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Published ahead of print on March 27, 2003, doi:10.1164/rccm.200210-1215OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1633-1640, (2003)
© 2003 American Thoracic Society

Original Article

Atelectasis Causes Vascular Leak and Lethal Right Ventricular Failure in Uninjured Rat Lungs

Michelle Duggan, Conán L. McCaul, Patrick J. McNamara, Doreen Engelberts, Cameron Ackerley and Brian P. Kavanagh

The Lung Biology Program, The Research Institute, and the Departments of Critical Care Medicine, Anaesthesia, Pediatrics, and Pathology and Laboratory Medicine, The Hospital for Sick Children and the Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Brian P. Kavanagh, M.B., Department of Critical Care Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada. E-mail: brian.kavanagh{at}sickkids.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
During mechanical ventilation, lung recruitment attenuates injury caused by high VT, improves oxygenation, and may optimize pulmonary vascular resistance (PVR). We hypothesized that ventilation without recruitment would induce injury in otherwise healthy lungs. Anesthetized rats were ventilated with conventional mechanical ventilation (VT 8 ml/kg; respiratory frequency 40 per minute) and 21% inspired oxygen, with or without a recruitment strategy consisting of recruitment maneuvers plus positive end-expiratory pressure, in the presence or absence of a laparotomy. Additional experiments examined the impact of atelectasis on right ventricular function using echocardiography, as well as functional residual capacity and PVR. Lack of recruitment resulted in reduced overall survival (59% nonrecruited vs. 100% recruited, p < 0.05), increased microvascular leak, greater impairment of oxygenation and lung compliance, increased PVR, and elevated plasma lactate. Echocardiography demonstrated that right ventricular dysfunction occurred in the absence of recruitment. Finally, samples from nonrecruited lungs demonstrated ultrastructural evidence of microvascular endothelial disruption. Although such effects clearly do not occur with comparable magnitude in the clinical context, the current data suggest novel mechanisms (microvascular leak, right ventricular dysfunction) whereby derecruitment may contribute to development of lung injury and adverse systemic outcome.

Key Words: lung injury, acute • vascular permeability • functional residual capacity • ventricular function, right

Loss of lung volume has been known for decades to cause increased intrapulmonary shunt and impaired arterial oxygenation in patients without established lung injury (1, 2). Recruitment of atelectatic lung is achieved through a variety of means and is usually maintained through application of positive end-expiratory pressure (PEEP) (3). Development of atelectasis is associated with impaired oxygenation and decreased compliance (4), and in the setting of pre-existing injurious processes or extremely high VT, it can potentiate acute lung injury (5–8). The prevalence of atelectasis may be increased with the use of low VT. Because of the compelling evidence in terms of outcome (9), low VT ventilation is believed to be beneficial in patients with acute respiratory distress syndrome (ARDS). This assumption has recently been challenged (10), and from a clinical perspective, remains unresolved. However, low VT is a potentially important factor in the development of atelectasis (11, 12), and this may need to be considered whether caring for healthy patients or for patients suffering from ARDS.

Atelectasis may develop through the use of low VTs or in the absence of adequate recruitment (1, 2). This may be especially likely where mechanical ventilation (1, 2) and high concentrations of inspired oxygen (O2) (13) are used in the absence of lung injury (e.g., intraoperative anesthesia). Recently, it has been reported that recruitment during general anesthesia can attenuate the development of atelectasis (14), although absence of recruitment does not cause cytokine elevations in this context, for brief periods of mechanical ventilation (15).

The role of atelectasis in the development of pulmonary vascular leak or lung injury has received little attention. Because atelectasis leads to reduced local alveolar lung tissue O2 tension, impaired oxygenation may be a mediating influence of atelectasis-induced increases in lung permeability. Recent data indicating that alveolar hypoxia may result in pulmonary vascular leak via decreased lung neprilysin expression (16) or induce lung inflammation through macrophage recruitment (17) support this contention. Indeed, atelectasis resulting from pulmonary artery occlusion depletes rabbit lung adenosine triphosphate (18), consistent with a role for local O2 depletion.

Although mechanical stretch causes (6, 8, 19, 20) or worsens (5, 21, 22) lung injury, the overall lung volume appears to be important also because low levels—or absence—of PEEP worsens stretch-induced injury (7, 8, 23), whereas elevated PEEP is protective (8).

