Objectives

1. Understand the concept of ventilator-induced lung injury (VILI).
2. Understand the role of overdistention and underrecruitment in VILI.
3. Understand the mechanisms of injury in VILI.
4. Understand ventilator management strategies to minimize VILI.
5. Understand new approaches to managing VILI.

Key words

lung injury; lung-protective ventilatory strategies; mechanical ventilation; overdistention; recruitment; surfactant

Abbreviations

APRV = airway pressure release ventilation; FIO₂ = fraction of inspired oxygen; HFV = high-frequency ventilation; I:E = inspiratory to expiratory; NIH = National Institutes of Health; PEEP = positive end-expiratory pressure; PPV = positive pressure mechanical ventilation; PV = pressure volume; TNF-a = tumor necrosis factor a; VILI = ventilator-induced lung injury; VT = tidal volume

It has been known for decades that high levels of positive pressure mechanical ventilation (PPV) can physically rupture alveolar units and produce extra alveolar air.^1,2 By the 1950s, it also became apparent that high levels of inspired oxygen could also produce lung injury through the formation of toxic oxygen radicals.³ In the 1970s, elegant experiments by Webb and Tierney⁴ clearly demonstrated two additional important concepts: First, distending pressure and volume above normal maximums but below those required for alveolar rupture could also produce a lung tissue injury characterized by lung edema, surfactant abnormalities, inflammation, and hemorrhage. Second, preventing cyclical alveolar collapse/reopening could significantly reduce this lung injury (Fig 1). An emerging concept over the last decade is that overdistention (or stretch) injury in the lung is associated not only with physical lung injury but also with the production of a number of inflammatory cytokines.^5-14 This cytokine release creates not only local inflammation, but also systemic inflammation and organ dysfunction elsewhere.¹⁵

Figure 1: Lung injury induced by high ventilatory pressures in a rat model. The lung on the left received normal ventilatory pressures. The lung on the right received ventilatory pressures exceeding normal maximal transpulmonary pressures. The lung in the middle also received excessive ventilatory pressures but received PEEP, in addition. Note the severe injury induced by excessive pressures and how it can be attenuated with PEEP. (Reprinted with permission from Webb and Tierney)

The remainder of this chapter will be divided into two parts. The first part will review the mechanisms of the lung injury associated with overdistention and cyclical alveolar collapse. This is the injury commonly referred to as ventilator-induced lung injury (VILI). The second part will review current (and potentially future) management strategies that have been designed to minimize VILI.

Mechanisms and Pathogenesis of VILI

Alveolar Overdistention and the Development of Lung Injury

The normal human lung is fully inflated when transalveolar pressures are approximately 30 to 35 cm H₂O. The risk for VILI has been shown in multiple studies to increase when this distention threshold is exceeded.^1,4-25 In the animal experiments inducing VILI, this pressure generation is usually produced by delivering high tidal volumes. In disease states, however, lung injury is often heterogeneous with very abnormal lung units interspersed with much healthier units. Under these conditions, tidal volumes of gas delivered by PPV will preferentially be distributed to the healthier units. A seemingly normal-sized tidal volume delivered to the trachea could thus create abnormally high regional tidal volumes (Fig 2) and consequent regional overdistention, even in the setting of a normal overall end-inspiratory distention.

Figure 2: Regional compliance differences can create regions of poor inflation in diseased units while grossly overinflating healthier units during a positive pressure breath. (Reprinted with permission from MacIntyre NR, Branson RD, eds. Mechanical ventilation. Philadelphia, PA: WB Saunders, 2000.)

