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Lung Injury Caused by Mechanical Ventilation^*

^* From the Samuel Lunenfeld Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Supported in part by Medical Research Council (Canada).

Correspondence to: Arthur S. Slutsky, MD, FCCP, Mount Sinai Hospital, 600 University Ave, Suite 656A, Toronto, Ontario M5G 1X5; e-mail: arthur.slutsky{at}utoronto.ca

Over 250 years ago, John Fothergill presented an interesting case report, addressing for the first time the issue of lung injury that could be induced by artificial respiration.¹ The case involved a surgeon, William Tossack, who observed an apneic, pulseless individual who had collapsed due to noxious fumes from a coal pit. As described by Fothergill, "Mr. Tossack applied his mouth close to the patients, and by blowing strongly, pulling the nostrils at the same time, raised his chest fully by his breath. The Surgeon immediately felt six or seven very quick beats of the heart; the Thorax continued to play and the pulse was soon felt in the arteries. In one hour, the patient began to come to himself; within four hours he walked home; and in as many days, returned to his work." Fothergill went on to expand on the case report and suggested that mouth-to-mouth resuscitation may be better than using a mechanical method of insufflating the lungs with air using a pair of bellows because "the lungs of one man may bear, without injury, as great a force as those of another man can exert; which by the bellows cannot always be determin'd." Thus, Fothergill clearly understood and proposed the concept of lung injury that could be produced by artificial respiration.

Two hundred twenty-five years later, a classic article was rejected by the New England Journal of Medicine because one of the reviewers believed that the syndrome being described—ARDS² —was not really a new syndrome but rather another manifestation of respirator lung, or what now would be termed ventilator-induced lung injury (Dr. Tom Petty, personal communication at the 1998 Aspen Conference).

These episodes, separated by more than two centuries, highlight the importance placed on iatrogenic lung injury that has episodically highlighted the scientific literature. Although mechanical ventilation is one of the ultimate life-supporting technologies, over the past decade, there has been renewed interest in the injury that it can cause. This article will very briefly review the types of injury that can be caused by mechanical ventilation, and suggest that the iatrogenic injury caused by mechanical ventilation may have consequences not only in the lungs but also in distal organs and thus may be a major contributing factor to the morbidity and even mortality of some ventilated patients. In-depth reviews covering all or some of the topics described below have been published in the past 10 years, and the reader is referred to these for a more comprehensive analysis.^{3 4 5 6}

Types of Ventilator-Induced Lung Injury

Definitive evidence that mechanical ventilation can cause damage to the lungs in humans is difficult to obtain, since it is clearly not possible to perform experiments in which humans are exposed to strategies of ventilation that are thought to be injurious, solely for the purpose of examining the lung injury that it can cause. Thus, a better term that might be used in many human studies is ventilator-associated lung injury. Nevertheless, the weight of evidence obtained from experimental animal studies, correlative human studies, and interventional human studies addressing side effects of different ventilatory strategies is quite convincing that this entity is of clinical importance. For the purposes of this review, the forms of lung injury will be discussed according to the following headings: barotrauma, volutrauma, atelectrauma, and biotrauma.

Barotrauma
The concept that high airway pressures during positive pressure ventilation can cause gross injury manifest as air leaks has been well known and investigated for > 50 years. In a classic study, Macklin⁷ observed the close apposition of the alveoli to the bronchovesicular sheath and suggested that the "...pressure gradient between the alveoli and vessel sheath can be transiently increased, and air can gain access into the interstitial tissues." Air could then track along the bronchovesicular sheath toward the mediastinum and hence produce many of the manifestations that would now be recognized as barotrauma (pneumomediastinum, subcutaneous emphysema, pneumothorax, pneumopericardium, pneumoretroperitoneum, pulmonary interstitial emphysema, and systemic air embolism).

This form of ventilator-induced lung injury (VILI) can be very dramatic, and has been recognized clinically for many decades. What has not been entirely clear is which pressure (peak, mean, positive end-expiratory pressure [PEEP]...) is of paramount importance and what values of these pressures are injurious. What is certainly clear is that absolute airway pressure per se does not directly lead to injury. Although airway pressures are usually monitored clinically, transpulmonary (alveolar minus pleural) pressures are clearly more relevant. This can be best appreciated by the observation that very high airway pressures are often reached, but barotrauma is relatively uncommon. For example, Bouhuys,⁸ in examining the physiology of musical instruments, observed that trumpet players can reach airway pressures of 150 cm H₂O hundreds of times per day without developing barotrauma. As will be discussed below, the critical feature appears to be the degree of regional lung distention, rather than the absolute pressure reached.