The potentiating effect of atelectasis in the setting of lung injury, as well as the benefits of recruitment, formed the rationale for this study. We hypothesized that in mechanically ventilated animals with normal lungs, absence of recruitment would be associated with lung injury, whereas use of a recruitment strategy would not. The specific aims were to examine the effects of a nonrecruitment strategy versus a recruitment strategy on pulmonary microvascular leak, lung compliance, and right ventricular function in previously healthy animals. Because mechanical ventilation is common in the setting of general anesthesia for surgery without known lung injury, we initially assessed the effect of laparotomy (a common surgical procedure involving general anesthesia) on atelectasis-induced events. Some of the results of these studies have been previously reported in abstract form (24).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After Institutional Ethics approval (conforming to the guidelines of the Canadian Council for Animal Care), male Sprague–Dawley rats (350–400 g) were used in all experiments. General anesthesia was induced with ketamine and xylazine, and maintained with ketamine. A surgical tracheotomy was performed, and a 14° tracheal cannula was secured in place. Pancuronium was used for muscle relaxation. The following ventilation parameters were used: VT 8 ml/kg; frequency 38 to 40 per minute; PEEP 1 cm H2O; FIO2 0.21. Stable physiologic conditions were obtained before group allocation, and animals were excluded where baseline inclusion criteria (i.e., hemoglobin, acid–base status, oxygenation, compliance, hemodynamic status—see online supplement) were not met. Systemic arterial blood pressure, airway pressure, arterial blood gas, and temperature were recorded throughout. Lung compliance was assessed by measuring static inflation pressure response to incremental injections given at baseline and at completion of the protocol. Pulmonary alveolar–capillary permeability was assessed by measurement of Evans blue in bronchoalveolar lavage fluid after intravenous administration. The volume of fluid recovered from the lungs was recorded.

Animals allocated to "recruitment" received PEEP of 2 cm H2O throughout as well as standardized recruitment maneuvers (PEEP increased to 8 cm H2O for 10 breaths, every 30 minutes for the duration of the experiment). Animals allocated to "no recruitment" received zero PEEP throughout and did not receive any recruitment maneuvers. Animals allocated to laparotomy received a standardized incision through the abdominal wall (from the xiphisternum to the pubis), with no removal or handling of the bowels, followed by opposition of the incision margins with a nontraumatic clamp. The duration of the experiment for all groups was 2.5 hours. Initial allocation for Series 1 and 2 was by selection of blinded envelopes from a single box of envelopes. Where animals did not survive the experimental protocol, an envelope assigning a subsequent animal to that group was replaced. Animals were considered to be nonsurvivors if cardiac arrest occurred or if the mean blood pressure fell below 40 mm Hg.

The following series of experiments were performed:

  • Series 1—A laparotomy was performed, and animals were allocated to receive either a recruitment strategy or no recruitment strategy.
  • Series 2—No laparotomy was performed, and animals were allocated to receive either a recruitment strategy or no recruitment strategy.
  • Series 3—No laparotomy was performed, and animals were allocated (within a single allocation schedule) to one of three groups: recruitment every 30 minutes; no recruitment throughout; or, no recruitment until development of hypotension, at which stage a recruitment maneuver was performed. In the latter group, transthoracic echocardiography was performed every 30 minutes, and right ventricular dysfunction was quantified by a blinded expert echocardiologist. In all animals in Series 3, FRC was measured at end-expiration by direct volume displacement (25, 26) at completion of the experiment.
  • Series 4—Animals were anesthetized, and the inspired oxygen was decreased to achieve a PaO2 of less than 50 mm Hg. At completion of the protocol (2.5 hours), plasma lactate was measured. Midline sternotomy was then performed, and the main pulmonary artery cannulated. The mean pulmonary arterial pressure and mean arterial blood pressure were recorded simultaneously, and pulmonary vascular resistance (PVR) was expressed as a fraction of systemic vascular resistance during nonrecruited and recruited conditions.

Additional experiments (n = 2) were performed (with and without recruitment), and samples from the dependent zones were collected and submitted for electron microscopy (27). Alveolar–arterial O2 gradients were measured with FIO2 1.0, after "final" blood gas samples were taken.

Data from nonsurviving animals were used for recording mortality only. For statistical analysis t tests or analysis of variance followed by Student–Newman–Keuls testing for all data except survival data, which were compared using Fisher's exact tests, were used. Significance was set at p values less than 0.05. Results are expressed as mean ± SEM.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A tabular summary of all experimental aims and animal numbers is provided in the online supplement (Table E1).

