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Pulmonary Perspective The Role of Ventilation-induced Surfactant Dysfunction and Atelectasis in Causing Acute Respiratory Distress Syndrome Richard K. Albert1 1

Department of Medicine, Denver Health, Denver, Colorado; and University of Colorado Health Sciences Center, Aurora, Colorado

This Pulmonary Perspective describes a new pathophysiologic scenario by which the acute respiratory distress syndrome (ARDS) might develop, summarizes the literature on which this new scenario is based, and discusses the resulting implications with respect to patient management. Rather than ARDS occurring as a result of the inflammatory response associated with predisposing risk factors, the proposed scenario theorizes that the initiating problem is atelectasis that develops as a result of a surfactant abnormality that is caused by spontaneous or mechanical ventilation, together with our current approaches to patient positioning and sedation. The proposed pathophysiology implies that ventilation-induced lung injury occurs before, and causes, ARDS (rather than developing after the fact and only serving to magnify the existing injury) and that some instances of ARDS are iatrogenic. If the proposed scenario is correct, it also implies that at least some instances of ARDS might be prevented by implementing a number of simple, safe modifications in patient care. Keywords: surfactant; atelectasis; ARDS

The pathophysiology of the acute respiratory distress syndrome (ARDS) is currently believed to begin with an inflammatory response that occurs in association with various predisposing risk factors (Figure 1). This inflammatory response increases alveolar epithelial and pulmonary vascular endothelial permeability causing alveolar filling, which in turn causes atelectasis and shunt, in part by inactivating surfactant. Critical hypoxemia ensues, resulting in the need for mechanical ventilation, thereby providing the setting in which ventilator-induced lung injury can develop as a result of amplified tissue tensions at the junctions of closed and open units when they are subjected to high alveolar pressure (i.e., volutrauma) and/or from cyclical airspace opening and closing (i.e., atelectrauma). These stresses are believed to further stimulate the inflammatory response (termed biotrauma), resulting in progressive lung injury and systemic inflammation (1). The purpose of this Pulmonary Perspective is to propose a different pathophysiologic scenario for ARDS, one that is supported by considerable literature and is focused on the adverse effects of ventilation (both spontaneous and mechanical) on surfactant and the atelectasis that develops from the increase in surface tension together with our current approaches to patient positioning and sedation (Figure 2). If this scenario were correct, at least some instances of ARDS might be iatrogenic, and some of these may be potentially preventable by altering our current

(Received in original form September 15, 2011; accepted in final form December 14, 2011) Correspondence and requests for reprints should be addressed to Richard K. Albert, M.D., Denver Health, 777 Bannock, MC 4000, Denver, CO 80204-4507. E-mail: [email protected] Am J Respir Crit Care Med Vol 185, Iss. 7, pp 702–708, Apr 1, 2012 Copyright ª 2012 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201109-1667PP on January 6, 2012 Internet address: www.atsjournals.org

approaches to patient care that contribute to ventilation-induced surfactant dysfunction and atelectasis. As depicted in Figure 2, if the proposed pathophysiology is correct, spontaneous or mechanical ventilation of normal lungs has to alter surfactant, increase surface tension, and cause atelectasis; supine positioning and sedation also have to cause atelectasis; increased surface tension has to be necessary and sufficient to cause atelectrauma via spontaneous or mechanical ventilation; and changes in surfactant and surface tension have to precede the onset of ARDS. If the proposed pathophysiology can be interrupted, thereby preventing ARDS, different approaches to care have to be able to restore surfactant and reduce or prevent atelectasis. The following summarizes the literature supporting each of these requirements.

