Lessons from Experimental Studies |
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INTRODUCTION: VENTILATOR-INDUCED LUNG INJURY: NOT ONLY AIR LEAKS |
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Mechanical ventilation has been used to support acutely ill patients for several decades. But clinicians are aware that, despite the life-saving potential of this assistance, it has several potential drawbacks and complications. A State of the Art review published several years ago in the American Review of Respiratory Disease recapitulated these complications (1). The present review focuses on what has recently emerged as one of the most serious potential complications of mechanical ventilation, ventilation-induced lung injury (VILI). VILI was, for years, synonymous with clinical barotrauma, the leakage of air due to disruption of the airspace wall. The extra-alveolar accumulation of air causes several manifestations (2), of which the most threatening is tension pneumothorax. The adverse consequences of these macroscopic events are usually immediately obvious, and this form of barotrauma has been the subject of clinical studies and the remarkable experimental studies of Macklin and Macklin (3). It is only very recently that the possibility that more subtle physiologic and morphologic alterations may occur during mechanical ventilation has been recognized. This form of injury is now a major preoccupation of most physicians caring for patients needing ventilatory support. Although several fundamental experimental studies were published before 1975, it was only 10 yr later that renewed interest in this subject stimulated the major research effort which has considerably expanded our knowledge. Unlike the classic forms of barotrauma (i.e., extra-alveolar air), our knowledge of these alterations has come only from experimental studies. Alterations in lung fluid balance, increases in endothelial and epithelial permeability, and severe tissue damage have been seen following mechanical ventilation in animals. The macroscopic and even microscopic damage observed in VILI (4) is not specific. It closely resembles that observed in other forms of experimental acute lung injury (7). More importantly, it does not fundamentally differ from the diffuse alveolar damage observed during human acute respiratory distress syndrome (10). Thus, were VILI to occur in humans, it would be indistinguishable from most of the initial acute offending processes that lead to respiratory failure and the need for ventilator assistance. The possibility that mechanical ventilation can actually worsen acute lung disease is now widely accepted (11), despite the lack of a clear demonstration of a clinical equivalent of the experimental observations. Any demonstration of superimposed VILI during the course of human acute respiratory distress syndrome may be illusive. Thus, this concept derived from animal studies has resulted in complete reassessment of the use of mechanical ventilation for patients with acute lung diseases and underlies current trends in the clinical practice of mechanical ventilation (12). Indeed, the current orientation is to emphasize the potential importance of easing the stress on acutely injured lungs by using modes of ventilation that limit the pressure and volume of gas delivered to the lungs (13).
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VENTILATION-INDUCED PULMONARY EDEMA AND RELATED FINDINGS: A HISTORICAL PERSPECTIVE |
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The safety of mechanical ventilation for the treatment of patients with acute respiratory failure has been a matter of concern ever since its introduction into medical practice. Several early experimental and clinical studies suggested that mechanical ventilation may adversely affect the lungs. Greenfield and colleagues (19) ventilated closed-chest dogs for 2 h at 26-32 cm H2O peak inspiratory pressure. The animals were then allowed to recover for 24 h before undergoing thoracotomy. Zones of atelectasis were found at gross examination and the extracts of these lungs had increased surface tension, suggesting altered surfactant properties.
A few years later, Sladen and colleagues (20) reported that patients ventilated for long periods suffered from deteriorated lung function, an increased alveolar-arterial oxygen gradient, and a fall in respiratory system quasi-static compliance. However, the potential harmful effects of mechanical ventilation remained controversial. In an experimental study published in 1971, Nash and colleagues (21) claimed that the term "respirator lung" was a misnomer. They subjected goats to intermittent positive pressure ventilation with 13 cm H2O peak airway pressure, using either 100% fraction of inspired oxygen (FIO2) or room air as the inspired gas. The animals given 100% O2 did not survive for more than 4 d. At autopsy, their lungs had severe edema and hyaline membranes. In contrast, animals ventilated with room air remained well for up to 2 wk and their lungs did not differ from control animals. The conclusion was that even prolonged mechanical ventilation does not cause lung damage. However, they rightly pointed out that they used physiologic, low peak inspiratory pressures. Subsequently, it was conclusively demonstrated that "respirator lung" is in fact a true morbid entity, especially when higher peak inspiratory pressures are used. Many studies have sought to identify risk factors, or the potential adverse effects of the various forms of mechanical ventilation, and to develop strategies for preventing VILI. The deleterious effects of mechanical ventilation depend on numerous factors, among which (as will be detailed in the following sections), the level of airway pressure applied and the resulting volume changes, animal size, duration of ventilation, and whether the thorax is open or closed are the most significant.
Webb and Tierney conducted the first comprehensive study in intact animals that unambiguously demonstrated that mechanical ventilation may produce pulmonary edema (22). They subjected rats to positive airway pressure ventilation with peak pressures of 14, 30, and 45 cm H2O. No abnormality was observed after 1 h of ventilation with 14 cm H2O peak pressure. However, pulmonary edema occurred when animals were ventilated with higher peak pressures. Edema developed more rapidly and was more severe in animals ventilated with 45 cm H2O than in those ventilated with 30 cm H2O peak pressure: moderate interstitial edema was found in animals ventilated for 60 min with 30 cm H2O peak pressure, whereas profuse edema and alveolar flooding developed within 13 to 35 min in animals ventilated with 45 cm H2O peak pressure. Other studies (4, 6) subsequently showed that mild interstital edema can be demonstrated after a few (2 to 5) minutes of ventilation in rats with such a high peak airway pressure. Replication of these observations in larger animals requires much longer periods of ventilation (23), for reasons that are not yet understood. The implications of these differences between large and small species will be discussed later. For instance, Kolobow and colleagues found that several hours were necessary to produce lung injury in sheep, even when very high airway pressures were used (24). All the sheep had decreased pulmonary compliance and reduced blood oxygenation after 2 d of mechanical ventilation with 50 cm H2O peak pressure. Some sheep died before the 48-h endpoint. Pathologic examination of their lungs showed congestion and severe atelectasis. The cause of the lung alterations after long-term ventilation in large animals is probably more composite than that responsible for the rapid onset of edema in smaller ones. This issue is discussed in the section, MECHANISMS OF ALTERED PERMEABILITY. Attention was recently drawn to the fact that mechanical ventilation, even at low airway pressure and tidal volume (VT), may cause additional damage to injured lungs (28). We now understand something of the way these injuries develop, although there are still many blanks to fill in.