Baseline Parameters
All baseline parameters were comparable in the recruited versus nonrecruited groups in both Series 1 (laparotomy, Table 1) and Series 2 (no laparotomy, Table 2) .


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  		TABLE 1. Baseline characteristics in series 1 (laparotomy)

 

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  		TABLE 2. Baseline characteristics in series 2 (no laparotomy)

 
Survival
For Series 1 and 2 combined, the survival was 59% (n = 19/32) in the nonrecruited versus 100% (n = 20/20) in recruited animals (p < 0.05, Figure 1A) . In Series 1 (with laparotomy) the differences are statistically significant (p < 0.02, Table 3) , whereas in Series 2 (without laparotomy) the differences are close to statistical significance (p = 0.051, Table 4) .



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  		Figure 1. (A) Survival was significantly less with nonrecruitment versus recruitment (Series 1 and 2 combined; *p < 0.05). (B) Lung protein leakage (bronchoalveolar [BAL] Evans blue absorbance) was significantly greater with nonrecruitment versus recruitment (Series 1 and 2 combined; *p < 0.05).

 

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  		TABLE 3. Final values for series 1 (laparotomy)

 

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  		TABLE 4. Final values for series 2 (nonlaparotomy)

 
Microvascular Leak
For Series 1 and 2 combined, pulmonary alveolar–capillary permeability (concentration of Evans blue in bronchoalveolar fluid) was greater without versus with recruitment (0.45 ± 0.08 vs. 0.23 ± 0.04; p < 0.02) (Figure 1B). Absence of recruitment resulted in significantly increased leak in Series 2 (Table 4) and a trend toward increased leak in Series 1 (Table 3). These results were not altered after correction for recovered volume of bronchoalveolar fluid. The combination of Series 1 and 2 undertaken after two-way analysis of variance (recruitment x laparotomy) demonstrated no interaction on Evans blue leak.

Presence of laparotomy.
In the presence of a laparotomy (Series 1, Table 3), recruitment versus no recruitment resulted in the following: less decrement of static compliance (final - baseline compliance, Figure 2A) , lower alveolar–arterial O2 gradient (Figure 2B); lower peak airway pressure (Paw), higher final PaO2 (Figure 3A) , and less elevation in plasma lactate (Figure 3B) and base excess.



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  		Figure 2. (A) The decrement in static lung compliance (final - baseline compliance) was significantly greater with nonrecruitment versus recruitment (Series 1; *p < 0.05). (B) Alveolar–arterial oxygen gradient as measured at the end of the experiment was significantly greater with nonrecruitment versus recruitment (Series 1; *p < 0.05).

 


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  		Figure 3. (A) Final PaO2 was significantly less with nonrecruitment versus recruitment (Series 1; *p < 0.05). (B) Plasma lactate levels were significantly higher with nonrecruitment versus recruitment (Series 1; *p < 0.05).

 
Absence of laparotomy.
In the absence of a laparotomy, recruitment versus no recruitment resulted in the following outcomes: higher final static compliance, lower alveolar–arterial O2 gradient; lower peak Paw, higher final PaO2, and less elevation in plasma lactate (Table 4).

Effects of Laparotomy
The analysis of the relative effects of laparotomy versus recruitment strategy was performed using a two-factor analysis of variance, which demonstrated that recruitment, but not laparotomy, was an independent determining factor of microvascular leak (p < 0.05).

Cardiovascular Effects
Given the combination of high mortality, hypoxemia, and elevated plasma lactate, we suspected systemic hypoperfusion due to right ventricular dysfunction on the basis of atelectasis-induced elevation in PVR. Series 3 consisted of three groups (recruitment throughout, late recruitment, and no recruitment). Echocardiography was performed in the "late recruitment" group, wherein recruitment was not performed until after the first 120 minutes. This demonstrated that right ventricular dysfunction occurred in the absence of recruitment (Figure 4A) . The right ventricular dysfunction was progressive and was partially reversible in animals that had a recruitment maneuver performed late in the protocol (Figure 4A). The echocardiographic recordings were scored by an echocardiologist blinded to group allocation. These readings were obtained on two occasions, and comparison of each assessment demonstrated excellent agreement (weighted {kappa} value = 0.9). An illustrative example of the impairment of right ventricular function and underfilling of the left ventricle (compared with control conditions, Figure 5A) is presented (Figure 5B); these changes are reversed after recruitment (Figure 5C). Finally, the mean arterial blood pressure did not change over time during the experimental protocol, regardless of whether recruitment or no recruitment was employed (Table 5 , combined Series 1 and 2).