Petersen and Baier⁹ studied the relationship of barotrauma (manifest as extra-alveolar air) as a function of airway pressure and noted a dose response relationship with levels of PEEP and peak inspiratory pressure, such that all patients with PEEP levels > 40 cm H₂O and/or all patients with peak inspiratory pressures > 100 cm H₂O developed barotrauma. This is an example of a correlative human study that may indicate that damage that can be caused by overdistention, but just as likely may indicate that patients who require such high pressures have extremely severe underlying lung disease that may predispose them to lung injury. There is, however, a suggestion in the literature that barotrauma may not be related to ventilation pressures or volumes. Weg and colleagues¹⁰ analyzed data from a trial of aerosolized synthetic surfactant in 725 patients with ARDS induced by sepsis; 10.6% of patients developed pneumothorax or other leaks, but there were no significant differences between patients with air leaks and those without air leaks in PEEP, peak inspiratory pressure, mean airway pressure, tidal volume (VT), or minute ventilation. Furthermore, there was no difference in mortality between these two groups. The authors concluded that their "data cast substantial doubt on the view that high ventilatory pressures and volumes are harmful in such patients." However, there are limitations of this study, including the fact that barotrauma was not a primary end point of the original study, patients were followed up for only 5 days, and the volumes and pressures used were reasonably low (mean VT = approximately 11.5 mL/kg), and the fact that the retrospective analysis of peak pressures and volumes was carried out for different time periods for the two groups.

Volutrauma
In addition to the obvious manifestations of overdistention discussed above, there is also more subtle injury that can be induced by mechanical ventilation. Webb and Tierney¹¹ produced dramatic evidence that overdistention associated with high peak airway pressures could lead to the development of pulmonary edema and the death of rats within 1 h (of note, a high level of PEEP could abrogate this injury). Since this seminal finding, a large number of investigators have observed that high end-inspiratory lung stretch could lead to diffuse alveolar damage, pulmonary edema, increased fluid filtration, epithelial permeability, and microvascular permeability. For example, Egan¹² showed that static inflation of sheep lungs up to pressures of 40 cm H₂O produced an increase in equivalent pore radius of a magnitude that could lead to increased leak of fluid into the alveoli. Parker and colleagues¹³ studied isolated dog lungs that were ventilated for 20 min and noted that increased peak airway pressures > 20 cm H₂O produced an increase in the capillary filtration coefficient in a dose-dependent fashion.

Dreyfuss and colleagues¹⁴ coined the term volutrauma to indicate that the critical variable causing injury was not airway pressure per se, but rather volume. They ventilated rats with three strategies: (1) high pressure and high VT—this produced an increase in lung water; (2) low pressure, high volume in which they ventilated rats with a negative pressure ventilator using high VTs—this produced an increase in lung water; and (3) high pressure, low volume in which they strapped the chest wall of rats and ventilated them with high pressures, but with low VTs due to the decreased chest wall compliance—lung water was within normal limits in this group of animals¹⁴ (Fig 1) . Thus, they showed that lung volume as opposed to pressure was paramount in inducing increased lung water. In further studies of rats, they showed that the time course of such injury was very rapid, with a > 50% increase in lung water and a quadrupling of albumin space within 20 min.¹⁵ Resolution of lung injury was also relatively rapid if the high VTs were decreased reasonably quickly. Dreyfuss and colleagues¹⁶ also showed that there was an interaction between preexisting acute lung injury and mechanical ventilation in a study in which they used an injury model in which lungs were damaged with alpha-naphthyl-thiourea. A combination of both injurious factors (high volumes and alpha-naphthyl-thiourea produced a synergistic effect on the increase in extravascular lung water.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Wet weight/body weight (Qwl/BW), dry lung weight/body weight (DLW/BW), and albumin space (Alb Sp) for rats ventilated with three ventilatory strategies: high peak airway pressure of 45 cm H2O, high volume (HiP-HiV); low pressure (generated with an iron lung), high volume (LoP-HiV); and high pressure, low volume (HiP-LoV) generated by strapping the chest walls of the rats during positive pressure ventilation. These data indicate that the degree of lung stretch as opposed to the airway pressure per se is the critical variable generating increased permeability edema (from reference 14, with permission).