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VENTILATION-INDUCED PULMONARY EDEMA: HYDROSTATIC OR PERMEABILITY EDEMA? |
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This issue has been a matter of debate for some time, and the answer to this question is not only of theoretical importance. Because the properties of the alveolar-capillary barrier are abnormal during acute lung injury such as the adult respiratory distress syndrome (ARDS), it is essential to ascertain whether mechanical ventilation-induced alterations will only result in further fluid accumulation, or whether they will create new lesions, or aggravate existing ones. In their fundamental contribution to the description of ventilation-induced pulmonary edema, Webb and Tierney (22) speculated that hydrostatic mechanisms were responsible for edema. However, light microscope examination revealed deep eosinophilic staining of interstitial edema fluid, suggesting that this fluid was rich in proteins. The hydrostatic or permeability origin of the edema has subsequently been investigated by several groups. The present state of knowledge suggests that alterations in microvascular permeability are the main determinants of this pulmonary edema.
Experimental Evidence for Increased Vascular Transmural Pressure
The first explanation advanced for ventilation-induced edema was an increase in vascular transmural pressure at both extra-alveolar and alveolar levels (22) via mechanisms that will be considered in detail in the section, MECHANISMS OF INCREASED VASCULAR TRANSMURAL PRESSURE.
Few data are available on vascular pressures during high-pressure mechanical ventilation (25, 27). It is difficult to deduce from the reported mean pressures what actually happens at the microvascular level, because of the regional (zone I-IV) inhomogeneity of pulmonary blood flow in the large animals in which these measurements were obtained (32). Moreover, intraregional heterogeneity further complicates this issue, because alveolar corner vessels remain open and may expand during zone I conditions (33). Finally, the site of maximum resistance may move as lung volume varies (37). Demonstration of a substantial increase in mean transmural vascular pressure would argue in favor of a hydrostatic origin. No such increase was reported in the literature summarized below.
Parker and colleagues (25) ventilated open-chest dogs for 30 min at 64 cm H2O peak airway pressure, which resulted in a mild pulmonary edema. They calculated the capillary filtration pressure from measurements of mean pulmonary artery and left atrial pressures. They found that mean microvascular pressure increased by 12.5 cm H2O. The authors acknowledged that this change in microvascular pressure would probably be even smaller in intact animals because of the decreased cardiac output caused by the high intrathoracic pressure. The better pulmonary hemodynamics in open-chest animals may explain in part the observation by Woo and Hedley-Whyte (38). They reported development of severe lung injury, with pulmonary edema and tracheal flooding, in open-chest dogs after 8 h of ventilation with very large (50 ml/kg body weight [BW]) tidal volumes. By contrast, closed-chest animals ventilated with the same settings showed no discernible abnormality.
The small magnitude of the change in mean transmural microvascular pressure during high airway pressure ventilation was also suggested by the work by Carlton and colleagues (27). They ventilated closed-chest lambs with 58 cm H2O peak inspiratory pressure and observed that the mean pulmonary arterial pressure increased by 11 cm H2O and the left atrial pressure by 5 cm H2O over the baseline values for animals ventilated with 19 cm H2O peak airway pressure. The resulting change in capillary pressure was therefore mild. In addition, mean intrathoracic (pleural) pressure (referenced to the atmosphere) increased by 4 cm H2O at the same time, suggesting a rather limited increase in mean transmural microvascular pressure.
The conclusion that can be drawn from these few observations is that there is probably no large, uniform increase in transmural pressure over the whole pulmonary vascular network during high airway pressure ventilation. Either increased filtration by this mechanism is very localized or other mechanisms are involved, especially if one considers the extreme severity of the edema that may be produced in small species, such as rats (4, 5, 22). However, it should be pointed out that theoretical considerations based on lung interdependence predict that considerable increases in regional microvascular transmural pressure may occur during the inflation of very heterogeneous lungs (39). The magnitude of this increase would be such that edema might be not only of the hydrostatic type, but also associated with permeability alterations because of the stretched pore phenomenon (40, 41) or capillary stress failure (42). This point is examined thoroughly in the section on the mechanisms of alterations in permeability.
Evidence for Alterations in Alveolar-Capillary Permeability
By contrast with the lack of firm demonstration that hydrostatic pressure changes are sufficient to cause ventilator-induced edema, major alterations in pulmonary epithelial and, more surprisingly, endothelial permeability have been reported for isolated lungs, as well as for open-chest and intact animals subjected to high airway pressures.
Alterations of alveolar-airway epithelial permeability.
Small solutes. The increase in epithelial permeability to small hydrophilic solutes that occurs as lung volume increases is a physiologic phenomenon. The clearance of aerosolized 99mTc-DTPA increased when the functional residual capacity (FRC) was increased by positive end-expiratory pressure (PEEP) during mechanical ventilation (43), or spontaneous ventilation (44) in sheep. The changes in clearance were larger than would be expected from those of the alveolar exchange surface area. The same observation has been made in humans (45, 46). An increase in DTPA clearance was obtained regardless of whether the lung volume was changed by positive pressure breathing or voluntary hyperinflation (45). DTPA clearance in intact rabbits increased more after pressure-controlled inverse ratio ventilation than after volume-controlled ventilation with the same end-expiratory pressure (5 cm H2O) and a normal VT (47). Prolonged inspiration resulted in a larger time-adjusted lung volume, which could explain the greater increase in epithelial permeability.
Larger solutes: the effects of static inflation of fluid-filled lungs. The equivalent pore approach was used by Egan (48) to describe the permeability of the epithelium to hydrophilic solutes of various sizes during the static overinflation of lobes filled with fluid in closed-chest sheep. The equivalent pore radius of the epithelium increased from about 1 nm at 20 cm H2O inflating pressure to 5 nm at 40 cm H2O inflating pressure (Figure 1), reflecting a moderate increase in permeability. But albumin sometimes freely diffused across the epithelium, indicating the presence of large leaks (Figure 1). These findings were subsequently reproduced in dogs (49). The changes in permeability persisted, or even increased after cessation of inflation, suggesting irreversible epithelial injury. However, high airway pressures applied to lobes rather than to the whole lung produced an inflation greatly exceeding the maximal regional capacity. Indeed, hyperinflation limited to a small area of the lung allowed this area to compress other lobes and the contralateral lung, producing an expansion many times greater than what would have been reached if the whole lung were subjected to the same distending pressure. Egan (50) therefore performed experiments in closed-chest rabbits in which both segments and entire lungs were distended with 40 cm H2O airway pressure for 20 min. Static segmental inflation resulted in 6- to 12-fold increases in volume from FRC and in an epithelium that was permeable to all (small and large) the solutes tested (cyanocobalamin, cytochrome c, and albumin: molecular radius of 0.6, 1.7, and 3.5 nm, respectively). In contrast, inflation of whole lungs resulted in only a 3- to 4-fold increase in lung volume, a much smaller increase in permeability to the smallest solutes, and little or no change in permeability to albumin. Similarly, Kim and Crandall (51) found that the permeability of the epithelium of isolated bullfrog lungs was not modified when inflation remained within the physiologic range, but was increased by overinflation. Hence, only major increases in lung volume alter epithelial permeability to large molecules during static inflation.
