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Mechanical Ventilation Strategies for Lung Protection Neil R. MacIntyre, M.D.

ABSTRACT A large body of animal literature has shown that lungs stretched beyond their normal maximum are likely to be injured and release inflammatory cytokines into the systemic circulation. Moreover, this injury seems to be compounded if alveolar collapse also occurs. This has give rise to the notion that adequate positive end expiratory pressure (PEEP) to prevent derecruitment coupled with a tidal volume–PEEP combination that limits maximal distention to below the normal maximum is the ideal way to provide positive pressure ventilatory support. Some have argued that static pressure-volume plots to describe upper and lower inflection points are particularly important in implementing this approach. Supporting this concept is the recently completed NIH trial showing improved survival in acute respiratory distress syndrome (ARDS) when a small tidal volume strategy was used. Key Words: Ventilator-induced lung injury, pressure-volume plots, overdistention injury, alveolar recruitment, volutrauma

LUNG INJURY FROM POSITIVE PRESSURE VENTILATION Numerous animal studies have shown that the lung is subject to physical injury during mechanical ventilation.1–16 Two mechanisms appear important in producing this injury. The first is a physical stretch injury resulting from lung regions being inflated beyond their physiologic maximum. This produces a tissue injury characterized by inflammation, edema formation, hyaline membranes, and the release of inflammatory mediators into the circulation. Lungs with a heterogeneous distribution of disease are at particular risk for this injury because healthier regions will be preferentially overdistended when a positive pressure breath is delivered

(Fig. 1). The second mechanism is a shearing injury from repeated opening and closing of atelectatic but potentially recruitable alveoli in an injured lung. The use of expiratory pressure to prevent alveolar derecruitment can ameliorate this injury.17–19 To minimize this injury potential, mechanical ventilation goals should be twofold. The first goal should be to provide enough positive end expiratory pressure (PEEP) to recruit the “recruitable” alveoli while at the same time not applying so much PEEP that healthier regions are unnecessarily overdistended. The second goal should be to avoid a PEEP–tidal volume(VT) combination that unnecessarily overdistends lung regions at end inspiration. These goals embody the concept of a “lung protective” mechanical ventilatory strategy.1,20–22

Objectives Upon completion of this article, the reader will be able to understand the mechanisms of ventilator induced lung injury and the various ways to limit it. Accreditation The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. Credit The University of Michigan designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award.

Duke University Medical Center, Durham, North Carolina Reprint requests: Dr. Neil MacIntyre, Box 3911, Duke University Medical Center, Durham, NC 27710. Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 760-0888. 1069-3424,p;2000,21,03,215,222,ftx,en;srm00029x

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Figure 1. Schematic showing how healthier lung regions are subjected to regional overdistention in heterogeneous lung injury.

DETERMINING UNDERRECRUITMENT AND OVERDISTENTION IN THE LUNG Conceptually, the upper and lower inflection points on a static pressure volume (PV) plot should be the best guide to determining lung recruitment

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and overdistention (Fig. 2).23–27 These inflection points are thought to represent the attainment of optimal recruitment (rise in compliance at the lower inflection point) and the development of overdistention (reduction in compliance at the upper inflection point). However, the “whole lung” PV plot that is clinically available reflects an amalgam of the mechanical properties of numerous lung regions with potentially widely varying regional PV relationships. It thus may be overly simplistic to assume that the measured lower and upper inflection points represent the ideal points to set PEEP and VT. Another concern with the static PV plot is that it is technically difficult to perform and often requires heavy sedation or paralysis. A new technique, the single breath “slow flow” pressure volume measurement (so called because the slow inspiratory flow minimizes resistive pressures so that a single dynamic measurement can approximate the true static plot) may make this mechanical assessment more clinically useful.28 Even without complex PV assessments, clinicians can still use routinely monitored parameters to assess the risk of overdistention and underrecruitment. Conceptually, overdistention is likely to occur when lung regions are subjected to transalveolar pressures exceeding the normal physiologic maximum of 30–35 cm H2O. Indeed, animal studies have almost uniformly verified the importance of exceeding this “stretch” level in producing lung injury.1–16 In mechanically ventilated patients, the end inspiratory in-

Figure 2. A static pressure volume plot showing lower (A) and upper (B) inflection points during the inflation phase. The lower inflection point represents attainment of maximal compliance and thus optimal recruitment. The upper inflection point represents the onset of a reduction in compliance and thus overdistention. The deflation limb is shifted leftward due to hysteresis properties (surfactant function) of the lung. Conceptually, a lung protective strategy should have PEEP above the lower inflection point and the PEEP–VT combination below the upper inflection point.