There is compelling evidence that limiting end-inspiratory distention during PPV reduces lung injury and improves outcome.^16-18,22-29 This was most dramatically shown by the large National Institutes of Health (NIH) ARDS Network trial in over 800 patients in whom a low-stretch strategy (tidal volume, 6 mL/kg; mean plateau pressures from days 1 to 7, 25 to 26 cm H₂O) had improved survival as compared with a high-stretch strategy (tidal volume, 12 mL/kg; mean plateau pressure from days 1 to 7, 33 to 37 cm H₂O).²⁷ Moreover, the low-stretch group also had lower blood levels of interleukin 6 and fewer organ failures, which speaks to the systemic nature of VILI. Interestingly, earlier smaller trials addressing this issue did not find much benefit to this "lung-protective" concept.^30,31 However, these other trials generally had smaller numbers and less stretch separation between the two groups, and the high-stretch groups usually had end-inspiratory plateau pressures generally considered in the safe range (ie, <35 cm H₂O).

Recent studies have addressed not only the magnitude of the end-inspiratory distention but also the pattern of distention. Two studies have suggested that a rapid rate of lung distention may be as important as, or even more important than, the magnitude of the distention in producing VILI.^32,33 This would suggest that stretch injury may be significantly influenced by a shear stress phenomenon induced by rapid flows in addition to the ultimate maximal stretch. The frequency of the stretch (respiratory rate) and the duration of the stretch (inspiratory time) have also been assessed as risk factors for VILI. Increasing stretch frequency may increase the risk of VILI but this finding is not consistent among studies.^33,34 Interestingly, increasing inspiratory time for the same tidal volume, inspiratory flow pattern, and respiratory frequency does not appear to affect VILI development.³³

The pulmonary circulation may also play a role in the development of VILI. Studies have shown that VILI is increased as pulmonary vascular pressures and flows are increased.³⁴ This effect is no doubt compounded if a capillary leak syndrome is already present.^35,36

Mechanisms of Lung Injury and the Development of Systemic Inflammation

The mechanisms of stretch injury are incompletely understood. Cyclical strain may have effects on a number of lung cells through alterations in membrane ion channels, changes in membrane-associated molecules, and physical membrane disruption.⁵ Once the stretch signal has been sensed by the cell, a wide variety of intracellular signaling mechanisms (eg, nuclear factor kB) appear to be activated that are responsible for increased gene expression and production of cytokines and other pro- and anti-inflammatory molecules that regulate VILI.^5,37,38

These processes have been studied in a number of lung cells including alveolar epithelial cells, alveolar macrophages, and pulmonary endothelial cells. For example, cultured alveolar epithelial cells subjected to > 130% stretch vs baseline have been shown to release interleukin 8.⁶ Other studies have shown that injured alveolar epithelial cells can produce a number of other inflammatory modulators such as tumor necrosis factor a (TNF-a).^6,39,40 Alveolar macrophages subjected to mechanical stretch are also known to be a source of a variety of proinflammatory modulators (eg, interleukin 8) as well as substances involved in lung remodeling (eg, matrix metalloproteinase-9).⁴¹ Pulmonary vascular endothelial cells have been shown to possess a number of stretch-inducible enzyme systems and pathways responsible for cytokine release.^42,43

Once stretch-induced lung injury has been initiated, the neutrophil plays an important role in the subsequent inflammatory response. This was first demonstrated by the observation that neutrophil-depleted animals receiving mechanical ventilation had markedly reduced VILI compared with control animals.⁴⁴ Other observations have shown marked neutrophil recruitment in VILI.⁴⁵ Moreover, BAL fluid from ARDS patients who underwent high-stretch ventilation produced significant neutrophil activation as compared with BAL fluid from those who received ventilation with a low-stretch strategy.⁴⁶

Both animal and clinical studies have validated the concept that VILI is accompanied by a systemic inflammatory process.^5,9,13,15 As noted above, the NIH ARDS Network trial demonstrated higher interleukin 6 levels and more distal organ failures in patients who received ventilation with the high-stretch strategy than in those with the low-stretch strategy.²⁷ Several animal studies^9,11,12 have clearly shown that inflammatory mediators in both BAL fluid and blood are associated with ventilator strategies designed to produce VILI (although controversy exists on the relative importance of the various substances¹⁴). More recently, Ranieri and others¹³ have shown that a wide array of inflammatory mediators appear in the blood and BAL fluid of patients who undergo ventilation with a high-stretch strategy. Another factor that may potentiate the systemic inflammatory process in VILI is the translocation of bacteria across an injured alveolar-capillary interface into the systemic circulation.^47,48