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Larger solutes: the effects of mechanical ventilation with high airway pressure in intact animals. In contrast to the modest effect of static lung inflation on epithelial permeability, prolonged cyclic lung inflation during mechanical ventilation produces severe alterations. Epithelial permeability to large solutes is probably not significantly altered during the early stages of ventilator-induced lung edema provided there is no alveolar flooding. For instance, positive pressure ventilation in lambs with a peak inspiratory pressure of 41 cm H2O for 8 h did not induce pulmonary edema, but resulted in altered alveolar permeability to small (DTPA) but not large (albumin) solutes (52). Similarly, no obvious increase in alveolar permeability to proteins was observed during the mild pulmonary edema produced by very short periods (several minutes) of high-pressure ventilation in rats (6). But there were undoubtedly major alterations of epithelial permeability later, when pulmonary edema was severe. Indeed, ultrastructural examination revealed widespread destruction of the alveolar epithelium at this stage, which must necessarily alter its barrier properties (4, 5). These abnormalities are detailed under ELECTRON MICROSCOPE STUDIES.
Changes in microvascular permeability during mechanical ventilation at high airway pressures.
Isolated lungs. Parker and colleagues (53) showed that the ventilation of isolated blood-perfused dog lobes for 20 min with graded increases in peak airway pressure up to 30 cm H2O did not affect microvascular permeability, as assessed by the capillary filtration coefficient (Figure 2). Higher peak inspiratory pressures (45 to 65 cm H2O, which corresponds to a lung volume well above the total lung capacity in these isolated lungs) increased the capillary filtration coefficient and decreased the isogravimetric capillary pressure (the maximal hydrostatic pressure at which lungs do not gain weight). The estimated protein reflection coefficient was also decreased only at the highest airway pressures. The increase in capillary filtration coefficient observed by Parker and coworkers (53) was immediate when airway pressures were above the 30 cm H2O threshold, and it sometimes persisted after airway pressure was lowered. These results show that increasing lung volume ultimately alters endothelial permeability to solutes of both small and large molecular weight and suggest the presence of an airway pressure threshold below which these modifications do not occur. However, the fact that edema probably due to increased permeability occurred with a peak inspiratory pressure as low as 13 cm H2O in isolated perfused rat lungs (54) raises questions about the precise level of such a pressure threshold. This issue will be discussed under POSSIBLE PRESSURE-VOLUME THRESHOLD FOR EDEMA AND PERMEABILITY ALTERATIONS.
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Intact animals. Demonstration of microvascular permeability abnormalities was easier in small than in large animals during mechanical ventilation with high airway pressure. The possibility of changes in capillary permeability in intact animals was assessed by measuring extravascular lung water and bloodless dry lung weight in mechanically ventilated rats (4). Dry lung weight increases during edema due to increased permeability, but not during hydrostatic edema (55). Changes in dry lung weight reflect the efflux from the vascular spaces and the accumulation in the interstitium and alveoli of plasma proteins. Changes in permeability were more refinely assessed using the pulmonary extravascular distribution space of intravenously injected 125I-labeled albumin, which reflects the rate at which albumin leaks from blood vessels into the lung. Pulmonary edema developed very rapidly in animals ventilated at 45 cm H2O peak airway pressure and was readily apparent after only 5 min of ventilation (Figure 3). Light microscope examination revealed a mild edema confined to interstitial spaces, resulting in peribronchovascular cuffs (detailed in PATHOLOGIC FINDINGS). No alveolar flooding was apparent at this stage. The presence of unequivocal microvascular permeability alterations was evidenced by significant increases in dry lung weight and albumin space (Figure 3). Pulmonary edema was more abundant after 10 min of high peak airway pressure ventilation, but still involved only the interstitial spaces. But the findings were strikingly different after 20 min of ventilation, with widespread alveolar flooding in all animals. The severity of the permeability changes was attested by the 125I-albumin activity in the tracheal fluid which was close to that in plasma. Indeed, a high protein concentration in edema fluid strongly suggests permeability type edema (3, 55). There were massive increases in extravascular lung water, dry lung weight, and albumin distribution space (Figure 3). The relationship between dry lung weight and extravascular lung water (Figure 4) indicated that the extravasated fluid had the same protein content as plasma, confirming the very severe permeability defect (55) and suggesting the presence of numerous, large capillary leaks. Subsequent studies in closed-chest and open-chest animals using different approaches confirmed that high airway pressure ventilation is associated with changes in microvascular permeability (25, 27, 59). Hernandez and colleagues (59) ventilated closed-chest rabbits with a peak pressure of 45 cm H2O for 1 h, then removed the lungs and measured the capillary filtration coefficient. It was 430% that of controls ventilated with a peak pressure of 15 cm H2O. In their work on the contribution of increased filtration to high peak airway pressure edema in open-chest dogs, Parker and coworkers (25) found changes in lymph protein clearance and lymph/plasma protein ratio compatible with altered microvascular protein permeability. Protein clearance and ratio were rather variable, but were significantly higher in dogs that had been ventilated for 30 min with 64 cm H2O peak airway pressure than in those ventilated for the same time with 22 cm H2O peak airway pressure. This study did not include a control group, but the lymph-plasma protein ratios in the 22 cm H2O peak pressure group were comparable to those reported for uninjured lungs (60). The reflection coefficient for total proteins (derived from the slope of lymph protein clearance versus lymph flow) after high (64 cm H2O) peak pressure ventilation was as low (0.42) as that previously found by these authors (61) in lungs with permeability edema after exposure to the toxin alpha-naphthylthiourea (0.38), suggesting that high peak pressure ventilation may be as deleterious as usual models of toxic lung injury. The variability in the permeability changes may have been due to the study design, which consisted of rather short periods of high-pressure ventilation (30 min only) in large animals (dogs). The amount of edema was mild in these dogs under such conditions, probably because it takes more time for overinflation edema to occur in large animals than in small ones. This may have precluded accurate assessment of permeability changes. These changes may become detectable only after longer ventilation times, in contrast to the immediate occurrence of microvascular pressure changes. Another potential factor which may have led to underestimation of the permeability alterations in the study by Parker and colleagues (25) is that 1 h elapsed between the ventilation challenge and measurement of the reflection coefficient. Microvascular permeability has been shown to rapidly return to normal after short periods of high-pressure ventilation (6) (see REVERSIBILITY OF LIMITED ABNORMALITIES).
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Increased microvascular permeability was also reported by Carlton and colleagues in lambs mechanically ventilated with 61 cm H2O peak airway pressure. There was a very important (3- to 13-fold) increase in lung lymph flow. The presence of permeability alterations was ascertained by the unchanged lymph-plasma protein concentration ratio during edema development (27).
