized are like, blood and blood products are to be administered according to need (eg: to maintain haematocrit 30%). Albumin may be given in hypoalbuminemic patients. Glycemic controlkeeping blood sugar between 110-180 mg/dl, preferably by intravenous insulin infusion. Care must be taken to avoid hypoglycaemia. Proton pump inhibitors (PPI) and H2 receptor blockers are to be given for stress ulcer prophylaxis. Heparin, low molecular weight heparin (LMWH) and pressure stockings for deep vein thrombosis (DVT) prophylaxis. Head of bed should be elevated to 3045 degrees to prevent aspiration.

CONCLUSION

Septic shock is a life threatening condition, associated with high fatality rate. Prompt identification and appropriate treatment is mandatory for better outcome. Treatment should include airway management, hemodynamic stabilization and appropriate antibiotics in first hour of arrival of patients. Monitoring the response to therapy is crucial by careful clinical evaluation and blood lactate measurements.

REFERENCES

Singer M, Dutchman CS. The third international consensus definitions for sepsis and septic shock. JAMA 2016; 315:80110.

2. Dellinger RP, Levy MM. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine 2013; 41;2:580637. 3. Vincent JL, Backer DD. Circulatory Shock. NEJM 2013; 369;18;1726-34. 4.

Vincent JL, Rhodes A, Perel A, et al. Clinical review: update on hemodynamic monitoring- a consensus of 16. Crit care 2011; 15:229

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. NEJM 2003; 348:138-150.

Source Control

Control of source of infection in the form of drainage, debridement, and device removal gives better outcome.

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Name

Hand Hygiene

AKI in ICU – Diagnosis and Management

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Georgi Abraham, Neethu Venkitakrishnan

Acute kidney injury (AKI) is a rapid decrease in kidney function over hours to days, due to an an injury that causes functional or structural changes in the kidneys, resulting in inability to maintain acid-base, fluid and electrolyte balance and to excrete nitrogenous wastes. AKI is a complex disorder that comprises the entire spectrum of acute renal failure for which currently there is no accepted

Table 1: Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE) classification Class

Glomerular filtration rate criteria

Risk

Serum creatinine < 0.5 ml/kg/hour × 1.5 × 6 hours

Injury

Serum creatinine < 0.5 ml/kg/hour ×2 × 12 hours

Failure

Serum creatinine × 3, or serum creatinine ≥ 4 mg/dl with an acute rise > 0.5 mg/dl

Loss

Persistent acute renal failure = complete loss of kidney function > 4 weeks

End-stage kidney disease

Urine output criteria

< 0.3 ml/kg/ hour × 24 hours, or anuria × 12 hours

End-stage kidney disease > 3 months

definition. To establish a uniform definition for AKI, the ADQI formulated the Risk, Injury, Failure, Loss and Endstage Kidney (RIFLE) classification.RIFLE defines three grades of increasing severity of acute kidney injury- risk (class R), injury (class I) and failure (class F)- and two outcome classes (loss and end-stage kidney disease)(see Table 1). Here, the grades of severity of AKI is based on changes in either serum creatinine or urine output from their baseline condition over 7 days. The AKIN criteria formulated more sensitive criteria as given in Table 2 in which a 0.3mg/dl rise in creatinine over 48 hours was considered AKI. KDIGO in 2012 combined these two criteria and came up with the latest classification of AKI (Table 3).

ETIOLOGY OF AKI

Acute kidney injury is anatomically classified (Figure 1) into three categories: pre-renal causes (kidney hypoperfusion leading to low GFR), renal causes (intrinsic kidney diseases like glomerulonephritis GN,Acute tubular necrosis ATN, acute interstitial nephritis AIN etc) and post renal causes (obstructive uropathy or other obstruction to outflow). Identifying the cause is the step toward treating the patient.

