Preemptive Application of Airway Pressure Release Ventilation Prevents Development of Acute Respiratory Distress Syndrome in a Rat Traumatic Hemorrhagic Shock Model : Shock

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Preemptive Application of Airway Pressure Release Ventilation Prevents Development of Acute Respiratory Distress Syndrome in a Rat Traumatic Hemorrhagic Shock Model

Roy, Shreyas K.*; Emr, Bryanna*; Sadowitz, Benjamin*; Gatto, Louis A.*†; Ghosh, Auyon*; Satalin, Joshua M.*; Snyder, Kathy P.*; Ge, Lin*; Wang, Guirong*; Marx, William; Dean, David§; Andrews, Penny; Singh, Anil*; Scalea, Thomas; Habashi, Nader; Nieman, Gary F.*

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Shock 40(3):p 210-216, September 2013. | DOI: 10.1097/SHK.0b013e31829efb06
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Acute respiratory distress syndrome (ARDS) is a grave clinical problem afflicting up to 30% of severely injured trauma patients annually (1); the disease retains disturbingly high mortality (2), costs of care (3), and severe sequelae for survivors (4) despite decades of therapeutic research (5). Trauma and hemorrhage result in massive systemic inflammation with attendant increases in vascular permeability leading to severe lung injury with pulmonary edema (6). Resuscitation for hemorrhagic shock (HS) often requires transfusion of blood products, which are independently associated with the systemic inflammatory response syndrome, acute lung injury (ALI) and ARDS (7). Thus, traumatically injured patients with HS are highly susceptible to development of ALI and ARDS.

Low tidal volume (LTV) ventilation is the only treatment strategy to emerge that appeared to be effective in reducing established-ARDS mortality in a large clinical trial (8). However, more recent data demonstrate that even with application of LTV, the mortality of ARDS remains as high as 40% to 60% (2). Furthermore trauma-induced ARDS remains significantly underrepresented in LTV ventilation clinical trials, with only 170 trauma patients in the 4,341-patient database, which represents less than 4% of the patient population in all currently published ARDSnet studies and makes extrapolating LTV benefits to this ARDS phenotype very limited (8). The resistance of established ARDS to the current standard of care treatment and the limited applicability of LTV data to the trauma patient suggest strategies for preventing ARDS before it becomes established must be sought.

Prevention is based on targeting the key early mechanisms of pathogenesis to interrupt disease progression. Early ARDS pathogenesis is driven by increased vascular permeability resulting in pulmonary edema, which deactivates surfactant; mechanical ventilation in this milieu causes alveolar instability, which is both biologically and mechanically injurious to the lung (6, 9). In our initial studies designed to prevent ARDS, the ventilation strategy consisted of applying a mechanical breath with an extended airway pressure/time profile (P/TP) delivered via the airway pressure release ventilation (APRV) mode, utilizing a clinically applicable porcine sepsis-induced ARDS model. We hypothesized that extended P/TP alters the Starling forces of the lung, reducing permeability, the most proximal pathologic event in the pathogenesis of ARDS, thereby preventing the downstream events of edema, surfactant deactivation, and alveolar instability. Our group has recently shown that preemptive mechanical ventilation, applied before clinical signs of lung injury, can prevent the development of ARDS in a porcine model of peritoneal sepsis + ischemia/reperfusion (PS + I/R)–induced lung injury (10, 11). Although the end point (i.e., ARDS) is identical, the pathogenesis leading to ALI may vary depending on the source of the systemic inflammation—PS + I/R or trauma/HS (T/HS). Therefore, we developed a rat T/HS model and tested the efficacy of our preemptive ventilation strategy at preventing lung injury specifically in the context of the traumatically injured patient. The results of the present study support our central hypothesis and build on our prior work in PS + I/R–induced ARDS by demonstrating that ARDS secondary to T/HS can be prevented, if the appropriate ventilation strategy is applied before clinical lung injury develops.


All techniques and procedures described were reviewed and approved by the Committee for the Humane Use of Animals at Upstate Medical University.


Male Sprague-Dawley rats (350–400 g; Taconic Farms, Germantown, NY) were anesthetized using intraperitoneal injection of a ketamine (90 mg/mL) and xylazine (10 mg/mL) mixture (10 mL/kg). Using aseptic technique, a tracheotomy was performed with a 14-gauge angiocatheter. Rats were attached to a Dräger ventilator (Evita Infinity v500; Dräger Medical Inc, Telford, Pa) and allowed to spontaneous breathe on 100% FIO2. Respiratory pressure and volume were recorded every 30 min. The external jugular vein and internal carotid artery were then cannulated with polyethylene-50 tubing that had been previously flushed with heparinized saline (10 U/mL).