VENTILATION OF NORMAL LUNGS ALTERS SURFACTANT, INCREASES SURFACE TENSION, AND CAUSES ATELECTASIS In 1947, Drinker and Hardenbergh (2) noted that anesthetized, spontaneously breathing, supine animals developed hemorrhagic consolidation in their dorsal-caudal lung regions and documented that these areas were atelectatic. Wu and colleagues (3) reported that lung compliance decreased during mechanical ventilation of anesthetized humans in 1956, and several others confirmed this observation in the 1960s studying patients who were using tank respirators. Bernstein (4) found similar changes in normal rabbit lungs, as did and Mead and Collier (5) in lungs of dogs that were either breathing spontaneously or mechanically ventilated, and Mead and Collier (5) first linked the observed changes in compliance to dorsal-caudal atelectasis in 1959. Clements (6) first suggested that surfactant “might be an ‘antiatelectasis factor’” in 1957, that the “long-term stability of the lungs requires periodic replenishment of surfactant,” and that “the mechanism and speed with which the lungs spontaneously decrease in compliance and become atelectatic.probably depend significantly, and perhaps solely, on the viscoelastic parameters of the surface films” (6–8). Greenfield and colleagues (9) first suggested that the increase in surface tension and atelectasis developed as a result of ventilation depleting, altering, or interfering with surfactant. Subsequently, numerous studies confirmed that ventilation for as little as 5 minutes increased lung elastic recoil, opening pressures, and surface tension of lung extracts and caused atelectasis, and that the changes were directly related to the size of the VT and the duration, and possibly the rate, of ventilation and were inversely related to the level of positive end-expiratory pressure (PEEP) (e.g., 10–13). Wyszogrodski and colleagues (13) found that large VT ventilation released surfactant into the alveolar space but also increased the surface tension of lung extracts and proposed that ventilation inactivated, rather than depleted,

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Figure 1. Current schematic of the pathophysiology of ARDS.

surfactant. The effect of PEEP on surface tension was explained by Clements and colleagues, Brown and colleagues, and Tierney and Johnson (8, 14, 15), who found that compressing surfactant to less than 50% of its initial area resulted in the film rupturing on reexpansion with loss of its ability to lower surface tension. Webb and Tierney (16) found that rats ventilated with large VT and no PEEP developed severe hypoxemia and decreased compliance. All the animals died within 1 hour, with evidence of alveolar edema as well as other pathological abnormalities. Although this study is frequently interpreted as showing that mechanical ventilation injures lung as a result of overdistension and/or cyclical airspace opening and closing, the authors found no evidence of tissue disruption and concluded that overdistension was probably not the explanation for the observed abnormalities. Cyclical airspace opening and closing was never mentioned in the manuscript, but the authors suggested that atelectasis was unlikely because of the high inflation pressures used. Rather, Webb and Tierney (16) attributed their findings to surfactant depletion that occurred as a result of the large ventilatory excursions and/or surfactant dysfunction that developed from repeated compression of the fluid film in the absence of PEEP. Accordingly, although most attribute the mortality benefit of low VT ventilation in ARDS to reduced lung distension,

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the findings of Webb and Tierney (16), together with those cited above, suggest that the benefit might result from it causing less surfactant dysfunction. Surfactant can be separated by centrifugation into large aggregates and small aggregates, with the latter having much less surface activity. Cycling surfactant ex vivo or ventilating lungs in vivo or in situ with large VT and no PEEP converts large aggregates to small aggregates and impairs large aggregate function. Larger changes in surface area result in greater conversion (17, 18), but compliance and surface tension decrease in as short a time as 15 minutes even when VT is low or normal, with accompanying increases in inflammatory cytokines and histologic evidence of lung damage (18–21). Young and colleagues (22) demonstrated that compliance decreased when lungs were held in inflation with air at 3 cm H2O for 20 minutes with no VT. They attributed the changes to increases in surface tension (because no change in compliance occurred when the lungs were distended with liquid to the same volume) and postulated that the change in surface forces would likely result in atelectasis at low transpulmonary pressure (and transpulmonary pressures are lowest in dorsal-caudal lung regions where much of the atelectasis develops in ARDS).