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  		Figure 4. (A) Right ventricular (RV) impairment was scored at four time points: baseline, 60 minutes, 120 minutes, and after recruitment maneuver in the late-recruitment group. There was no difference in the RV scores between baseline and 60 minutes. The RV score at 120 minutes was significantly worse than at baseline and 60 minutes. A recruitment maneuver significantly improved the RV impairment after 120 minutes (Series 3; *p < 0.05). (B) Functional residual capacity (FRC) was measured at the end of the experiment by a direct measurement technique. The recruited group had a significantly greater FRC than either the nonrecruited group or the group who received a late recruitment maneuver. There was no significant difference between the nonrecruited group and the late recruitment group (Series 3; *p < 0.05).

 


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  		Figure 5. (A) Parasternal short-axis view of left and right ventricles demonstrating baseline configuration at end-diastole. (B) Parasternal short-axis view of left and right ventricles after 150 minutes of derecruitment demonstrating: marked dilation of the right ventricle (solid arrow); paradoxical position of the interventricular septum (arrow, small dashes); and, a small underfilled left ventricle (arrow, long dashes). (C) Parasternal short-axis view of left and right ventricles after a recruitment maneuver demonstrating a return toward baseline ventricular configuration with a reduction in right ventricular overload (dashed arrow) and improved left ventricular filling (solid arrow). The images in (A)–(C) were taken at different time points from the same animal.

 

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  		TABLE 5. Mean blood pressure recordings for series 1 and 2

 
FRC
FRC was measured in all animals in Series 3 using the technique of direct volume displacement. This demonstrated that FRC was greatest where a recruitment strategy was used throughout, minimal where no recruitment was used, and intermediate when a recruitment maneuver was applied only at the end of the experiment (Figure 4B).

Relationship between PaO2 and Lactate
To determine if there was a relationship between the degree of hypoxia (PaO2 44.6 ± 2.8 mm Hg) and the elevated lactate (4.3 ± 0.7 mmol/L) observed in the nonrecruited animals in Series 2 (no laparotomy), a final series of experiments (Series 4) was performed. The PaO2 was reduced to a mean value of 44.1 ± 1.5 mm Hg by reduction of FIO2, and the resulting mean lactate level was 2.4 ± 0.3 mmol/L. The PaO2 levels, therefore, were similar to the nonrecruited animals in Series 2 (no laparotomy), and significantly lower than the recruited animals in Series 2 (no laparotomy, Figure 6A) . The lactate levels were significantly lower than the nonrecruited animals in Series 2 (no laparotomy) and similar to the recruited animals in Series 2 (no laparotomy, Figure 6B). These data indicated that the level of hypoxemia achieved in the absence of recruitment (Series 2) was insufficient to fully account for elevated lactate.



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  		Figure 6. (A) Final PaO2 in animals administered reduced FIO2 (Series 4) was similar to PaO2 in the nonrecruited (Series 2, no laparotomy) group and was significantly less than the PaO2 in the recruited (Series 2, no laparotomy) group (*p < 0.05). (B) Final plasma lactate in animals administered reduced FIO2 (Series 4) was similar to the lactate values in the recruited (Series 2, no laparotomy) group and was significantly less than the lactate in the nonrecruited (Series 2, no laparotomy) group (*p < 0.05).

 
Recruitment and PVR
The PVR expressed as a fraction of systemic vascular resistance, was significantly lower during recruited versus nonrecruited conditions (Figure 7) .



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  		Figure 7. The ratio of pulmonary vascular resistance (PVR) to systemic vascular resistance (SVR) was significantly greater in the nonrecruited versus recruited state in each animal (Series 4; *p < 0.05).

 
Lung Ultrastructure
Ultrastructural characterization tissue obtained from recruited lungs demonstrated relative uniformity in endothelial cell thickness (Figure 8A) . In contrast, tissues collected from lung that had not been recruited demonstrated thickening and disruption of the endothelium, with bleb formation (Figures 8B and 8C). This raises the possibility that the protein leak observed with atelectasis may be due to endothelial disruption.