GLOBAL STATUS AND INDIAN SCENARIO

The incidence rate of acute kidney injury (AKI) around the world is not well known Acute Kidney Injury is common, complicating 5% of all medical and surgical admissions

Table 3: KDIGO Criteria

Table 2: AKIN Classification AKIN CRITERIA Creatinine criteria

Urine output – Criteria

Creatinine – ≥0.3 mg/dl

UO <0.5 mL/ kg/h for 6 h

Stage Serum creatinine (SCr) criteria

Urine output criteria

<0.5 ml/kg/hour for >6 consecutive hours

Risk or Stage 1

Increase > 1.5 to 1.9 x reference SCr

Creatinine ≥150% and < 200% than baseline Injury for stage 2

UO <0.5 mL/kg/h for 12 h

Creatinine≥ 200% and <300% than Baseline Failure or stage 3 Creatinine ≥300% than baseline Or ≥4.0 mg/dl and ≥ 0.5 mg/dl

Increase >26 umol/l within 48 hours OR

UO <0.3 mL kg/h for 24 h, or anuria for 12 h

Increase ≥2 to 2.9 x reference SCr

Increase >3 x reference <0.3ml/kg/hr for >24 SCr OR hours or anuria for 12 hours increase >354u.mol/l OR

commenced on renal replacement therapy (RRT) irrespective of the stage

<0.5ml/kg/hour for >12 hours

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Intrinsic renal disease

Glomerular ● Glomerulonephritis

Tubular (obstruction and dysfunction) ● Ischaemic ATN ● Nephrotoxic ATN ● Myeloma cast nephropathy

Tubulointerstitial ● Drugs ● Myeloma ● Sarcoid

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Pre-renal (reduced renal perfusion) 1. Hypovolaemia + hypotension ● Diarrhoea/vomiting ● Inadequate fluid intake ● Blood loss through trauma ● “Third space” fluid losses 2. Reduced effective circulating volume ● Cardiac failure ● Septic shock ● Cirrhosis 3. Drugs ● ACE-I ● NSAIDs 4. Renal artery stenosis

Single nephron

Plost-renal ● Renal papillary necrosis ● Kidney stones (at any level) ● Retroperitoneal ﬁbrosis ● Carcinoma of the cervix ● Prostatic hypertrophy/malignancy (including retroperitoneal spread) ● Urethral strictures

Fig. 1: Anatomical classification of acute kidney injury and its causes in a large American study. Age wise 17 cases annually per million population aged 16-50 years rising to 949 cases annually per million population in those aged 80-89 years. The relatively wide disparity in reported incidence rates and the increasing frequency of the condition raise concerns as to the real magnitude of the problem. It is recognized that the epidemiology of AKI in developing countries differs from that of the developed countries in many important ways.Whereas in developed regions elderly patients predominate, in developing countries, AKI is a disease of the young and children but the trend shows an increasing incidence in older population in India as diagnostic tools are available in secondary care

private and government hospitals.The case of critically ill patients in ICU involves effective multi disciplinary approach, evidence based practice protocols and clear communications with patients relatives and cost effective modalities of treatment. Overall mortality seems to be lower in developed countries, However in developing countries while taking age group into consideration, among children and the young, mortality is high. In developing countries, the most common causes of AKI are frequently seen with volume-responsive “prerenal”, obstetric, infectious, or toxins thus inexpensive, simple interventions such as education on oral rehydration, improved cross-cultural

CRITICAL CARE

580

Fig. 2: Clinical course and biochemical parameters and biopsy picture interaction with traditional healers, change in obstetric management policies, or management of infection may result in a dramatic reduction in the incidence and severity of AKI. Renal causes like acute glomerulonephritis, both primary and secondary to infectious diseases appears to be higher than in developed countries. Malaria represents an especially important problem. There is an upsurge in worldwide malarial incidence. In India, for example, the overall yearly incidence is 13 to 17.8% of malarial cases. Given that in developing countries the costs of renal replacement therapies are prohibitively high, prevention is often the only realistic way to decrease the incidence of AKI.

HOW IS AKI IN ICU DIFFERENT FROM OTHER HOSPITAL SETTINGS?