Whatever their respective magnitude, increased microvascular filtration pressure and altered microvascular permeability probably act in concert to produce high airway pressure pulmonary edema. Even if the hydrostatic component is probably moderate, at least in closed-chest animals, it may have important consequences. Any increase in driving pressure will favor edema when the sieving properties of the microvascular barrier are abnormal (62). The synergistic actions of hydrostatic forces and altered permeability may explain the (occasional) occurrence of fulminating pulmonary edema.
Pathologic findings. Animal lungs injured by mechanical ventilation display a pattern of atelectasis, severe congestion and enlargement because of edema (22, 24, 26). There is an obvious relationship between the duration of the injury and the overall appearance of the lung (Figure 5). Figures 5-8 show the changes revealed by gross pathologic, light microscopic, and electron microscopic examinations during VILI of different severity in rats. Ventilator-induced pulmonary edema is associated with severe endothelial and epithelial abnormalities, the structural counterpart of the alterations in permeability (4).
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Light microscope studies. Interstitial and alveolar edema have been reported after mechanical ventilation with high peak airway pressure (4, 22, 23). The degree of edema varies with the magnitude of the peak airway pressure (22) and the duration of mechanical ventilation (4). Edema is initially confined to the interstitial spaces and is visualized as peribronchovascular cuffs (56, 65) under the light microscope (Figure 6A). High peak pressure mechanical ventilation for less than 1 h causes profuse alveolar edema (Figure 6B). Although it is difficult to assess the respective responsibility of hydrostatic and permeability alterations on the basis of light microscopic examination alone, certain histologic features suggest that permeability changes are prominent in ventilation-induced pulmonary edema. As already mentioned, Webb and Tierney (22) found that the edema in their moribund animals was deeply eosinophilic, suggesting that it was rich in proteins and, hence, might be an exsudate rather than a transudate. Changes in permeability during high airway pressure-large tidal volume mechanical ventilation are also suggested by the observations reported by Tsuno and coworkers (66) for baby pigs. The pigs were ventilated with a peak inspiratory pressure of 40 cm H2O for about 22 h to produce overinflation lung injury characterized by severe hypoxemia. Some were killed immediately after this period of high-pressure ventilation, whereas the others were subsequently supported with normal pressure and volume mechanical ventilation for several days. Microscopic examination of the lungs of animals killed immediately after the high-pressure ventilation period showed severe diffuse alveolar damage, with hyaline membranes, alveolar hemorrhage, and neutrophil infiltration. These alterations were similar to those found during the early stages of human ARDS. The piglets kept for several days after being injured by high-volume ventilation also had damaged lungs that looked similar to lungs in late stage ARDS, with collapsed alveolar spaces and proliferation of fibroblasts and type II cells.
The difference between the pathologic appearance of the lungs of small animals (4, 5, 22) and those of larger ones (66) at the early stage of VILI is probably related to the differing durations of the challenge. Edema develops so rapidly (a few minutes) in small animals that there is not enough time for the development of noticeable inflammation and neutrophil infiltration of lung tissue. In contrast, the several hours necessary to produce patent edema in larger animals is sufficient for activation, adherence, and significant migration of neutrophils into airspaces (66, 67). The importance of this distinction will be highlighted in the section devoted to the mechanisms of VILI.
Electron microscope studies. Electron microscope observations clearly showed the major abnormalities that resulted in increased permeability during VILI. Discontinuities in alveolar type I cells have been reported in rabbits ventilated with moderate (20 cm H2O) peak airway pressure for 6 h (68). Widespread alterations of endothelial and epithelial barriers were evidenced when a higher peak airway pressure was used (4). If VILI were the result of changes in hydrostatic forces only, there should be no (7, 8, 69) or little (70, 71) ultrastructural alteration.
As detailed above, the lungs of rats ventilated for short periods (5 to 10 min) with 45 cm H2O peak airway pressure had only interstitial edema by light microscopic examination (Figure 6A). In addition to the confirmation of interstitial edema, electron microscopy revealed endothelial abnormalities (Figure 7) similar to those found during toxic pulmonary edema, showing that the ventilation edema was of the nonhydrostatic type (4). Some endothelial cells were detached from their basement membrane, resulting in the formation of intracapillary blebs that were filled with a material having the same density as plasma (Figure 7a). There were also occasional breaks in endothelial cells (Figure 7b). Ventilation for longer periods resulted in alveolar flooding (Figure 6B) and diffuse alveolar damage (Figure 8) (4). There were profound alterations in the epithelial layer in addition to the capillary lesions. The severity of the alterations was unevenly distributed: the epithelial lining appeared to be intact in some areas, whereas there were discontinuities and sometimes almost complete destruction of type I cells in many others, leaving a denuded basement membrane (Figure 8). In contrast, type II cells always appeared to be preserved. Hyaline membranes filled the alveolar spaces in most of the sections examined of animals with severe alveolar edema (4, 5) (Figure 8). Endothelial breaks allowed direct contact between polymorphonuclear neutrophils and the basement membrane (Figure 8). The severity of alveolar cell destructions probably explains the marked elevation of lung lavage cellular enzymes such as lactate dehydrogenase and aspartate aminotransferase observed in rats with VILI (72). Interestingly, alveolar edema and epithelial destructions were prevented by the application of a 10 cm H2O PEEP (Figure 9) (5). This point will be discussed in the following section.
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These electron microscopy findings strongly support the contention that permeability alterations are a main determinant of ventilator-induced pulmonary edema. Indeed, endothelial blebs like those shown in Figure 7 have been reported only in experimental high-permeability edema, regardless of the causative agent, and in ARDS (7). Ultrastructural studies of experimental hydrostatic pulmonary edema in intact animals have disclosed no such alterations (7, 8, 69). Hydrostatic type edema was for a long time not considered to be associated with ultrastructural cellular abnormality, at either the microvascular or epithelial levels (7, 69, 73). It is only very recently that refined ultrastructural studies have shown epithelial breaks and blebbing and rare endothelial lesions in excised rabbit lungs with vascular pressures in the 30 mm Hg range (70, 71). These mild changes are quite different from those observed recently when transmural capillary pressure is raised very high (more than 50 mm Hg) in isolated lungs, leading to the very particular entity termed "capillary stress failure". This entity will be discussed in the section devoted to the mechanisms of ventilator-induced lung injury.
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CONTRIBUTIONS OF THE STATIC AND DYNAMIC LUNG VOLUME COMPONENTS TO VENTILATOR-INDUCED EDEMA |
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High-volume ventilation may overstretch both normal and diseased alveoli and thus directly produce lung injury. Recently, attention has focused on the potential for ventilation at low lung volume (i.e., with a reduced FRC) to worsen preexisting lesions, through the periodic opening and closing of distal airspaces. The specific effect of ventilation on diseased lungs will be discussed in the section, EFFECTS OF HIGH-VOLUME VENTILATION ON ABNORMAL LUNGS.