Although these mechanical factors causing cell damage are certainly important, recent studies by Parker and colleagues¹⁹ suggest that increased permeability due to VILI may be caused by a much more subtle and complex mechanism. These investigators examined the hypothesis that microvascular permeability might be actively modulated by a cellular response to mechanical injury, and that this response might be initiated by stretch-activated cation channels through increases in intracellular calcium concentration. They found that the capillary filtration coefficient increased to 3.7 times baseline in lungs ventilated with a peak airway pressure of 35 cm H₂O, whereas it was unchanged from baseline when the lungs were ventilated at the same ventilatory pressures, if the lungs were infused with gadolinium, a trivalent lanthanide element that blocks nonselective, stretch-activated cation channels.

Atelectrauma
In addition to the injury caused by ventilation at high lung volumes, there is a large body of evidence indicating that ventilation at low lung volumes may also contribute to injury. This injury is thought to be related to opening and closing of lung units (hence the term atelectrauma). This concept of damage caused by repetitive opening/collapse of distal airways was first proposed by Robertson and colleagues²⁰ to explain the lung injury observed in infants with respiratory distress syndrome. They suggested that in an atelectatic lung, the air-liquid interface may be found relatively proximal in the terminal conducting airways, rather than in the alveoli. Opening of this airway would require relatively high forces and the shear stresses produced might cause epithelial disruption. Evidence for lung injury by ventilation at low lung volumes has been obtained by many authors using various species (rat, rabbit, dog), different lung injury models (lung lavage, ventilator-induced), and examined by the use of different ventilatory strategies (high PEEP vs low PEEP, conventional mechanical ventilation vs high-frequency oscillation [HFO]).^{21 22 23 24 25 26}

One group compared conventional mechanical ventilation with HFO in a number of studies using a rabbit lung lavage model.^{23 24} Animals ventilated with HFO exhibited better oxygenation throughout the study and had decreased lung injury as assessed pathologically by hyaline membrane formation. McCulloch and colleagues²⁶ demonstrated that this beneficial effect was not simply due to the use of HFO per se, but depended greatly on the mean airway pressure (and hence mean lung volume) employed. Rabbits ventilated at low mean airway pressures had significantly greater lung injury than those ventilated at a higher mean airway pressure, even though both groups were ventilated with HFO. Other studies using conventional mechanical ventilation with different levels of PEEP revealed similar findings that high mean lung volume ventilation appeared to be protective, although there is not unanimity in this regard.²⁷

All the studies described above were performed using in vivo models. These models have the advantage of dealing with intact animals and thus are closer to the clinical situation; however, the use of such models is invariably associated with different PaO₂, fraction of inspired oxygen, and/or arterial BPs between groups. This can make interpretation of data from these studies difficult, especially when one is trying to dissect out the direct mechanical effects of ventilation on the lung vs other indirect factors. Muscedere et al²⁵ overcame some of these difficulties by using an ex vivo nonperfused rat lung model system. In this study, we observed that a ventilatory strategy using PEEP above the inflection point markedly decreased the worsening in lung compliance observed with lower PEEP strategies (Fig 2) , and there was also decreased pathologic evidence of lung injury as assessed by airway injury scores and hyaline membrane formation. Interpretation of results from this model must take into account the fact that the degree of collapse and reopening is magnified because there is no chest wall and hence at a PEEP of 0, transpulmonary pressure is also 0. This is not the case in vivo.

View larger version (39K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Pressure-volume (PV) curves after 2 h of ventilation with four different strategies in an ex vivo, nonperfused rat lung model. Ventilatory strategies using PEEP lower than the inflection point (PEEP = 0; PEEP = 4 cm H2O) resulted in a marked decrease in compliance, whereas lungs ventilated with PEEP greater than the inflection point (PEEP > Pinf) or no ventilation (CPAP) resulted in little to no change in the PV curve over a 2-h period (from reference 25, with permission).

Biotrauma
The types of injury described above are largely thought to be mechanical injuries caused by mechanical factors. In the last few years, there has been increasing evidence that mechanical factors can lead to injury that is cell and inflammatory mediator based, with a greater emphasis on biological mechanisms of injury—a type of injury we have called biotrauma.²⁹

A number of studies have suggested that mechanical ventilation of injured lungs could produce further injury that was inflammatory in nature. Kawano and colleagues³⁰ studied lung-lavaged rabbits ventilated with conventional ventilation. They found that the animals developed severe hypoxemia, and a pathologic picture characterized by a large number of neutrophils in the lung, whereas animals that were neutrophil depleted with nitrogen mustard prior to the lung lavage had markedly improved oxygenation. They suggested that mediators released from neutrophils played a critical role in VILI. Imai et al³¹ compared conventional mechanical ventilation with HFO in a lung lavage model and observed that HFO was associated with a significant decrease in a number of mediators in the lung lavage, including platelet-activating factor and thromboxane B₂.