The Role of Cyclical Alveolar Collapse

As noted above, it has been known for several decades that cyclical alveolar collapse can potentiate (or produce) VILI.^4,24,49,50 In recent years, the term atelectrauma has been coined to describe this.¹⁵ Physically, there is a shear stress injury that occurs when a collapsed alveolar stucture "pops open," especially if adjacent to alveolar units with different mechanical properties. Cytokine release and both local and systemic injury occur as in overdistention injury. Levels of positive end-expiratory pressure (PEEP) that prevent collapse in expiration ameliorate this injury.^4,24,49-52 In one clinical trial,²⁶ a strategy utilizing both low tidal volume and high PEEP had better outcomes compared with a standard ventilator strategy.

Management Strategies To Reduce VILI

To minimize VILI, mechanical ventilation goals should be twofold. The first goal should be to provide enough PEEP to recruit the "recruitable" alveoli while at the same time not applying so much PEEP that healthier regions are unnecessarily overdistended.^53-56 The second goal should be to avoid a PEEP-tidal volume (VT) combination that unnecessarily overdistends lung regions at end inspiration.^55,56 These goals embody the concept of a lung-protective mechanical ventilatory strategy.

Determining Underrecruitment and Overdistention in the Lung

Conceptually, the upper and lower inflection points on a static pressure volume (PV) plot might be the best guide to determining lung recruitment and overdistention.^57,59 These inflection points were initially 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 actually reflects an amalgam of the mechanical properties of numerous lung regions with potentially widely varying regional PV relationships. Indeed, recruitment of alveoli may well be occurring throughout much of the steep part of the whole lung PV plot. 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.⁶⁰

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.⁶¹ As noted below, the PV curve must take into account the effect of an abnormal chest wall compliance when it exists.⁶²

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 to 35 cm H₂O. In mechanically ventilated patients, the end-inspiratory intra-alveolar 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 (ie, the pleural pressure on the other side of the alveolar walls is so low that it can be ignored). In patients with abnormal chest wall compliance (eg, bindings, obesity), however, the plateau pressure may grossly overestimate transalveolar pressure.⁶² An esophageal balloon to measure pleural pressure can be helpful under these conditions. These chest wall considerations also apply to the PV maneuver as described above.

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.⁵⁴ Fortunately, gas exchange improvements also generally correlate with improved recruitment⁵⁴ and the ratio between PaO₂ and the fraction of inspired oxygen (FIO₂) 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. Aggressive recruitment strategies with positive airway pressure must thus be balanced against the risk of producing overdistention injury.

Conventional 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 assures that all breaths have positive pressure supplied by the ventilator to provide virtually all of the work of breathing.⁵⁵

Choosing pressure- vs flow/volume-targeted ventilation for total support depends upon 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 upon changes in lung mechanics or patient effort. Worsening of compliance or resistance in a sick lung region can thus increase airway/alveolar pressures and divert tidal volume to healthier regions with consequent regional overdistention (Fig 2). Pressure-targeted 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. With pressure-targeted ventilation, worsening of compliance or resistance in a sick region results in a loss of overall tidal volume but no change in pressures or distention in the healthier regions.

Pressure-targeted ventilation also has a variable decelerating flow wave form. On one hand, this flow pattern may improve gas mixing⁶³ and may interact with any patient efforts more synchronously.⁶⁴ However, the recent demonstration in animals that very rapid inspiratory pressure changes can produce a shear stress injury (see above^32,33) raises the concern that the rapid initial flows of pressure-targeted breaths may be detrimental.