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  		Figure 8. (A) Electron micrograph of a distal airway in a recruited lung. Endothelial cells (arrowheads) appear normal and are all of the same thickness. The picture width is 20 µm. (B) Thickened endothelial cells (arrowheads) from a nonrecruited lung. Approximately 40% of the capillaries were affected in this way. The picture width is 9 µm. (C) Endothelial cell for the nonrecruited lung that has a comparable thickness to the endothelial cells in (A). A cytoplasmic lesion is seen where a focal portion of the cell has failed to recover to a normal thickness. The cytoplasm in this area is electron lucent and void of any material except for vesicles. Endothelial cells had multiple lesions. Image width is 5 µm.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The findings in this paper are dramatic and are clearly not observed in patients who are routinely subjected to general anesthesia in the absence of PEEP. Nonetheless, the experimental model, which is prone to atelectasis, identifies two novel mechanisms (microvascular leak and right ventricular failure) whereby atelectasis might initiate, or contribute to, lung injury in other settings. Lung derecruitment—resulting in atelectasis—may occur under several circumstances and has been well recognized to have pathologic effects on lung mechanics, PVR, gas exchange, and stretch-induced lung injury. The finding that it may cause injury in previously normal lungs has not been previously described in an intact animal preparation, and this finding, together with the demonstration of lethal right ventricular failure, represents the key findings in the current paper.

Atelectasis and Mechanical Ventilation
The association of atelectasis and lung injury is well established in the setting of ventilator-induced lung injury (28), where atelectasis potentiates (5, 23)—and recruitment inhibits (7, 8)—such injury. However, atelectasis is important in other contexts and is common in the absence of identified lung injury. For example, during general anesthesia, atelectasis is potentiated by anesthesia and muscle relaxants altering diaphragmatic position (29). In addition, the use of high FIO2 in an attempt to prevent hypoxemia during endotracheal intubation results in exacerbation of microatelectasis (30); such "preoxygenation" is ubiquitous before induction of anesthesia. A recent study reported less atelectasis in healthy children undergoing general anesthesia when a recruitment strategy was used (14).

Although associated with atelectasis, low VT may be beneficial in ARDS. There is an increasing acceptance that lower VT reduces stretch-induced lung injury in patients with ARDS (31), and that this approach is translated into improved patient survival (9). Although these assumptions have been challenged by a recent meta-analysis (10), editorial comment supports the use of low VT as an appropriate aim in ARDS (32). However, extrapolation of the low VT approach to patients without lung injury (or ARDS) requires caution for two principal reasons. First, it has been long recognized that low VT increases the development of atelectasis in the absence of lung injury (1, 2, 33, 34). Second, in the presence of ARDS, the ARDSnet protocol is specific: the data indicate 6 ml/kg (vs. 12 ml/kg) in the context of a precise ventilatory management protocol that stipulates many ventilatory parameters in addition to VT (9). A recent study has sugested that the specific "low VT" approach used in the ARDSnet study (9) was actually associated with the development of intrinsic PEEP (35), raising the possibility that recruitment—not simply low tidal stretch—played a protective role in these patients. Therefore, if a low VT strategy is used that does not result in the development of intrinsic PEEP, the propensity for development of atelectasis might be significant, and adverse consequences of atelectasis may be far greater than previously appreciated.

Mechanisms of Atelectasis-induced Injury
Although the potentiating role of atelectasis in stretch-induced lung injury has been firmly established, the mechanism(s) whereby this occurs is not clear. Several phenomena are believed to occur. Local intrapulmonary shear forces generated during repeated reopening of atelectatic alveoli may accelerate injury (23, 36, 37). The current study demonstrates that atelectasis involves increased alveolar–capillary protein leakage, and representative ultrastructural samples suggest that the mechanism involves disruption of the vascular endothelium, possibly via shear stress. It is possible that, as in any lung injury context, exudative plasma proteins inhibit surfactant function in the air spaces (38) and contribute to a cycle of injury whereby mechanical stretch is exacerbated by reduced surfactant function, further potentiating atelectasis, and in turn exacerbating the injury. Other investigators have found that high lung volume increases stress failure in pulmonary capillaries. The intensity of lung perfusion or blood flow also contributes to ventilator-induced lung injury in ex vivo models (39–41). The current data underscore the importance of lung volume in pathogenesis of injury, and the right ventricular failure introduces a new in vivo application of previous ex vivo findings (39–41).