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traalveolar pressure (reflected in the “plateau” airway pressure under no-flow conditions) is a reasonable approximation of transalveolar pressure if chest wall compliance is near normal. In patients with abnormal chest wall compliance (e.g., bindings, obesity), however, the plateau pressure may grossly over estimate transalveolar pressure.29 An esophageal balloon to measure pleural pressure can be helpful under these conditions. Determining adequate recruitment may be more problematic. Static compliance improvements from changes in ventilator settings correlate with improved recruitment, but these measurements are time consuming and may require patient sedation/paralysis.27 Fortunately, gas exchange improvements also generally correlate with improved recruitment27 (Fig. 3), and the PaO2/FiO2 ratio is often used as a surrogate for recruitment assessment. It must be remembered, however, that pressures required for recruitment of the sickest regions may produce overdistention in healthier regions (recall Fig. 1). Aggressive recruitment strategies with positive airway pressure must thus be balanced against the risk of producing overdistention injury.

Figure 3. Measurements of PaO2, shunt (Qs/Qt), respiratory system compliance, and O2 transport as PEEP is increased. “Best PEEP” is defined as that level of PEEP providing maximal O2 delivery. Note that PaO2 and shunt improvements correlate with respiratory system compliance improvements below “Best PEEP.” However, above “Best PEEP,” although gas exchange continues to improve, compliance begins to fall as lung overdistention develops and O2 delivery falls as cardiac output is reduced by the excessive intrathoracic pressures. (From Ref. 27, with permission.)

MECHANICAL VENTILATION STRATEGIES FOR PROVIDING LUNG PROTECTION MODES Generally, severe respiratory failure is managed during the acute phases with an assist control mode of ventilation. This ensures that all breaths have positive pressure supplied by the ventilator to provide virtually all the work of breathing.22 Choosing pressure versus flow/volume targeted ventilation for total support depends on the clinical situation. Flow/volume targeted ventilation guarantees a certain tidal volume. This in turn gives clinician control over minute ventilation and CO2 clearance. Under these conditions, however, airway and alveolar pressures are dependent variables and will rise or fall depending on changes in lung mechanics or patient effort. Worsening of compliance or resistance can thus cause abrupt increases in airway and alveolar pressures. Pressuretargeted ventilation, on the other hand, does not guarantee volume but rather controls airway pressure. Volume is thus a dependent variable and will change as lung mechanics or patient efforts change. Worsening of compliance or resistance with pressure-targeted ventilation results in a loss of volume. Pressure-targeted ventilation also has a variable decelerating flow wave form that may improve gas mixing30 and may interact with any patient efforts more synchronously. The choice of pressure versus volume-targeted breaths depends on which feature is required for the clinical goal. Specifically, if CO2 clearance is of primary concern and patient comfort and lung stretch are less of an issue (e.g., mild lung injury with a cerebral mass lesion), flow/volume targeted ventilation would be preferable. On the other hand, if overdistention risk is high and/or patient synchrony is more of an issue than CO2 clearance (e.g., severe acute respiratory distress syndrome (ARDS) with normal cardiac and neurologic function), pressure-targeted ventilation is probably the correct choice. There are several ventilator modes that offer pressure targeting and volume cycling features.31 Although these modes do offer the decelerating wave form of pressure-targeted breaths and thus may help patient comfort and gas mixing, the volume guarantee means that pressure must increase if lung mechanics worsen. Thus, although these breaths in these modes have pressuretargeting features, they are not pressure limiting.