High-volume Lung Edema
Roles of increased airway pressure and increased lung volume. The high intrathoracic pressures that occur during mechanical ventilation result in large lung volumes, provided the respiratory system is sufficiently compliant. However, these high pressures also have hemodynamic effects in the systemic circulation (74) and in the lungs, where blood flow distribution may be affected by the extension of zone 1 conditions during overinflation. Several studies have examined the roles of intrathoracic pressure and lung distention in the genesis of pulmonary edema.
Experimental studies often indicate the peak airway pressure reached during mechanical ventilation. Given the fact that ventilator-induced injury depends mainly on lung volume, and in particular the end-inspiratory volume, it would be more appropriate to indicate the end-inspiratory (plateau) pressure. The clinical importance of plateau pressure was recently underlined in a Consensus Conference on mechanical ventilation (12). In the experiments in rats reported below, the increase in inspiratory pressure was monotonic, with the end of inspiration being under quasi-static condition, so that the maximal airway pressure coincided with end-inspiratory volume.
Intact rats were subjected to large or low VT ventilation, but with identical peak airway pressures (45 cm H2O) to distinguish between the effects of lung distention and increased intrathoracic pressure (5). Low-volume ventilation with high airway pressure was obtained by limiting thoracoabdominal excursions by strapping during conventional, intermittent positive airway pressure ventilation. The rats subjected to high tidal volume-high airway pressure ventilation developed permeability pulmonary edema (Figure 10) with ultrastructural abnormalities as described above (5). In striking contrast, strapped animals ventilated with a high airway pressure but a normal VT had no edema (Figure 10) and the ultrastructure of their lungs appeared normal (5). To further demonstrate that high airway pressures are not a prerequisite for pulmonary edema, rats were ventilated with large VT but negative airway pressures by means of an iron lung. Permeability edema developed even when airway pressure was negative (Figure 10) (5). The conclusion of this study was that the increase in VT is responsible for ventilator-induced pulmonary edema and not high airway pressure per se. It would therefore be wise to replace the term barotrauma by "volutrauma" (6, 75).
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These findings have been replicated in several species, using different approaches. Hernandez and associates (59) studied the effects of ventilation at three peak airway pressures (15, 30, and 45 cm H2O) and that of ventilation with the same peak pressures but with thoracic excursion restricted by placing plaster casts around the chest and abdomen of rabbits. The capillary filtration coefficient of the lungs removed after ventilation was normal in animals ventilated at 15 cm H2O peak pressure, increased by 31% after ventilation at 30 cm H2O peak pressure and by 430% after ventilation at 45 cm H2O peak pressure in the animals without VT restriction. Restricting lung inflation with the plaster cast prevented this increase in the filtration coefficient, even at the highest peak airway pressure. Carlton and coworkers confirmed this observation in lambs (27). In animals ventilated for 4 to 8 h with a peak inspiratory pressure of 58 cm H2O, lung lymph flow increased 6-fold in the absence of volume limitation, but remained unchanged when the chest and abdomen were strapped. This pivotal role of lung distention was further emphasized by Adkins and colleagues (76), who observed that the lung capillary filtration coefficient increased more in young rabbits than in adult ones after 30 to 55 cm H2O peak pressure ventilation, probably because the lung and chest wall compliance of the young animals was larger, allowing greater distention for the same peak airway pressure. Besides the lung distention that occurs during mechanical ventilation, the rate at which lung volume varies may also affect microvascular permeability. Peevy and coworkers (77) determined the capillary filtration coefficient in isolated perfused rabbit lungs ventilated with various tidal volumes and inspiratory flow rates. They found that, for the same peak airway pressure of 53 cm H2O small tidal volume ventilation (9 to 12 ml/kg BW) with a high flow rate (8.3 L/min) increased the filtration coefficient to the same extent (about 6 times baseline value) as ventilation with a markedly higher VT (25 to 35 ml/kg) but a low inspiratory flow rate (1.9 L/min).
All these studies suggest that, at least in normal lungs, large lung volumes but not high intrathoracic pressures per se are crucial in the genesis of ventilator-induced lung edema. High inspiratory flow rates may aggravate lesions, except that this was shown only in isolated lungs (77). In intact animals, increased intrathoracic pressure produces specific hemodynamic alterations which may conceal the role played by other factors, as discussed in the next section.
Roles of VT, PEEP, and overall lung distention. The consequences of PEEP during acute lung injury or pulmonary edema have sometimes been misinterpreted, mainly because of failure to distinguish between its direct effects, which are to increase FRC and open the lung, and its indirect effects, which are to displace end-inspiratory volume toward total lung capacity when VT is kept constant. Thus, any beneficial effect of PEEP may be offset by the consequences of lung distention. The increase in mean intrathoracic pressure produced by PEEP will also affect hemodynamics (74), and consequently lung fluid balance. The effects of PEEP must therefore be analyzed systematically.
Extensive studies have been done on intact animals and isolated lungs during hydrostatic or permeability type edema to clarify the relationships between PEEP, oxygenation, and the accumulation of extravascular lung water. The effects of PEEP on lung water content seem to depend on whether the study is performed on intact animals or on isolated lobes, on the level of PEEP and its effect on inspiratory airway pressure, and on whether VT is reduced.
Effects of PEEP, with VT kept constant. If the application of PEEP is followed by a significant change in FRC (depending on the shape of the pressure-volume curve), it may result in overinflation of the more distensible areas, depending on the magnitude of VT and the homogeneity of ventilation distribution. Overinflation is probably the explanation for the usual lack of reduction or even the worsening of edema reported with PEEP during most experiments (78).
The differing responses of intact animals and isolated lungs to PEEP is well illustrated by the study by Caldini and colleagues (79). They showed that PEEP as high as 20 mm Hg reduced shunt but did not oppose the formation of hydrostatic edema in closed-chest dogs. A lower PEEP (8 to 10 mm Hg) increased the accumulation of water in isolated lobes perfused at a constant blood flow rate. It seems likely that such a high PEEP (20 mm Hg) applied in closed-chest animals decreased cardiac output. Neither pulmonary blood flow nor lung vascular pressures were measured in the intact animals in this study, thus a reduction in microvascular filtration pressure as compared with isolated lungs may have escaped detection, but would explain this difference in lung fluid balance. Moreover, PEEP probably resulted in greater FRC and end-inspiratory volume for the same VT in isolated lobes than in closed-chest animals, producing some degree of overinflation which may have contributed to its aggravating effect, as discussed subsequently. In fact, PEEP aggravated edema in isolated, ventilated-perfused canine pulmonary lobes injured by the intrabronchial instillation of hydrochloric acid (80). Lobes were ventilated with the same VT and various PEEP levels applied just after acid instillation. Pulmonary blood flow was kept constant. Edema fluid accumulated at the same rate in the presence of a 5 cm H2O PEEP (which may be considered to allow the maintenance of physiologic residual capacity in isolated lungs) and at 10 cm H2O PEEP, whereas shunt was significantly lower with this higher PEEP. Shunt was not further reduced by increasing PEEP to 15 cm H2O but there was twice as much edema (Figure 11) and peak inspiratory pressure was markedly higher with this PEEP. The authors concluded that PEEP had beneficial effects on gas exchange, but worsened pulmonary edema during acute lung injury. The improvement of oxygenation is the consequence of the reopening of flooded alveoli because of the redistribution of edema fluid toward interstitial spaces (35, 81, 82).