The ultimate choice of pressure- vs volume-targeted breaths depends on which features are required for the clinical goal. Specifically, if CO₂ clearance is of primary concern and patient comfort and lung stretch are less of an issue (eg, 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 (eg, severe ARDS with normal cardiac and neurologic function), pressure-targeted ventilation is probably the correct choice. The ability to limit initial flow may be important if there is clinical concern about the shear-stress phenomenon noted above. With a flow/volume-targeted breath, this can be accomplished by direct clinician control of the flow pattern. With a pressure-targeted breath, this can be accomplished on newer ventilators with "rate of rise" adjusters.⁶⁵

There are several ventilator modes that offer pressure-targeting and volume-cycling features.⁶⁶ While these modes do offer the decelerating flow wave form of pressure-targeted breaths, the volume guarantee means that pressure must increase if lung mechanics worsen. Thus, while these breaths in these modes have pressure-targeting features, they are not pressure-limiting. To date, there are no clinical studies suggesting benefit to these combined modes.

Frequency–tidal volume settings. The tidal breath, in conjunction with the baseline pressure, should be set in such a way that the plateau pressure is < 30 to 35 cm H₂O (or some other index of overdistention does not occur). Generally, this involves a tidal volume (VT) of 5 to 7 mL/kg as was used in the NIH ARDS Network trial.²⁷ 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.⁶⁷ Under these conditions, minute ventilation will either decrease (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 (I:E) ratio is high or the time constant for lung emptying (resistance x 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 to 7.2, this appears well-tolerated in most patients (exceptions might include CNS injuries and unstable cardiovascular systems).⁶⁸ A new technique, tracheal gas insufflation, flushes the endotracheal tube free of CO₂ during expiration and may be helpful under these circumstances.^69,70

PEEP/ Fio₂. The goal of PEEP application is to maintain patency of alveoli that are opened (recruited) by a positive-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.^26,71 Recommended strategies include lung inflation to near-maximum (ie, pressures of 30 to 40 cm H₂O) for 30 to 60 s.²⁶

Determining the proper PEEP level can utilize either mechanical criteria or gas exchange criteria. Mechanical criteria involve assessments that attempt to insure that PEEP recruits "recruitable" alveoli but does not overdistend alveoli already recruited. Two approaches have been reported: (1) Use PV curves to set the PEEP above the lower inflection point on the PV curve (see above⁵⁹); and (2) use step increase in PEEP to determine the PEEP level that gives the best compliance.⁵⁴ As noted previously, both of these 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 (eg, a minimal PEEP of 5 cm H₂O is unlikely to produce overdistention) and some maximal level of PEEP at the other extreme (eg, a maximal PEEP of 25 cm H₂O will still maintain plateau pressures < 30 to 35 cm H₂O with a minimal VT). In between these extremes, PEEP and FIO₂ are adjusted to maintain an oxygenation goal. One such strategy is the one used in the NIH ARDS Network trial²⁷ (Table 1). Note that this approach may not produce the maximal PaO₂/FIO₂ ratio or the minimal shunt. This tradeoff, however, may be important in providing lung protection from overdistention.

Inspiratory:expiratory timing. Setting the inspiratory time and the I:E ratio involves several considerations. The normal I:E ratio is roughly 1:2 to 1:4. This produces the most comfort and thus is the usual initial setting. Assessment of the flow graphic should also be done to insure 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 conceptually employed as an alternative to increasing PEEP to recruit lung units and improve ventilation/perfusion relationships in severe respiratory failure.^72-74 Generally, inspiratory time prolongation is reserved for patients in whom the plateau pressure from the PEEP-VT combination has approached 30 to 35 cm H₂O and/or potentially toxic concentrations of FIO₂ are being employed without meeting arterial oxygen saturation 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 can develop.⁶⁷ A number of studies have shown improved gas exchange as a consequence of longer inspiratory times but it is not clear which of these physiologic mechanisms is or are responsible.