SUPINE POSITIONING AND SEDATION CAUSE ATELECTASIS Dr. William Dock seems to be the first to link patient positioning and sedation with atelectasis. In a 1944 article entitled “The evil sequelae of complete bed rest,” he noted that, in spontaneously breathing patients: . many disturbances of function, such as massive collapse of the lung . have become evident only because the patient was forced to spend hours or days in the dorsal recumbent position . so far as I know no other animal lies on its back when ill.. Since this is not a restful way to sleep, sedatives are given to many patients who are required to live in this fashion . serious evil sequelae of complete bed rest may appear in a few days.. The pathologist has known for years that patients dying after only a day or two in bed may have airless patches scattered through the dorsal and caudal parts of the lungs. (23) In 1944, Drinker wrote: . man is never absolutely sure to remain still physically for any length of time unless he is anesthetized or dead.. In animals subjected to prolonged anesthesia, livid hyperemic areas in the dependent parts of the lungs are [nearly] invariable. Experimental observation thus displays exactly the lung changes Dock has described for human patients. . If used on supine patients, resuscitators are perfectly organized to add to already present lung lesions, from which the patient must recover if he survives acute asphyxia. (24)

Figure 2. Proposed pathophysiology of ARDS.

Investigators from Sweden performed an extensive series of studies demonstrating that dorsal-caudal atelectasis and shunt develop in nearly 90% of normal, supine subjects within minutes of receiving anesthesia, regardless of whether they were spontaneously breathing or mechanically ventilated; that PEEP consistently decreased, but did not eliminate, the atelectasis but was less effective in reversing the shunt; that the degree of atelectasis

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correlated with body weight and the shape of the thorax; that the atelectasis could be reduced or prevented by moving the subjects out of the supine position, by applying PEEP after performing a recruitment maneuver, by stimulating the phrenic nerve (indicating the role of a noncontracting diaphragm), or by having patients inhale 30% rather than 100% oxygen (suggesting that absorption atelectasis contributes to the problem) (25–30). Others have demonstrated that atelectasis relates to the mass of the heart, mediastinum, and abdomen, the shape and function of the thoracic cage and the diaphragm, and to differences in regional diaphragm movement (31–34).

Large aggregate forms of surfactant decrease before increases in permeability or gas exchange abnormalities occur (48), and surfactant pool sizes and surface lowering activity are altered 1 hour before oxygen decreases after instituting high-stretch ventilation (40). Thammanomai and colleagues (49) found that SP-B levels decreased after ventilating normal mice for only 20 minutes. Greene and colleagues (50) reported that SP-A and SP-B concentrations were reduced in bronchoalveolar lavage fluid of patients who were at risk for developing ARDS before the time they met roentgenographic or gas exchange criteria for ARDS.

INCREASED SURFACE TENSION IS NECESSARY AND SUFFICIENT TO CAUSE ATELECTRAUMA IN THE SETTING OF SPONTANEOUS OR MECHANICAL VENTILATION

RESTORATION OF SURFACTANT PREVENTS AND RESTORES ATELECTASIS

Coker and colleagues (35) and Taskar and colleagues (36) both found that ventilator-induced lung injury only occurred in animal models when surfactant was inactivated. Bilek and colleagues (37) found that fluid forced between glass plates that were coated with epithelial cells and separated by a distance that was similar to the diameter of small airways generated large pressure gradients that damaged the cells. When surfactant was added to the fluid, a lower pressure was needed to force the fluid through the opposed surfaces and the epithelial injury was prevented. Ikegami and colleagues (38) developed mice that conditionally expressed normal levels of human surfactant-associated protein B (SP-B) when they were receiving doxycycline. When doxycycline was withdrawn, SP-B decreased at 4 days, accompanied by increases in surface tension, proteins, and inflammatory cells in bronchoalveolar lavage and IL-1b increased in lung tissue. Forty percent and 70% of the spontaneously breathing animals died at 4 and 6 days, respectively, from cyanosis and respiratory distress. The changes reversed when doxycycline was reintroduced. Increasing endogenous surfactant pools or intratracheal administration of exogenous surfactant protects against the hypoxia, the decrease in compliance, the protein leakage, and the release of inflammatory cytokines that occur when ventilating animals with large VT and no PEEP (39–43). Walker and colleagues (44) confirmed this effect in mice ventilated with a small VT (i.e., 5 ml/kg) and a PEEP of 3 cm H2O.