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Hopewell and Murray also found that a 10 cm H2O PEEP did not counteract the accumulation of edema fluid during hydrostatic type edema in intact dogs (83). PEEP nevertheless improved oxygenation and mechanical lung properties, as illustrated by the lower peak inflation pressure for a given VT in animals ventilated with PEEP (83). Comparable observations were made during acute lung injury and permeability type edema by Hopewell, who reported that closed-chest dogs whose lungs were injured with alloxan had the same amount of pulmonary edema whether they were on 0 or 10 cm H2O PEEP when VT was kept constant (84). Peak airway pressure increased in exact proportion to the level of PEEP, and cardiac output was reduced in the animals ventilated with PEEP, suggesting a decrease in microvascular filtration pressure. Similarly, prophylactic application of 10 cm H2O expiratory positive airway pressure (a form of PEEP) did not reduce edema formation during oleic acid injury in closed-chest dogs (85).
In contrast with the above studies, which all showed no change in the amount of pulmonary edema in intact animals ventilated with PEEP, two teams reported apparently conflicting findings (86, 87). Demling and associates (86) found that PEEP aggravated lung edema in intact animals. They measured the extravascular lung water content in closed-chest dogs in which hydrostatic edema was induced by lobar venous occlusion. Animals ventilated with a 10 cm H2O PEEP had a significantly higher lobar increase in lung water content than those ventilated with zero end-expiratory pressure, despite comparable net intravascular filtration pressures. However, these animals were ventilated with a large VT (25 ml/kg BW). Such a VT in the presence of PEEP may have increased end-inspiratory volume sufficiently to produce supplemental injury (88, 89). This point will be considered in the following section. The recent study by Colmenero-Ruiz and coworkers (87) investigated the effect of a 10 cm H2O PEEP on the postmortem extravascular lung water content of pigs ventilated with a normal VT (12 ml/kg BW) after acute lung injury caused by the intravenous infusion of oleic acid. Animals subjected to PEEP had higher mean intrathoracic pressure and significantly less edema than those ventilated with zero end-inspiratory pressure. It is possible that the reduction in edema was caused by the decreased cardiac output (due to higher airway pressure) and filtration in those animals subjected to PEEP. The decrease in cardiac output was important (25%), but did not reach significance perhaps because of a type-2 statistical error caused by the small number of experiments.
These observations show that, for a given VT, increasing FRC with PEEP has different effects on the amount of edema in isolated lungs and in intact animals. The usual lack of effect of PEEP on edema formation in intact animals probably depends on the balance between the PEEP-induced increase in end- inspiratory volume which will favor fluid filtration in extra- alveolar vessels because of lung interdependence (this concept will be detailed in the section, INCREASED TRANSMURAL PRESSURE IN EXTRA-ALVEOLAR VESSELS) and the hemodynamic depression due to elevated intrathoracic pressure which will decrease filtration pressure (see following section). The preservation of perfusion in isolated lungs favors the increase in edema.
The situation is different when end-inspiratory volume is controlled by VT reduction during application of PEEP.
Effects of PEEP, with end-inspiratory volume kept constant. All published studies report that ventilation with PEEP and reduced VT is less injurious than ventilation with zero end-expiratory pressure and a higher VT for the same peak airway pressure. Webb and Tierney showed that edema was less severe when a 10 cm H2O PEEP was applied during ventilation with 45 cm H2O peak airway pressure (22). This resulted in a lower extravascular lung water content than in animals ventilated without PEEP. They attributed this beneficial effect of PEEP to the preservation of surfactant activity (the importance of surfactant activity in the control of lung fluid balance and the effect of PEEP on surfactant function is discussed in the section on INCREASED TRANSMURAL PRESSURE IN ALVEOLAR VESSELS). It was subsequently shown (5) that PEEP decreased the amount of edema, but did not change the severity of the permeability alterations, as assessed by the increase in dry lung weight, with respect to that in extravascular lung water (5). Edema remained confined to the interstitium in the presence of PEEP, whereas alveolar flooding occurred in its absence (5, 22). As already mentioned, whereas diffuse alveolar damage occurred in animals ventilated without PEEP, no such alteration was observed in the lung epithelium of animals ventilated with PEEP (Figure 9). The only ultrastructural abnormality was endothelial blebbing. The possible explanations for this intriguing observation will be discussed subsequently.
PEEP reduces the VT and increases the mean intrathoracic pressure when end-inspiratory pressure and thus volume are fixed, and each of these can affect edema formation. Studies on perfused canine lobes in situ (90) have shown that the rate of hydrostatic edema formation increases with VT for equivalent perfusion flow rates and microvascular pressures. When identical increases in mean airway pressure were produced by applying PEEP or by increasing VT, edema developed less rapidly under PEEP, suggesting that large cyclic changes in lung volume promote edema. This was also the conclusion of the study by Corbridge and coworkers (91), who observed that ventilating dogs with hydrochloric acid-injured lungs with a small VT and a high PEEP produced less edema than ventilation with a large VT and a low PEEP at the same end-inspiratory volume, despite identical cardiac outputs and pulmonary vascular pressures. In keeping with this observation, it was recently shown (87) that ventilation of pigs having oleic acid- induced lung injury with 10 cm H2O PEEP resulted in less edema when the VT was reduced from a normal (12 ml/kg BW) to a low value (6 ml/kg BW).
For a given end-inspiratory airway pressure, the application of PEEP produces an increase in mean intrathoracic pressure, which adversely affects cardiac output (35, 74). This decrease in cardiac output could explain the abovementioned finding that rats ventilated with 45 cm H2O peak airway pressure and a 10 cm H2O PEEP had less edema than those ventilated at the same peak pressure but without PEEP (5, 22). When the fall in systemic arterial pressure consecutive to this ventilation modality was corrected by dopamine infusion, the edema was more severe (Figure 12) (88). The amount of edema was correlated with the systemic blood pressure, suggesting that increased filtration (because of higher pulmonary capillary pressure) was responsible for this aggravation. Nevertheless, the animals ventilated with PEEP that received dopamine had less edema than those with no PEEP, despite similar arterial pressures, suggesting that hemodynamic alterations were not the only explanation for the effect of PEEP on pulmonary edema formation (Figure 12).