In addition to impairment of oxygenation, atelectasis increases PVR (42, 43). In patients with ARDS, elevated PVR is associated with adverse outcome (44), and titration of PEEP in such patients has been attempted with the aim of optimizing , oxygenation, and global O2 delivery (45). In the absence of lung injury, the relationship among atelectasis, PVR, and impairment of right ventricular function has not been established. Finally, because of their far greater chest wall compliance, neonates are more prone to develop atelectasis (46). Thus, it may not be possible to extrapolate previous studies of recruitment performed in adults with acutely injured lungs to other patient populations (45).

Atelectasis and Right Ventricular Dysfunction
There are several mechanisms whereby atelectasis can result in adverse effects on the pulmonary vasculature. First, the absolute lung volume—FRC—is related to PVR through direct static effects on vascular compression. Studies in ex vivo lungs suggested that the relationship of lung volume with PVR followed a "U" shaped curve, with the PVR nadir at FRC (47, 48). Second, data from in vivo isolated lung lobes suggest that the effects of atelectasis on PVR may actually reflect alveolar and mixed venous O2 tension, rather than lung volume per se (49). Third, atelectasis may influence PVR via a hysteresis phenomenon (50). Thus, for a comparable distending airway pressure, the PVR during inspiration and expiration will depend on end-tidal lung volume. Fourth, capillary folding has been described as a result of altered lung volume (51), potentially increasing PVR. Fifth, the toxic effects of hypoxia such as occurs during atelectasis have been studied. In young rats, hypoxia decreases lung neprilysin expression, contributing to increased pulmonary vascular leak via substance P release and bradykinin receptor activation (16). Finally, the role of cytokines in the modulation of atelectasis-induced injury is unclear. No elevation—in fact no detection—of cytokines was demonstrable in lethal atelectasis in an in vivo model of acid aspiration (52). The current study provides new data concerning the pulmonary vascular effects associated with atelectasis, specifically microvascular leak and elevated PVR. Although the animals in our study were not in "hypotensive" shock (blood pressure was maintained), the impaired right ventricular function suggests that they were in "cardiogenic" shock.

Limitations of Current Study
The current study has several limitations that limit extrapolation to the clinical context. First, atelectasis occurred passively and was not directly induced; however, the FRC was directly measured. Second, measurement of FRC has limitations, and although similar to techniques reported previously (53), the values in the current study are higher. This discrepancy can be accounted for by the differences in assumed lung tissue specific gravity and the lack of developed injury in the previous report (53). Third, the measurement of Evans blue in the lavaged fluid reflects protein permeability but could also indicate—in part—an increased hydrostatic microvascular filtration coefficient also. Fourth, because mortality developed in nonrecruited animals only (and not in recruited animals) that were then excluded from the experiment (and all analyses except mortality statistics), an experimental bias can occur that selects more resilient animals perhaps less likely to develop injury. Although this is a potential bias, it is a bias against there being a positive result because data from surviving animals only was included in the analysis and data from nonsurvivors was not included. Because all of the nonsurvivors (and the sicker animals) were in the nonrecruited groups, the positive results (organ injury) are likely underestimated. Fifth, use of a model without established lung injury limits the relevance to injury states. It is possible that such mechanisms exist in injury states, if only in atelectatic lung areas. Sixth, the high mortality rate raises issues about relevance to practice. In fact, others examining atelectasis in a model of established lung injury found 100% mortality in the same species (vs. 59% in the current study) where low VT was employed in the setting of zero PEEP (52). Thus, the presence of preexisting injury is likely to amplify the current findings. Finally, randomization is preferable in all laboratory studies as is power analysis where sample size appears insufficient.

Implications of Current Data
There are several potential implications from the current study, although extrapolation of the findings to normal patients should be done with caution. In the absence of lung injury, atelectasis might not be benign, and conditions predisposing to atelectasis (neonates, low VT, absence of PEEP or recruitment maneuvers) should be recognized. In the presence of lung or systemic injury, development of atelectasis might serve to potentiate injury, conceivably as a "second hit" due to endovascular injury or impaired systemic perfusion (resulting from right ventricular impairment) and may be a reason for deterioration after anesthesia and emergency surgery in critically ill patients. Finally, assessment of right ventricular function in patients prone to atelectasis warrants further investigation.


   Acknowledgments
 
The authors are grateful to Drs. A. C. Bryan, J. G. Laffey, and R. Jankov for their insightful comments on the paper.


   FOOTNOTES
 
Supported by Canadian Institutes of Health Research (CIHR). Dr. Kavanagh is the recipient of a New Investigator Award (CIHR), and a PREA award (Ontario Ministry of Science and Technology).

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form October 24, 2002; accepted in final form March 25, 2003


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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