CHANGES IN SURFACTANT AND SURFACE TENSION PRECEDE THE ONSET OF ARDS Hedley-Whyte and colleagues (45) noted that lung compliance fell within 14 minutes of instituting large VT ventilation in dogs, but physiologic shunting and the alveolar-to-arterial oxygen tension difference did not increase until 30 minutes later. Finley and colleagues (46) found that surface tension fell before the development of experimental atelectasis. Hudson and colleagues (47) identified patients who required mechanical ventilation for sepsis, overdoses/aspiration, or trauma and followed them to determine when in their hospital course they developed ARDS. Only about 20% of the patients who ultimately developed ARDS had the syndrome at the time they were diagnosed with any of the three risk factors, fewer than 50% developed ARDS within 24 hours, and it took more than 6 days for everyone who developed the syndrome to do so. Accordingly, although the frequency with which ARDS might occur as a result of the proposed pathophysiologic scenario is unknown, it may represent as many as 50 to 80% of the instances of ARDS that develop after risk factors for the syndrome have been diagnosed.

In Dock’s paper on bed rest (23) he also noted that dorsalcaudal atelectasis was reduced when patients took large breaths, “patients with air hunger and deep respiration up to the final hour show notably less collapse post mortem than do those with normal blood levels of hemoglobin and base . it is the acidosis and air hunger which prevent collapse” (23). Drinker, on observing the first subject being tested in the mechanical ventilator devised by his brother in 1928, noted that: a more interesting matter relating to the comfort of the young man . was his request that from time to time the respirator be made to give him a deep inspiration, a sort of prolonged yawn or sigh. This gave comfort to him and thought to me . if [man] has remained quiet for a long time, without the possibility of movement, he indulges often in a long breath, a sigh, or a yawn. . The way to treat pulmonary stasis and atelectasis is to prevent their occurrence and, thereby, their eventual promotion of more serious conditions. This is accomplished by change in position and . best by a few deep respirations. (24) The first report describing treatment of poliomyelitis with mechanical ventilation published in 1930 by physicians who were using the Drinker respirator (51) included comments on the importance of periodically turning the patients from supine to prone and frequently administering deep breaths. Bernstein (4), studying rabbits, was the first to demonstrate that ventilation-induced changes in lung pressure-volume curves could be prevented if the lungs were periodically subjected to large inflations. His observation was confirmed by Mead and Collier (5) in dogs that were spontaneously breathing or receiving mechanical ventilation and by several other groups studying humans (52–56). In 1965 Pattle reasoned that: There thus exists a surface tension, g0, at which the free surface energy is at a minimum; if the surface tension is less than this, no recruitment of material to the lining film from the underlying complex can take place, and there will be a tendency for material to be desorbed from the surface film.. Any desorption of the surface film will result in a decrease in the internal surface area; there will be a consequent fall in the volume at maximum pressure and in the compliance calculated from that volume. Eventually collapse of some or all of the alveolar units will occur. If the ventilatory cycle is kept regular, therefore, increase in compliance and slow collapse are to be expected.. If desorption from the lining film during quiet breathing