AKI is very commonly encountered in ICU, medicine and surgical settings. It is common in critically ill patients and occurs in 18-65% of adult patients admitted in ICU. Upto 20% of patients who develop AKI require Renal replacement therapy (RRT) in ICU and carry high mortality,in excess of 50 percent. While the critically ill AKI patients have varible presentation:some have multiple organ failure, sepsis, hypervolemia, acute respiratory distress and underlying co-existing CKD. Patients with ischemic stroke who may have multiple medications and nutritional needs requires special attention. Consequently clinicians must distinguish patients who may recover spontaneously from those who will require renal replacement therapy (RRT). In addition, the benefits of RRT must be weighed against its inherent risks. Similarly, different schools of thoughts still exist regarding the choice of type of dialysis-haemodialysis or peritoneal dialysis in ICU settings. BP targets of 65 to 70 mm Hg vs 80 to 85 mm Hg inpatient with septic shock, a large randomized clinical trial conducted in France (sepsis and mean arterial pressure trial) did not show a benefit to higher blood pressure targets. In patients with chronic hypertension there is a significant interaction between BP and renal outcomes. In patients with chronic

hypertension those randomized to the higher BP target had lower rates of doubling of serum creatinine and the need for renal replacement therapy over the first seven study days. Here we describe AKI in a heart transplant recipient in the immediate post operative period who was critically ill. A female medical doctor 40 years age weighing 75 kg, with hypertrophic non-obstructive cardiomyopathy who was previously implanted with intracardiac defibrillator has undergone cardiac transplantation on july 13, 2016 Cold ischemia time was 249 minutes. She was inducted with with Basiliximab 20mg (two doses) and maintenance immunosuppression included tacrolimus, mycophenolate mofetil and prednisolone. Postoperatively she developed fever with non-oliguric AKI and sepsis. Inotropes and ventilatory support were continued. X ray chest showed bilateral lower zone infiltrates. Blood cultures and central venous catheter tip culture revealed growth of Burkholderia cepacia. She was treated with tigecycline 50 mg once a day and meropenam 500 mg once daily as per the renal dose. On the third postoperative day she developed acute pulmonary edema and hypotension. Echocardiography confirmed cardiac tamponade. She was re-explored and 500ml fresh blood with clots were evacuated from pericardium. Tenckhoff Swan-neck double-cuff peritoneal dialysis (PD) catheter was implanted. Low volume intensive PD was commenced with 750ml, 30 minutes dwell time and alternating 1.5 %, 2.5% and 4.25 % dianeal dialysis solution to produce adequate ultrafiltration to decongest the lungs. Dedicated peritoneal dialysis nurses manually did exchanges. Fill volume was not increased to prevent pericatheter leakage. Patient continued to have recurrent episodes of pulmonary edema for continuous supine peritoneal dialysis was continued with the low volume and short dwells till the eighteenth postoperative day. Endomyocardial biopsy was done on the fifteenth postoperative day which showed nonspecific inflammation and no evidence of acute rejection. Acute

Another issue is that in ICU, AKI is a common accompaniment in multiple organ failure. It is not uncommon for critically ill patients to be on multiple supports including inotropes and ventilators. Similarly, when the AKI is due to sepsis and multi organ failure, thrombocytopenia, coagulation abnormalities and bleeding from various sites are common, need for anticoagulation during extra corporeal therapies adds to bleeding risk. PD offers a significant advantage of not needing anticoagulation and a bedside single access with a flexible catheter. Hyperchloremic metabolic acidosis is the leading cause of acidosis in the early stages of AKI. This is due to the decreased regeneration of bicarbonate by the kidneys with an inability to excrete ammonium ions. Later, the accumulation of anions, such as phosphate, sulphate,urate ,hippurate,propionate, and oxalate, may lead to high anion gap acidosis. Lactic acidosis is also common in critically ill patients with AKI in shock. There is uncertaintly about the need to correct mild to moderate metabolic acidosis in the setting of AKI, further more, studies do not support the routine use of sodium bicarbonate infusion to treat lactic acidosis. However most experts believe that the use of bicarbonate is appropriate in patients with severe lactic acidosis and appropriate in patients with severe lactic acidosis and academia (arterial PH <7.1). Such severe academia may produce hemodynamic instability as a result of reduced left ventricular contractibility, arterial vasodilation, and impaired responsiveness to catecholamines.