The timeline for the experiment is seen in Figure 1. Following surgery, rats were allowed to equilibrate to a normal physiologic range of body temperature (36.5°C–37.5°C), heart rate (250–300 beats/min), mean arterial blood pressure (MAP) (70–90 mmHg) and arterial oxygen tension (>300 mmHg on FIO2 100%). At baseline and equilibrium, an arterial blood gas (3 μL) was drawn from the carotid line and analyzed using a Cobas 221 blood gas analyzer (Roche Diagnostics, Indianapolis, Ind). Inclusion parameters for the experiment were determined at equilibrium and were based on PaO2/FIO2 (>300), base excess (>−5.0), and lactate (<2.2). Rats were given intravenous lactated Ringer’s solution through the jugular line to maintain MAP of greater than 60 mmHg.

Fig. 1:
Timeline of experimental protocol. The experiment is broken into two sections: Phase 1—preparation/shock/resuscitation: surgical preparation followed by baseline measurements (BL) and an equilibrium period (EQ) to stabilize hemodynamics and body temperature. Following EQ, HS is induced for 40 min, followed by resuscitation (RES) with shed blood and Ringer’s lactate. It takes approximately 70 min from the beginning of HS to the end of RES; Phase 2—ventilator strategy: animals are randomized to their ventilation strategy (VC or APRV). Hemodynamics, blood gas, and lung function measurements are made every 30 min until the end of the study at 360 min (T 360) following RES. See Methods for detailed procedures.

Trauma/hemorrhagic shock

A traumatic injury was induced via a midline laparotomy (1 cm); a Foley catheter (size 8; DeRoyal Medical, Powell, Tenn) was placed in the abdomen for anesthesia delivery and temperature measurement, and the incision was closed. Body temperature was maintained at 37°C (±0.5°C) using a heating blanket and lamp. Hemorrhagic shock was induced by bleeding the rats through the jugular line at a rate no faster than 1 mL/min. Rats were bled until a MAP of 30 to 40 mmHg was reached. Animals were maintained in this MAP range by blood withdrawal or infusion for a period of 40 min (Fig. 1).


Rats were resuscitated using their shed blood mixed with twice the shed blood volume of lactated Ringer’s solution. Vasopressors were not used in this study.


Following resuscitation, rats were randomized to one of two ventilation modes.

  • (a) Volume cycled ventilation (VC, n = 5). Volume cycled ventilation with the following parameters: a tidal volume (Vt) 10 mL/kg, positive end-expiratory pressure (PEEP) 0.5 cmH2O, and respiratory rate 35 to 75/min. We chose the Vt and PEEP settings for the VC group to match the Vt and PEEP routinely delivered to patients undergoing surgery, which we felt would be most appropriate for our T/HS rat model (12–15). These studies show that surgery patients are typically ventilated with Vt of 10 or greater with zero end-expiratory pressure. In addition, we did a PEEP titration to directly measure what level of PEEP stabilizes alveoli in the normal rat lung (see below).

In vivo PEEP calibration. Determination of PEEP applied in this group was based on a series of in vivo microscopy exercises. Rats (n = 3) were surgically prepared as described above. Volume cycled ventilation with the following parameters was used: a Vt of 10 mL/kg, respiratory rate of 35 to 75 breaths/min, and initial PEEP of 5 cmH2O. Our in vivo microscopy methods are described below. While directly observing subpleural alveolar patency throughout the ventilation cycle, PEEP was titrated down from 5 cmH2O to 0 cmH2O in 0.5-cm increments. At PEEP 0 cmH2O, intratidal alveolar collapse was observed. It was observed that the lowest PEEP required to maintain alveolar patency throughout the ventilatory cycle was 0.5 cmH2O. Positive end-expiratory pressure was then titrated up from 0 cmH2O to 5 cmH2O in 0.5-cmH2O increments. Therefore, 0.5-cmH2O PEEP was chosen for the VC group based on the direct evidence of alveolar stability using in vivo microscopy.