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does in fact take place, it follows that one of the functions of a yawn or deep breath is to recruit more material to the lining film. If such reactions are prevented . slow collapse of the lining film, and eventually of the alveolar spaces, may be expected. If artificial respiratory is being used, the collapse might be prevented by giving the lungs an occasional maximal inflation. [emphasis added] (57) Tierney and Johnson (15) also theorized that instability of surfactant would cause gradual atelectasis during shallow breathing and that “the alveolar surface film can be replenished by a single deep breath.” A direct link between the effect of sighs and surfactant was subsequently demonstrated by numerous investigators observing that large VT ventilation, large gasps in spontaneously breathing animals, single large inflations with air or liquid, or even single stretches of type II cells all increased the release of active surfactant (58–62). Biologically variable ventilation is similar to sigh ventilation, but rather than delivering a sigh that is regularly interspersed among constant VT breaths, variable ventilation delivers breaths that vary in volume randomly over time (with the volume of the larger breaths being similar to those given by sighs). Variable ventilation facilitates recruitment of atelectatic lung, prevents deterioration in gas exchange that occurs with constant VT ventilation of animals with normal lungs, and improves mechanics and gas exchange in various models of acute lung injury (63–68). As was observed with sigh breaths, biologically variable ventilation also increases the release of surfactant into the alveolar space (65). Because of concerns that lower VT’s being used to ventilate patients with ARDS could precipitate atelectasis, a number of studies have evaluated the short-term effects of sighs in patients with ARDS or ALI. Pelosi and colleagues (69) delivered three consecutive sigh breaths over 1 minute for 1 hour and found that the PaO2 and lung volume increased and that lung elastance decreased. The improvements reversed 1 hour after stopping the sighs. Similar results were reported by Patroniti and colleagues (70). Although these groups attributed the benefits to recruitment of atelectatic lung, finding that derecruitment occurred when sighs were stopped despite the fact that PEEP did not change is also consistent with the idea that the benefits resulted from transient release of surfactant occurring during the time the sighs were administered. Although the effect of sighs may seem inconsistent with the direct relationship between the VT and surfactant dysfunction discussed above, the discrepancy is explained by the sizes of the VT’s used and the frequencies and durations with which they were administered under the two situations. Studies showing that larger VT’s altered surfactant and increased surface tension used VT’s that ranged from 30 to 100% of the control value administered continuously for minutes to hours (10, 12, 13, 17, 39, 40, 71–73). Those showing that large VT’s released surfactant and increased compliance used VT’s ranging from 130 to 400% of the control VT, with the sigh breaths given either intermittently or for very brief periods of time (5, 53, 54, 58, 62, 69, 70).

PRONE POSITIONING PREVENTS AND REVERSES ATELECTASIS AND LIMITS VENTILATION-INDUCED LUNG INJURY Dock (23) warned that “The physician must always consider complete bed rest as a highly unphysiologic and definitely hazardous form of therapy, to be ordered only for specific indications and discontinued as early as possible” and that the hazards associated with bed rest could be reduced by “. omission or rigid

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restriction of narcotics and sedatives, encouragement of deep breathing exercises, [and] frequent changes of posture .” (23). Numerous studies in normal subjects, in patients with ARDS or ALI, and in animal models of ALI have shown that ventilation is more uniformly distributed, shunt and ventilation-perfusion heterogeneity are decreased, oxygenation is improved, ventilatorinduced lung injury is reduced and delayed, and recruitment maneuvers are more effective when patients or animals are positioned prone rather than supine. Although the mechanism(s) of these changes is debated, the literature has consistently shown that the gravitational gradient in pleural pressure is more uniform in the prone compared with the supine position (74–80). A more uniform pleural pressure gradient will increase the endexpiratory volume of alveoli in dependent lung regions, thereby reducing atelectasis and limiting inactivation of surfactant by compression of the film that occurs at low end-expiratory volumes.

CONSIDERATION OF CONFLICTING FINDINGS Sighs

If sigh breaths release surfactant and surfactant release limits atelectasis, why have no studies found benefits of adding sighs to various ventilatory strategies? Housely and colleagues (81) found no difference in oxygenation or in dynamic compliance after adding sighs to nine patients receiving positive pressure ventilation, but potential benefits could have been obscured by the fact that the patients were also receiving hourly respiratory care that included a 2-L sigh given by Ambu bag or via their ventilators. Davis and colleagues (82) found no effect of sighs on oxygenation or compliance, but all the patients were spontaneously breathing and could alter their VT’s on demand. Levine and colleagues (83) found no effect of sighs but only sought changes in oxygenation and acknowledged that their study was too short to evaluate possible changes in atelectasis. Accordingly, although these studies have not observed benefits of sighs, all have problems with study design, all were only conducted for short periods of time, none evaluated the effect of sighs on atelectasis, and none administered sighs prophylactically. As noted above, two groups have demonstrated substantial shortterm physiologic improvements from short-term administration of sighs in patients with ARDS (67, 68). Surfactant Replacement