What is sepsis

Sepsis : Life threatening organ dysfunction due to dysregulated host response infection. Clinical criteria. An increase in the sequential (sepsisrelated) organ failure assessment (SOFA) score of 2 points or more due to infection itself. Rationale : This increase in SOFA score is associated with in hospital mortality > 10% Septic shock : A subset of sepsis in which circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Clinical criteria : Need for vasopressor therapy to maintain

mean arterial pressure > 65 mm Hg and serum lactate > 2 mmol/L after volume resuscitation.

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Rationale : patients who meet these clinical criteria have inhospital mortality rates >40%.

Intra – abdominal hypertention

Intra abdominal pressure (IAP) is the steady state pressure concealed within the abdominal cavity Normal value ranges from 0 to 5 mm Hg in healthy adults. Intra-abdominal hypertension (IAH) and abdominal compartments syndrome are increasingly recognized in both medical and surgical critically ill patients are predictive of death and the development of AKI. Although there are many risk factors for the development of IAH, in the era of goal–directed therapy for shock, brisk volume resuscitation and volume overlad are the most common contributors.Lowering intra-abodiminal pressure and increasing abdominal perfusion pressure may ameliorate or prevent AKI. Liberal use of vasopressors and volume removal can improve AKI and the resolve distend end organ effects of IAH.

MANAGEMENT

AKI in ICU the leading cause is sepsis. The initial clinical approach is identical in all patients- a thorough history and examination with simultaneous treatment of any life threatening features (severe hyperkalaemia > 7.5 mmol/L). Subsequent management should focus on determining the cause, which may demand specific treatment, maintaining the patient’s volume status, and avoiding further nephrotoxic insults (Figure 3).

Clinical approach to patients

The twin foundations of the approach to the patient with AKI are to: 1.

Treat any life threatening features: Hypotension, shock and respiratory failure should be immediately apparent when assessing the patient, and clearly these demand urgent treatment. Hyperkalaemia is less likely to be immediately obvious. Unless changes are evident on ECG or cardiac monitoring, it will only become apparent when chemistry is available.

Identify any cause of AKI that warrants specific treatment : Many patients with AKI present with other diagnoses. Dehydration secondary to gastrointestinal losses, pneumonia, bowel obstruction, and new impairment of functional capacity in the elderly patient are often the initial “on take” diagnose and a diagnosis of kidney injury is only made when laboratory parameters are available later. The clinician should then ask themselves the following questions:

Diagnosis of AKI in ICU

Critical care ultrasound can meaningfully expedite and improve the diagnosis of the underlying cause of organ dysfunction in the critically ill. Critical care ultrasound is not a replacement for formal imaging studies. Critical care ultrasound applications that may be of particular

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PD was converted to Continuous ambulatory peritoneal dialysis (CAPD) from nineteenth postoperative day. Tacrolimus levels were monitored and dosages were adjusted accordingly. Patient gradually recovered from sepsis and fluid overload. As patient developed a pericatheter leak on the twenty third postoperative day, peritoneal dialysis was stopped and PD catheter was removed. Echocardiography on discharge showed a left ventricular ejection fraction of 50%. Patients renal function recovered by twenty eighth postoperative day. The sequential renal function, immunosuppressive agents and clinical course are depicted in Figure 2. The total cost of peritoneal dialysis during the hospital stay of 30 days was Rs.35000.

Potential work flow for use in high risk for AKI 582

Patients at risk for AKI

Follow KDIGO AKI guideliness

CRITICAL CARE

RAI = Renal Angina Index (defined as >200% Increase in creatinine 72hrs

Use RAI and/or Biomarkers to assess AKI risk

High risk or develop early AKI

Use furosemide stress test and /or Biomarkers to assess risk of severity

low risk or no AKI

High risk or develop early AKI Negative Biomarkers or FS T

    



Continue to follow the KDIGO guidelines Avoid nephrotoxic drugs Ensure Volume status Ensure MAPs/Renal Perfusion Avoid Hyperglycemia Continue to serially monitor creatinine and urine Consider dose adjustment of renalexcretion medication

  

 

Consider early nephrology involvement Stop/Prevent further nephrotoxic agents Early interventions to treat AKI (RRT, optimize fluid status, decrease volume overload) Proactive Adjustment of Drug dosing Enroll in AKI therapeutic trials.