  • (b) Airway pressure release ventilation (APRV, n = 4). With the following parameters: high pressure (Phigh) was initially set similar to the plateau pressure on VC ventilation. Low pressure (Plow) was set at 0 cmH2O for the entire 6 h to minimize expiratory resistance and maximize peak expiratory flow rate (PEFR). The Thigh (duration of Phigh) was set at 1.3 to 1.5 s to equal 90% to 95% of the respiratory cycle. The Tlow (duration of release phase) ranged between 0.11 and 0.14 s in order to achieve a termination of PEFR equal to 75% of PEFR. The Tlow was calculated and adjusted based on the angle of deceleration noted on the expiratory flow waveform as described previously (10, 11, 16). The Phigh, Thigh, Tlow, and FIO2 were titrated throughout the study per published guidelines (16) to minimize lung derecruitment, optimize the efficiency of CO2 clearance, and minimize dead space ventilation.

In vivo microscopy

This technique has been described in detail (17), but briefly, the right superior and the right middle lobes were used for in vivo microscopy. The customized microscope (Olympus Medical, Center Valley, Pa) with a suction head was lowered onto the exposed lung surface. Subpleural alveoli were filmed in real time with a Stingray F-145C digital video camera (Allied Vision Technologies, Stadtroda, Germany) and stored in a custom-built digital video recording system (MD-PC-V251B). Still photographs from the movie stream of subpleural alveoli were digitized (StreamPix5) and subsequently analyzed to identify the profile of each alveolus in the photomicrograph, and their areas were measured directly with image analysis software (ImagePro; Media Cybernetics, Warrendale, Pa).

Euthanasia and necropsy

All rats were killed using sodium pentobarbital. The left lung was injected via tracheal instillation with 2.5 mL 0.9% NaCl, and the bronchoalveolar lavage fluid (BALF) collected for analysis and frozen in a −70°C freezer. The right inferior lobe was isolated, clamped at peak inspiration, and submerged in 10% formalin for histology.

Histologic assessment

The quantitative histologic assessment of the lung was based on image analysis of 90 photomicrographs (10 per animal), made at high-dry magnification following a validated, unbiased, and systematic sampling protocol. Each photomicrograph was scored using a 4-point scale for each of five parameters: atelectasis, fibrinous deposits, blood in air spaces, vessel congestion, alveolar wall thickness, and leukocyte infiltration, as previously described (10, 11).

BALF and lung tissue data

The left lobe of the lung was lavaged with 2.5 mL of normal saline, spun at 1,734g at 4°C, and snap frozen for later analysis. Western blot analyses of surfactant proteins A and B (SP-A and SP-B) expression in the BALF as well as of epithelial cadherin (E cadherin) in lung tissue homogenates were performed, as previously described (18, 19). The SP-B assay of one rat was excluded because the rat died only 3 h into the experiment secondary to the rapid development of ARDS. Total protein in the BALF was determined using the bicinchoninic acid method.

P/TP calculation

Pressure/time profile was calculated using Eq. 1 below, where P = pressure (cmH2O), and T = time (in seconds) over the period of one breath, defined as extending from the beginning of inspiration (Tinsp) to the end of expiration (Texp) (11).

Statistical analysis

Data were expressed as mean ± SE. Repeated-measures analyses of variance with rat number and treatment as random effects were performed to compare differences within and between treatment groups for continuous parameters. Probability values less than 0.05 were considered significant. Post hoc Tukey tests were performed on continuous data at specific time points only if significance was found in the group * time effect using repeated-measures analysis of variance. Categorical data were compared using an unpaired Student t test.


Lung and hemodynamic function

Oxygenation was dramatically improved with preemptive application of APRV (Fig. 2A). In the VC group, the P/F ratio began to decline significantly at T180 and continued to fall until the end of the experiment (T360). At T360, the P/F was 143.3 ± 42.4 in VC animals, meeting gas exchange criteria for ARDS (8). The APRV group maintained P/F at greater than 400 for the entire experiment with an FIO2 of 0.31% ± 0.09% (Fig. 2A). The improved P/F was not secondary to the peak inspiratory pressures, which were similar in both groups throughout the study (Fig. 2B). The MAP was similar in both groups (Fig. 2C).