A novel approach to improving comfort with a pressure-controlled long inspiratory time 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 (APRV; also called biphasic or bilevel ventilation).⁷⁷ It must be appreciated that with APRV, the spontaneous breaths during the long inflation period can further increase end-inspiratory lung volume beyond that set by the inflation pressure. APRV may thus be less effective as a strategy to limit alveolar overdistention.

It must be emphasized that none of the prolonged inspiratory time strategies to limiting maximal pressure have been evaluated in any meaningful outcome study. Indeed, it is conceivable that long inspiratory times, in and of themselves, may have injury potential through the rapid initial flow pattern, the long duration of inflation pressures, or the need for heavy sedation. Their use, therefore, should be reserved for only selected situations and provided only by clinicians well versed in lung mechanics.

Future Directions

New approaches to PPV. A number of important questions still remain regarding the use of lung-protective strategies during conventional mechanical ventilation. First, it is still unclear what are the important aspects of the tidal breath pressure/volume pattern (eg, frequency, flow magnitude, inspiratory time, tidal stretch) that affects injury? Second, what are the optimal tradeoffs 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^76-78) 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 nonparenchymal lung disease (eg, 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 PPV system.⁷⁹ Indeed, in infants at risk for overdistention injury, HFV has been shown to offer benefit. Adult data, however, are scant, although a recent unpublished randomized trial of HFV suggests a trend in survival improvement.

Surface active properties can be altered by either partial liquid ventilation or by surfactant administration. Partial liquid ventilation uses an oxygen-soluble fluorocarbon to provide alveolar recruitment (liquid PEEP) and thereby improve lung mechanics.⁸⁰ The need for high distending pressures should be reduced accordingly. Unfortunately, although lung mechanics and ventilation-perfusion matching appear improved with partial liquid ventilation, these substances are cumbersome to use and outcome data is lacking. The rationale behind the use of surfactant replacement is similar to that for partial liquid ventilation: By improving lung mechanics, high distending pressures can be avoided. Surfactant replacement in the premature neonate clearly improves outcome. 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.⁸¹

Pharmacologic approaches to VILI. As noted above, VILI has many features in common with ARDS and sepsis. Strategies to limit inflammation in these two processes might therefore be expected to apply to VILI.⁵ It should be pointed out, however, that there are some differences in the inflammatory signal transduction pathways in sepsis vs VILI, and thus anti-inflammatory strategies in one may not necessarily apply to the other.⁵ In animal studies, agents that modulate membrane ion/fluid channels,^82,83 antibodies to TNF-a,⁸⁴ glucocorticoids,⁸⁵ selective enzyme blockers,⁸⁶ and interleukin 1 receptor antagonist⁸⁷ have all been shown to ameliorate VILI. In their comprehensive review of VILI, Dos Santos and Slutsky⁵ suggested areas for future research that included studies on epithelial/endothelial barrier function, microbiologic translocation, surfactant function, alveolar repair mechanisms, dysregulation of cellular mediators, regulation of the inflammatory response, and apoptotic control in inflammation.

Conclusions

There are strong animal and human data suggesting that distending lung regions beyond the normal maximal transalveolar pressure of 30 to 35 cm H₂O produces both a direct lung injury (VILI) as well as a release of inflammatory mediators into the circulation (biotrauma). 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 tradeoff for this protection. Recent clinical trial results showing mortality benefits to lung protection, however, provide strong evidence that this tradeoff is worth it. Although there are novel ventilatory strategies and pharmacologic agents that may be used to reduce or eliminate VILI, the reduction of the need for invasive PPV (eg, by the use of mask ventilation), the incorporation of lung-protective strategies during respiratory failure requiring PPV, and the prompt recognition of ventilator withdrawal potential (eg, weaning protocols) are probably the best current strategies for reducing or preventing VILI.

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