There are also data in the literature indicating that injurious strategies of mechanical ventilation of normal lungs can lead to an increase of cytokine concentrations in lung lavage. Tremblay et al³² studied isolated, nonperfused ex vivo lungs and examined four different ventilatory strategies. Strategies in which moderately high VTs (15 mL/kg) were associated with underinflation (zero PEEP) or with overinflation (PEEP = 10 cm H₂O) were associated with a threefold to sixfold increase in lung lavage cytokines, respectively. There was a synergistic effect when high-end inspiratory lung stretch was combined with zero PEEP, leading to a 56-fold increase in lung lavage tumor necrosis factor- (TNF-) concentrations (Fig 3) . This increase in lavage cytokines was also associated with an increase in c-fos messenger RNA, an early response gene. These data suggest that mechanotransduction, the conversion of cell or receptor deformation into biochemical responses that activate intracellular signal transduction pathways, is an important mechanism relevant to biotrauma.³³

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Lung lavage cytokines after 2 h of mechanical ventilation in an ex vivo, nonperfused rat lung model. Each panel represents the results for a different cytokine (IL = interleukin; MIP-2; INF- = interferon-). The X-axis in each panel represents the ventilatory strategy used (C = control: VT = 7 mL/kg; PEEP = 3 cm H2O; MVHP = medium volume, high PEEP: VT = 15 mL/kg, PEEP = 10 cm H2O; MVZP = medium volume, zero PEEP: VT = 15 mL/kg, PEEP = 0; HVZP = high volume, zero PEEP: VT = 40 mL/kg, PEEP = 0). There was a synergistic effect of combining high end-inspiratory pressures along with zero PEEP on lung lavage cytokine levels; for example, TNF- concentrations increased 56-fold in the HVZP group, which was much greater than the combined increase of the MVHP and MVZP groups (from reference 32, with permission).

Most of the studies cited above have been performed in animal models that have limitations when one tries to extrapolate to human disease. There are, however, clinical data that bear on the question of the relevance of VILI as a distinct entity. Amato et al³⁹ examined the hypothesis that a ventilatory strategy that was aimed at minimizing lung injury would decrease mortality in patients with ARDS. They studied 53 patients who were randomized to receive a protective ventilatory strategy consisting of recruitment, high levels of PEEP, and pressure limitation at end-inspiration compared with a control group who received conventional mechanical ventilation. The patients who received the protective strategy had a mortality rate of 38% compared with 71% in the control group. An NIH-NHLBI trial showed that the use of a VT of 6 mL/kg resulted in about a 25% decrease in mortality compared to 12 mL/kg in patients with acute lung injury or ARDS.⁴⁰ One possible mechanism to explain this dramatic reduction in mortality was provided by Ranieri et al⁴¹ who used two similar strategies and found that the group treated with a minimal stress strategy (similar to the high PEEP strategy of Amato et al³⁹ ) had a decrease in BAL and serum cytokines compared with the control group.

These and other studies have led to the speculation that injurious strategies of mechanical ventilation could lead to the development of multisystem organ failure⁴² (Fig 4) . If this hypothesis is correct, it could explain the high mortality rate of patients with ARDS and most importantly would suggest further modifications of ventilator strategies in critically ill patients that might lead to a decrease in mortality.

View larger version (44K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Mechanical ventilation could have systemic effects and lead to the development of multisystem organ failure (MSOF) by a number of biophysical as well as "biochemical" (release of mediators) mechanisms (from reference 41, with permission).

Mechanical ventilation is a mainstay in the therapy of the critically ill patient with respiratory failure. Data that have accumulated largely over the past decade strongly suggest that ventilatory strategies associated with excessive end-inspiratory stretch and/or collapse/recruitment of lung units can cause further injury to the lung and perhaps lead to the development of multiple system organ failure. Insights into mechanisms causing this injury will hopefully lead to the development of novel strategies to abrogate or prevent these detrimental consequences.

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