FREQUENCY-TIDAL VOLUME SETTINGS The tidal breath, in conjunction with the baseline pressure, should be set in such a way that the

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plateau pressure is <30–35 cm H2O (or some other index of over distention does not occur). Generally, this involves VT of 7–9 mL/kg, although VT as low as 5–6 mL/kg may be needed. Older strategies of using higher tidal volumes arose from a need to prevent atelectasis. Now that PEEP strategies are better understood and the risk of overdistention better appreciated, this need has disappeared. The set ventilator frequency is generally used to control the CO2. A reasonable starting point is a normal frequency of between 12 and 20 breaths/min. Increasing the frequency will increase minute ventilation and generally will increase CO2 clearance. At some point, however, air trapping will develop because of inadequate expiratory times. Under these conditions, minute ventilation will either start to fall off (pressure-targeted ventilation) or airway pressures will start to rise (volume-targeted ventilation). In general, this begins to happen at breathing frequencies of approximately 35 breaths/min, although it can occur at much lower frequencies if the inspiratory to expiratory ratio is high or the time constant for lung emptying (resistance  compliance) is very high. In an effort to provide overdistention protection, alveolar ventilation may be compromised and hypercapnia can develop (“permissive” hypercapnia). As long as the pH remains above 7.1–7.2, this appears well tolerated in most patients (exceptions might include central nervous system injuries and unstable cardiovascular systems).32 A new technique, tracheal gas insufflation, flushes the endotracheal tube free of CO2 during expiration and may be helpful under these circumstances.33

itive pressure breath. In this sense, PEEP acts to prevent derecruitment. It then should follow that the initial application, a reinstitution or an increase in PEEP should be accompanied by a “volume recruitment” maneuver.21,34 Recommended strategies include lung inflation to near maximum (i.e., pressures of 30–40 cm H2O) for 30–60 seconds.21 Determining the proper PEEP level can use either mechanical criteria or gas exchange criteria. Mechanical criteria involve assessments that attempt to ensure that PEEP recruits “recruitable” alveoli but not overdistends alveoli already recruited. Two approaches have been reported: use pressure volume curves to set the PEEP above the lower inflection point on the PV curve (see above and Fig. 2) and use step increase in PEEP to determine the PEEP level that gives the best compliance. As noted previously, both approaches are technically challenging and time consuming. Gas exchange criteria to guide PEEP application involve balancing PaO2 goals, FiO2 goals, and lung distention goals. In general, these strategies provide some minimal level of PEEP at one extreme (e.g., a minimal PEEP of 5 cm H2O is unlikely to produce overdistention) and some maximal level of PEEP at the other extreme (e.g., a maximal PEEP of 25 cm H2O will still maintain plateau pressures < 30–35 cm H2O with a minimal VT). In between these extremes, PEEP and FiO2 are adjusted to maintain an oxygenation goal. An example is given in Table 1. Note that this approach may not produce the maximal PaO2/FiO2 ratio or the minimal shunt. This trade-off, however, may be important in providing lung protection from overdistention.

PEEP/FIO2

INSPIRATORY:EXPIRATORY TIMING

The goal of PEEP application is to maintain patency of alveoli that are opened (recruited) by a pos-

Setting the inspiratory time and the inspiratory to expiratory ratio (I:E) involves several considera-

Table 1. The PEEP–FiO2 Algorithm Used in the NIH ARDS Network Ventilation Management Trial OXYGENATION GOALS Acceptable Oxygenation 55  PaO2  80 or 88  SpO2 < 95 PEEP 5 PEEP 8 PEEP 10 PEEP 12 PEEP 14 PEEP 16 PEEP 18 PEEP 20 PEEP 22–24

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FiO2 0.3

FiO2 0.4

FiO2 0.5

FiO2 0.6

FiO2 0.7

FiO2 0.8

FiO2 0.9

FiO2 1.0

***** ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2

***** ***** ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2

↑ PEEP ***** ***** ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2

↑ PEEP ↑ PEEP ***** FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2

↑ PEEP ↑ PEEP ***** ***** ***** ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2

↑ PEEP ↑ PEEP ↑ PEEP ↑ PEEP ***** ↑ FiO2 ↑ FiO2 ↑ FiO2 ↑ FiO2

↑ PEEP ↑ PEEP ↑ PEEP ↑ PEEP ***** ***** ***** ↑ FiO2 ↑ FiO2

↑ PEEP ↑ PEEP ↑ PEEP ↑ PEEP ↑ PEEP ↑ PEEP ***** ***** ***** Max. Rx.