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In conclusion, the reduction of edema and severity of cell damage by PEEP during ventilation-induced edema may be linked to reduced lung tissue stress (by decreasing VT), and capillary filtration (at least in part because of hemodynamic depression), as well as to the preservation of surfactant, as suggested by Webb and Tierney (22). This latter point will be examined in the section on increased transmural pressure in alveolar vessels.
Effects of increasing PEEP when VT is kept constant: importance of end-inspiratory volume. The overall degree of lung distention, or the end-inspiratory volume, is probably one of the most harmful factors that contributes to the development of ventilator-induced edema. Hence, rats ventilated with a low VT (7 ml/kg BW) plus 15 cm H2O PEEP developed pulmonary edema, whereas those rats ventilated with the same VT plus a 10 cm H2O PEEP did not (Figure 13) (88). Doubling the VT, which nevertheless remained within the physiologic range, produced pulmonary edema only in animals ventilated with a 10 cm H2O PEEP (Figure 13). Thus, even small VT may be harmful if FRC is sufficiently increased. The important role of uncontrolled increases in end-inspiratory volume in the genesis of VILI when functional residual capacity is increased with PEEP was also illustrated by the work by Muscedere and colleagues (31). Large airway leaks occurred in two of nine surfactant-depleted isolated rabbit lungs ventilated with a low VT (5 to 6 ml/kg BW) and a PEEP at around 25 cm H2O (the results of this study will be further detailed in the discussion of low lung volume injury).
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In conclusion, mechanical ventilation-induced lung edema may occur whenever there is a certain degree of overall lung overinflation. Hence, end-inspiratory volume is the major determinant of ventilator-induced lung edema (75). Increasing VT promotes edema formation at a given end-inspiratory pressure (and volume), whereas adding PEEP seems to slow the development of edema and diminish the severity of tissue injury, but it does not prevent the alterations in microvascular permeability (5, 88). On the contrary, when PEEP results in additional overinflation, there is greater edema (Figure 13).
Roles of the magnitude of airway pressure and lung volume changes, duration of ventilation, and animal size.
Possible pressure-volume threshold for edema and permeability alterations. There is no well-defined volume above which alterations appear as the lung is overexpanded. The presence of an airway pressure threshold is however suggested by some of the above studies on isolated lungs by Parker and colleagues (53) (see ISOLATED LUNGS) and by the work by Carlton and coworkers (27) in intact animals. Carlton and coworkers produced graded increases in VT in lambs and studied their effect on lymph flow and protein concentration. Peak inspiratory pressure (and therefore VT) was increased in three successive steps (each of 4 h) from baseline (16 cm H2O) to 61 cm H2O. There was no change in lymph flow or protein composition during the first two steps (33 and 43 cm H2O peak inspiratory pressure). But there was a 4- to 6-fold increase in lung lymph flow at the highest peak inspiratory pressure (61 cm H2O, which corresponded to a VT of 57 ml/kg). Similarly, the lymph-plasma protein concentration ratio did not change until the highest peak inspiratory pressure was reached. It then increased significantly, indicating altered microvascular permeability. The investigators concluded that microvascular alterations occur above a pressure threshold at 43 to 61 cm H2O, rather than gradually. However, they also suggested that microvascular permeability and protein sieving properties were already altered at airway pressures below this hypothetical threshold. Indeed, the albumin-globulin ratio in the lymph became lower than in the plasma when peak airway pressure was only 43 cm H2O, reflecting the loss of the capillary sieving properties. This may indicate that the actual threshold may be lower than reported in this study. Indeed, pulmonary edema has been regularly produced with airway pressure levels lower than those used in this study. A peak inspiratory pressure of only 30 cm H2O was enough in small animals like rats that develop mechanical ventilation-induced lung edema much more rapidly (22). Similarly, intact rats developed moderate pulmonary edema after 1 h of mechanical ventilation with a VT of 20 ml/kg BW (92). Consistent with the absence of a well-delimited pressure or volume threshold, Tsuno and coworkers (26) found that ventilating sheep with a peak inspiratory pressure of 30 cm H2O for more than 40 h invariably resulted in increased wet lung weight and gross pathologic alterations. Finally, stable (2 h) isolated perfused rat lung preparations could not be obtained when peak airway pressure was above 13 cm H2O (54) (a pressure level which nevertheless resulted in a greater inflation than in closed-chest animals).
Several important conclusions can be drawn from these findings. First, it is very difficult to examine separately the effects of a given regimen of pressure and volume during mechanical ventilation and those of time. Indeed, as discussed previously, ventilatory settings which seem safe for as long as several hours (27) may prove deleterious when ventilation is prolonged for up to 2 d (26). This is analogous to the administration of a toxin: both individual doses and repeated doses must be taken into account. This issue is further complicated by the influence of species size, the smaller species being more prone to VILI. For instance, the ratio of extravascular lung water to blood-free dry lung weight in open-chest dogs ventilated for 30 min with 64 cm H2O peak pressure was only 28% greater than that of animals ventilated with low (22 cm H2O) airway pressures, indicating mild edema (25). By contrast, it took only 2 min to obtain edema of roughly the same severity (17% increase in the extravascular lung water to blood-free dry lung weight ratio) in rats ventilated with 45 cm H2O peak pressure (6). This increase reached 90%, indicating severe edema, when ventilation was continued for up to 20 min (5).
There are many other examples of the slower appearance of VILI in intact large animals. Carlton and coworkers (27) found an increase in the extravascular lung water to dry lung weight ratio of only 19% in intact lambs ventilated with 58 cm H2O peak inspiratory pressure for 6 h. Microscopic examination was either normal or showed only mild perivascular edema, but no alveolar edema. Alveolar flooding occurred in sheep, but after 18 h of ventilation with a peak inspiratory pressure of 50 cm H2O (93). Wet lung weight normalized for body weight was 189% that of normal lungs (values for normal lungs obtained from [26]). After 27 h of this ventilation, the lung weight was 236% that of normal lungs. Thus, whereas ventilation may produce severe edema in small animals in less than 1 h, ventilation for 24 h or more with similarly high airway pressures is necessary in larger animals. The reasons for these differences in sensitivity have not yet been explained. Their consequences will be discussed under MECHANISMS OF ALTERED PERMEABILITY.
These studies suggest that any pressure-volume threshold is probably low and that duration greatly influences the severity of ventilator-induced lung edema, in addition to the degree of distention.