If ventilation alters surfactant and causes atelectasis, why have none of the randomized trials of surfactant replacement in ARDS reduced mortality? Studies of surfactant replacement for ARDS are limited by concerns about differences in preparation composition, modes of administration and dosing, and the fact that a variety of proteins, lipids, proteases, and other substances can inactivate surfactant. In addition, all of the studies have been conducted in patients with established ARDS. The pathophysiology proposed in Figure 2 involves surfactant abnormalities developing before the onset of ARDS. In addition, increasing surfactant release into individual alveoli by incorporating sighs into a ventilator strategy should be a far more effective way of decreasing surface tension at the alveolar level than administering exogenous surfactant into the airway and hoping it distributes to atelectatic airspaces. Prone Positioning

If prone positioning reduces atelectasis, why have the trials of prone positioning in ARDS found no reduction in mortality? Although no reduction in mortality has been observed, all the studies to date had large type 2 errors such that they do not exclude

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the possibility that mortality was reduced. In addition, these studies also instituted prone positioning in patients with established ARDS, generally as a rescue therapy when other approaches to ventilatory support have failed. Accordingly, prone positioning has also never been assessed as a prophylactic intervention. PEEP

If atelectasis is so important in the pathophysiology of ARDS, why not just limit atelectasis by increasing PEEP? Countering an increased surface tension (thereby reversing the resulting atelectasis) requires increasing transpulmonary pressure either by increasing airspace pressure or by decreasing pleural pressure. PEEP increases end-expiratory airspace pressure, but because airspace opening pressures can vary markedly between and within patients, and because a gravitational pleural pressure gradient exists in the supine position, applying PEEP to reverse or limit dorsal-caudal atelectasis will almost always come at the expense of overdistending ventral lung regions and other areas having lower opening pressures. In addition, a number of early studies suggested that prophylactic administration of PEEP reduced the incidence of ARDS. These were limited by study design issues, however, and Pepe and colleagues (84) in a well-designed randomized, controlled trial subsequently found no such benefit. Concern for Volutrauma

Could the larger VT’s of sigh breaths cause ventilator-induced lung injury via volutrauma? Studies of biologically variable ventilation report reductions in atelectasis, benefits in gas exchange, and improvements in mechanics suggesting that intermittent administration of sigh breaths reduced rather than augmented ventilator-induced lung injury (66–68).

CONCLUSIONS The current pathophysiologic scenario of ARDS includes ventilator-induced lung injury as a factor that can worsen the severity of the syndrome. The literature reviewed above documents that spontaneous or mechanical ventilation of normal lungs alters surfactant and increases surface tension, that increased surface tension is necessary and sufficient to cause atelectasis, that atelectasis is augmented by supine positioning and sedation, that constant VT ventilation limits surfactant release from type II pneumocytes, and that changes in surfactant occur before the onset of ARDS. These findings suggest a new pathophysiologic scenario for ARDS, one in which normal lung regions become atelectatic from the increase in surface tension resulting from spontaneous or mechanical ventilation-induced decreases in surfactant, together with our current approaches to patient positioning and sedation. Spontaneous or mechanical ventilation of these atelectatic regions then causes the initial lung injury via atelectrauma. If the proposed scenario were correct, at least some instances of ARDS might be prevented by routinely administering sigh breaths in addition to ventilating with low VT’s and at least low levels of PEEP, by avoiding supine positioning, by increasing the frequency of repositioning and the use of prone or semiprone positioning, by limiting the use of sedation, and by implementing these changes in practice from the time patients are admitted and/or mechanical ventilation is initiated rather than waiting until ARDS has developed. Although these ideas are supported by considerable literature, they remain hypotheses that require testing in patients at risk for ARDS. Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: Some of the ideas discussed in this manuscript were clarified in discussions with Drs. John Clements and Jack Hildebrandt. Drs. Gordon Rubenfeld,

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John Marini, and Rolf Hubmyar read an earlier version of the manuscript and offered useful comments and suggestions.

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