Fig. 3: Potential work flow for use in high risk for AKI relevance to the nephrologist include renal ultrasound in patients at high risk for urinary tract obstruction, real time ultrasound guidance and verification during the placement of central venous catheters, and ultrasoundaugmented assessment of shock volume status. Improved AKI risk stratification techniques need to be developed as they may be used to better inform timing decisions for RRT initiation and AKI therapeutics. Several AKI risk prediction scores and kidney specific scoring models have been developed and validated in the setting of cardiac surgery: however most of these scores fail to predict milder form of AKI. Many novel AKI risk assessment techniques have been developed over the past 5 – 10 years including Renal Angina Index, functional and damage biomarkers, and the furosemide stress test: however these methods still require large scale validation. Urinary levels of tissue inhibitor of metalloproteinase 2 (TIMP-2) and Insulin like growth factor binding protein 7 (IGFBP 7) is approved to detect a early severe AKI in the new era of biomarker utilization. IL- 18, KIM – 1 cystatin C are other biomarkers for early detection of contrast induced AKI. Currently available risk scores to predict AKI are often not sensitive or specific enough to identify high risk individuals and poorly predict AKI progression. With early administration of appropriate antibiotics, volume resuscitation, and source control, mortality has declined from sepsis. Early goal- directed therapy with central venous pressures monitoring is not needed in all patients.

Dynamic ultrasound measurement of inferior vena cava (IVC) half shown to predict volume responsiveness in shock. IVC respiratory variation in mechanically ventilated patients with septic shock (SBP < 90 mm Hg or use of vasopressors showed absolute IVC distensibility was found to be predictive of volume responsiveness to shock (distensibility of 12%). IVC collapsibility of > 40% should prompt the clinician to administer a fluid challenge, but collapsibility of < 40% is not helpful. Low tidal volume ventilation is lifesaving for patients with the acute respiratory distress syndrome : additional studies are needed to confirm the potential benefit of prone positioning and neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome. Proton pump inhibitors should be used judiciously for gastrointestinal prophylaxis, given an increased risk of acute kidney injury and incident CKD, along with an increased risk of Clostridium difficle infection. Serum creatinine and urinary output have inherent limitations in the early diagnosis of AKI. In patients who are critically ill in ICU, the measured serum creatinine may under estimate the GFR and hence a correction should be done to over come the limitation. Correction factor for Creatinine in volume overload. Adjusted serum creatinine = Serum creatinine ×correction factor,where correction factor = [hospital admission weight (kg) ×0.6] + Σ(daily cummulative fluid balance (L))] Hospital admission weight ×0.6.

Table 4: Advantages and disadvantages of intermittent versus continuous renal replacement therapy Intermittent haemodialysis Advantages

Continuous therapy

Lower risk of Better systemic bleeding haemodynamic stability

may lead to increased utilization of this modality of renal replacement therapy. With early administration of appropriate antibiotics volume resuscitation, and source control, mortality has declined from sepsis. Early goal- directed therapy with central venous pressures monitoring is not needed in all patients.

Better fluid control Better biochemical control

Low tidal volume ventilation is lifesaving for patients with the acute respiratory distress syndrome : additional studies are needed to confirm the potential benefit of prone positioning and neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome..

More suitable for severe hyperkalaemia

Better pulmonary gas exchange

Lower cost

Improved nutritional support

Proton pump inhibitors should be used judiciously for gastrointestinal prophylaxis, given an increased risk of acute kidney injury and incident CKD, along with an increased risk of Clostridium difficle infection.

Shorter stay in ICU Disadvantages More difficult haemodynamic control

Higher risk of systemic bleeding

Availability of dialysis staff

Greater vascular access problems

Inadequate dialysis dose