Reversibility of limited abnormalities. Prolonged ventilation at high airway pressure results in substantial, probably irreversible, damage. For example, rats ventilated with intermittent positive pressure with 45 cm H2O peak pressure for 20 min, which is relatively long for a small animal (see preceding section), were moribund and their lungs had lesions analogous to those found in severe ARDS (4, 5). Similarly, sheep subjected to 50 cm H2O peak pressure ventilation (24) died within 48 h and piglets in which an acute lung injury was induced by high-pressure mechanical ventilation (66) showed diffuse alveolar cellular proliferation after several days of support by conventional mechanical ventilation. But the changes in permeability and the edema resulting from moderate insults may be reversible, as in certain types of permeability edema (56, 94). Carlton and colleagues (27) found that the lung lymph flow and lymph-plasma protein concentration ratio of lambs ventilated at 61 cm H2O peak pressure for 4 h (a relatively short time for closed-chest large animals, as explained in the preceding section) and allowed to recover returned to normal, indicating reabsorption of excess pulmonary fluid. But the albumin-globulin ratio in the lymph remained below that in plasma during the 6-h recovery period, suggesting the persistence of some altered microvascular permeability. Rats subjected to 35 mm Hg peak inspiratory pressure mechanical ventilation for only 2 min developed mild permeability edema with significant increases in extravascular lung water, dry lung weight, and albumin distribution space (6). There appeared to be no macroscopic alveolar edema after such a short period of ventilation, but ultrastructural examination disclosed endothelial blebbing identical to that described after longer periods (6). Hence, microvascular abnormalities are almost immediate, at least in small animals. The epithelial lining fluid volume (calculated using a modification of the method of Rennard and coworkers [95]) and protein content were increased by 180% and 80%, respectively, and a few blood cells were found in lavage fluid, indicating alveolar hemorrhage. Some animals were allowed to recover for as long as 3 h (6). Both extravascular lung water and dry lung weight promptly returned to normal, indicating that reabsorption of edema can be very rapid. Edema reabsorption does not necessarily indicate restoration of normal alveolocapillary barrier properties, but the 125I-albumin distribution space measured after the high-pressure ventilation period was normal, indicating no further altered albumin permeability. Extravascular lung water and epithelial lining fluid volume decreased in parallel, reflecting the resorption of the interstitial and alveolar edema. There were no marked changes in epithelial lining fluid protein content, reflecting the slower-than-water clearance of protein in alveolar edema fluid (96). Thus, very short periods of overinflation can profoundly affect microvascular permeability and deep lung fluid balance. Most of these lung fluid balance abnormalities are reversible within hours although recovery of normal alveolar homeostasis may be slower.
Low Lung Volume Injury
Healthy lungs tolerate mechanical ventilation with physiologic tidal volumes and low levels of PEEP for prolonged periods without any apparent damage. The terminal airways remain open even at end-expiration during the normal tidal cycle and close at lower volumes, near the residual volume. Moreover, healthy lungs do not seem to be damaged when terminal units are repeatedly opened and closed for short periods (1 h) by negative end-expiratory pressure (which nevertheless reduces compliance and alters gas exchange) (97). But mechanical ventilation, even without overinflation, may worsen any preexisting lung injury because of regional overinflation due to the shrinking of the injured lung and uneven distribution of its mechanical properties and because of the increased shear stress in terminal units due to the repeated opening and closing of small airways (these mechanisms will be detailed in the section entitled POSSIBLE MECHANISMS OF VENTILATION-INDUCED LUNG INJURY). This may have been the case in the work by Woo and Hedley-Whyte showing that closed-chest dogs ventilated with very large (50 ml/kg body wt) tidal volumes for 8 h had no discernible abnormalities, whereas severe pulmonary edema developed in open-chest animals after similar ventilatory settings (38). Besides the hemodynamic differences between the two situations, it is possible that the reduction of lung functional residual capacity in open-chest animals ventilated without PEEP caused cyclic collapse and opening of terminal airways and further damage during tidal ventilation. A recent study (98) confirmed that repeated collapse and reexpansion of surfactant-deficient terminal units during ventilation with negative end-inspiratory pressure for 3 h leads to severe functional (decreased compliance and arterial PaO2) and histologic lung damage (bronchiolar epithelial necrosis and hyaline membrane formation).
Lower inflection point on lung pressure-volume curve and VILI. There may be an increase in trapped gas volume during pulmonary edema and acute lung injury, especially when surfactant properties are altered, because of instability of terminal units (99). In such conditions, the slope of the inspiratory pressure-volume curve of the respiratory system often changes abruptly at low lung volume. This change occurs frequently within the VT, reflecting the massive opening of previously closed units (Figure 14). This has been termed the "lower inflection point." Most clinicians are aware of the importance of this phenomenon in terms of arterial oxygenation, because setting PEEP above this inflection point usually results in a very abrupt decrease in shunt and increase in PaO2 (100).
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Attention has focused only relatively recently on the possibility that pulmonary lesions may be aggravated if this inflection point lies within the VT. Experimental evidence for this was initially provided by studies comparing conventional mechanical ventilation with high-frequency oscillatory ventilation in premature or surfactant-depleted lungs. More recently, studies performed during conventional mechanical ventilation of surfactant-depleted lungs with various levels of PEEP also provide support to the possibility that the repeated opening and closing of terminal units causes additional injury (28, 29, 31).
Effects of conventional mechanical ventilation and high-frequency oscillatory ventilation on premature and surfactant-deficient lungs. The search for a way of avoiding the large changes in pressure-volume generated by conventional mechanical ventilation, which could be responsible for additional lung damage, has led to the development of high-frequency oscillatory (HFO) ventilation. Studies on prematurely delivered lambs (104), baboons (105), and adult rabbits made surfactant-deficient by repeated saline lavage (106) indicate that the efficiency of HFO on lung lesions depends on the performance of a preliminary sustained static inflation (also called "lung conditioning") to recruit the greatest possible number of lung units before starting HFO (14).
Hamilton and coworkers (106) compared oxygenation and lung pathology in saline-lavaged rabbits ventilated by conventional mechanical ventilation with a 6 cm H2O PEEP and HFO at similar mean airway pressure (15 cm H2O). Both groups underwent static inflation at 25 to 30 cm H2O for 15 s. HFO-treated animals had considerably higher PaO2. More importantly, whereas conventionally ventilated rabbits had extensive hyaline membrane formation, the lungs of HFO-treated animals had few if any hyaline membranes.
Meredith and coworkers, working on premature baboons, showed that hyaline membrane disease was prevented when HFO was preceded by a recruitment maneuver (105). The importance of successful recruitment for preventing lung injury during HFO was illustrated by the severity of the changes in microvascular and alveolar permeability and histologic damage, which were similar to those caused by conventionally ventilating premature newborn lambs, when recruitment was not successful (104). Failure to achieve recruitment was ascribed to the inability of premature lungs to secrete enough surfactant (104).
Another study (107) also indicated the pivotal role of lung recruitment. Rabbits made surfactant-deficient (by repeated lung lavage) were subjected to conventional mechanical ventilation with a PEEP (8 cm H2O) below the inflection point on the pressure-volume curve and a mean airway pressure of