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tions. The normal I:E ratio is roughly 1:2–1:4. This produces the most comfort and thus is the usual initial setting. Assessment of the flow graphic should also be done to ensure that an adequate expiratory time is present to avoid air trapping. I:E prolongation beyond the physiologic range of 1:2 to 1:4 can be used as an alternative to increasing PEEP to recruit lung units and improve ventilation perfusion relationships in severe respiratory failure.35–37 Generally, inspiratory time prolongation is reserved for patients in whom the plateau pressure from the PEEP–VT combination has approached 30–35 cm H2O and/or potentially toxic concentrations of FiO2 are being used without meeting SaO2 or oxygen delivery goals. Inspiratory time prolongation has several important physiologic effects. First, a longer inspiratory time results in a longer alveolar-conducting airway gas mixing time. Second, a longer inspiratory time can give slower filling alveolar units time to be ventilated and recruited. Finally, if expiratory time is inadequate for lung emptying, air trapping and intrinsic PEEP (PEEPi) can develop.38 A number of studies have shown improved gas exchange as a consequence of longer inspiratory times, but sorting out which physiologic mechanism is responsible is not clear. Indeed, long inspiratory times without air trapping have been shown in one study to improve PaO2, whereas others have argued that improved PO2 occurs only as a consequence of PEEPi development. Several other aspects of long inspiratory times strategies need to be considered when using this technique. First, the development of air trapping has different effects on pressure- versus volume-targeted ventilation. Second, although long inspiratory times are often used with pressure controlled breaths to use the rapid initial flow pattern and the pressure-limiting feature, long inspiratory time strategies have also been used with volume-targeted breaths, generally by adding an inspiratory pause. Third, long inspiratory time will increase mean airway pressure and thus can reduce cardiac filling. Fourth, in the presence of air trapping, the mean alveolar pressure will be higher than the mean airway pressure, making monitoring of intrathoracic pressure more difficult. Fifth, lengthening the inspiratory to expiratory ratio beyond 1:1 is also quite uncomfortable and usually requires heavy sedation and/or paralysis. A novel approach to improving comfort with this strategy is the use of a pressure relief mechanism. This permits spontaneous breathing during the long inflation period and has been termed airway pressure release ventilation (also called BIPAP in Europe).39 Finally, it must be emphasized that the inspiratory time approach to limiting maximal pressure has not been evaluated in any

meaningful outcome study. Indeed, it is conceivable that long inspiratory times, in and of themselves, may have injury potential. CLINICAL EVIDENCE THAT LUNG PROTECTIVE STRATEGIES ARE EFFECTIVE The original clinical trial that introduced the lung protective concept was that of Hickling et al.20 They used historical controls to illustrate that a mechanical ventilator strategy designed to limit maximal distension in severe lung injury could improve mortality. They concluded that the benefits of a lung “protective” ventilator support strategy were worth the trade-off of a substantial respiratory acidosis. In 1998, two studies were reported simultaneously—one showing a mortality benefit to a lung protective strategy and one not.21,40 In both studies, the “conventional” ventilator management was similar. However, in the positive Amato study,21 patients had a more severe lung injury such that the conventional strategy resulted in plateau pressures above the overdistention threshold (i.e., >30–35 cm H2O). In contrast, in the negative Stewart study,40 patients had less severe injury such that the conventional strategy resulted in plateau pressure well below the overdistention threshold. In both studies, the lung protective strategy reduced tidal volumes (and thus plateau pressures). However, in the Amato study, this brought patients below the overdistention threshold, whereas in the Stewart trial, patients in both groups were always below the overdistention threshold. The Amato strategy also applied a higher level of PEEP that was determined from the lower inflection point on a static PV plot. These differences in lung pressures in the two studies are summarized in Figure 4. Taken together, these two studies suggest a benefit in reducing lung stretch in patients at risk for overdistention. Perhaps the most important study to address this issue is the recently reported NIH ARDS Network study of ventilator management.41 In this trial, over 800 patients were randomized to receive either a low stretch strategy (VT, 6 mL/kg) or a high stretch strategy (VT, 12 mL/kg). Importantly, the high stretch strategy resulted in plateau pressures above the overdistention threshold (i.e., 30–35 cm H2O), whereas the low stretch strategy produced plateau pressures below this. The results showed a statistically significant 25% reduction in mortality in the low stretch group despite the fact that the low stretch group actually had a lower PaO2/FiO2 ratio during the first 2 days of the trial. Also of note was that fact that other organ failures were less and in-

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Figure 4. PEEP settings (left) and plateau pressure measurements (right) over the first 7 days in two studies of lung protective strategies. In the negative Stewart trial,40 PEEP values were comparable in both the conventional and the protective groups. In this study, the protective strategy lowered plateau pressures, but both the conventional and the protective group had plateau pressures well below the overdistention threshold of 35 cm H2O (horizontal line). In the positive Amato trial,21 PEEP was higher in the protective group. Perhaps more importantly, plateau pressures were lowered from an overdistention risk level in the conventional group to a safer level in the protective group. (From Ref. 47, with permission.)

flammatory cytokine values were lower in the low stretch group. This study provides compelling evidence that ventilator management strategies designed to prevent overdistention not only protect the lung from injury but also reduce systemic inflammation and improve mortality.42

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A number of important questions still remain regarding the use of lung protective strategies during conventional mechanical ventilation. First, are there other aspects of the tidal breath pressure/volume pattern (e.g., frequency, flow magnitude, inspiratory time, tidal stretch) that affects injury? Second, what are the optimal trade-offs in gas exchange, pH, and FiO2 when considering aggressive reductions in minute ventilation? Third, where is the optimal PEEP setting with regard to PV plots? Indeed, does it matter? Fourth, what is the role of positioning (especially proning)43 in redistributing lung water, lung perfusion, and lung ventilation so as to optimize a lung protective strategy? Finally, do these lung protective principles also apply to non parenchymal lung disease (e.g., obstructive diseases)? Logic would suggest that overdistention injury can also occur in any lung disease if excessive pressures and volumes are directed at healthier regions of the lung.

Potential nonconventional respiratory support strategies and adjuncts that might enhance lung protection include two approaches: high frequency ventilation (HFV) and techniques to alter surface active properties. HFV, by providing low maximal pressures, and high recruitment pressures, might be the “ultimate” lung protective strategy for a positive pressure ventilatory support system.44 Indeed, in infants at risk for overdistention injury, HFV has been shown to offer benefit. Adult data, however, are scant. Surface active properties can be altered by either partial liquid ventilation or by surfactant administration.45 Partial liquid ventilation uses an oxygen soluble flurocarbon to provide alveolar recruitment and improve lung mechanics.46 The need for high distending pressures should be reduced accordingly. This is the same rationale behind the use of surfactant replacement in premature neonates. Surfactant replacement in the adult has been less successful, but with newer preparations (that include surfactant proteins) and better delivery strategies, it may find utility in the future.

CONCLUSIONS There are strong animal data suggesting that distending lung regions beyond the normal maximal transalveolar pressure of 30–35 cm H2O produces both a direct lung injury and a release of in-


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flammatory mediators into the circulation. Animal data also suggest that additional injury results from inadequate alveolar recruitment. Ventilator management strategies aimed at limiting maximal distention (and optimizing recruitment) are called lung protective strategies. Because minute ventilation may be compromised by these strategies, gas exchange may suffer in a trade-off for this protection. Recent clinical trial results showing mortality benefits to lung protection, however, provide strong evidence that this trade-off is worth it.

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