Fig. 2:
A, PaO2/FIO2 ratio (P/F) over time in the VC (Δ) and APRV (□) groups. There was a significant fall in P/F in the VC as compared with APRV group, with the P/F falling below 200 at T 300 indicating the development of ARDS. B, Peak airway pressure over time in the VC (Δ) and APRV (□) groups. C, Mean arterial blood pressure over time in the VC (Δ) and APRV (□) groups. D, P/T P over time in the VC (Δ) and APRV (□) groups. P/T P was significantly elevated in the APRV as compared with VC group throughout the entire experiment. BL indicates baseline; EQ, equilibrium; HS, hemorrhagic shock; RES, resuscitation. Data ± SEM. *P < 0.05 vs. VC group.

Pressure/time profile

Application of APRV significantly increased the P/TP above that delivered by VC immediately following application (T0) and remained significantly higher for the entire experiment (T360) (Fig. 2D).

In vivo microscopy

Subpleural alveoli were photographed at peak inspiration in the VC (Figs. 3A, B) and APRV (Figs. 3C, D) groups. There were significantly fewer alveoli at peak inspiration in the VC (Figs. 3A, B; Table 1) than in the APRV (Figs. 3C, D; Table 1) group.

Table 1:
Quantitative histopathology
Fig. 3:
In vivo photomicrographs and image analysis of inflated subpleural alveoli in the VC (A, B) and APRV (C, D) groups. Measurement of the percent air space was accomplished by circling the inflated alveoli using computer image analysis. All inflated alveoli were then assigned the color yellow, and noninflated areas were assigned the color red, generating a sharp contrast for the image analysis software to identify and measure the percentage of inflated alveoli/microscopic field. Arrows (A, C) identify a single alveolus.


The lungs of rats receiving VC were marked by substantial amounts of edema (Fig. 4), as several rats exhibited areas where alveolar lumina appeared uniformly filled with fluid. In addition, all VC animals had fibrinous deposits in the air compartment. Alveolar walls in the VC animals were thickened by the presence of wandering cells, mostly hematogenous macrophages. In contrast, APRV animals featured slender alveolar walls and open alveoli with little or no fibrin in the lumen. The incidence of hemorrhage or capillary congestion was minimal and not significantly different between the treatment conditions (Table 1; Fig. 4). Lung protection in the APRV group was not secondary to lower Vt. The Vt was significantly higher in the APRV (12.9 ± 0.2 mL/kg) as compared with the VC (9.5 ± 0.2 mL/kg) group (P < 0.05)

Fig. 4:
Histologic comparison of a rats receiving VC versus APRV. The VC animal exhibits hallmarks of ARDS, including alveolar flooding (stars), fibrinous deposits in the air compartment (arrowheads), and high cellularity (between arrows). The APRV animal shows patent alveoli with notable preservation of nearly normal histology.

BALF and lung tissue data

Bronchoalveolar lavage fluid concentration of SP-A was higher in the APRV group but did not reach statistical significance, whereas the levels of SP-B, total protein of BALF, and E cadherin in lung tissue homogenates were all significantly different between groups (Table 2).

Table 2:
BALF and lung tissue analysis

Fluid balance

Volume cycled ventilation and APRV groups received a similar volume of fluid resuscitation with lactated Ringer’s solution (VC 176.1 ± 12.7 and APRV 169.3 ± 17.5 mL, not statistically significant).


The most important finding in this study was that a preemptive ventilation strategy with an extended airway P/TP applied following T/HS and before onset of ALI prevented the development of ARDS. This was evidenced by both lung function measurements and histopathology of lung tissue. The mechanisms of this protection include preventing the development of pulmonary edema (histology), which may have been secondary to a decrease in endothelial (total protein), and epithelial (E cadherin) permeability resulting in maintenance of normal surfactant function (SP-B). Lastly, in vivo microscopy of the subpleural alveoli demonstrated that APRV preserved alveolar patency and stability, which could be secondary to the extended time at Phigh as well as preventing loss of SP-B, preserving surfactant function. These data support the conclusions of two previous studies utilizing a porcine PS and gut I/R (PS + I/R)–induced ARDS model (10, 11) that preemptive APRV can prevent ARDS. The present study builds on this past work demonstrating that preemptive application of APRV is also effective at blocking lung injury in a T/HS-induced ARDS model. Lung protection in the T/HS model appears to be by mechanisms similar to the lung protection in the PS + I/R model (i.e., preventing increased permeability, alveolar edema, surfactant deactivation, and alveolar instability). Furthermore, the in vivo microscopy data in the present study allow direct visual confirmation of alveolar stability imparted by APRV, which was not possible in the porcine model. This study therefore represents an expanded application of our preemptive ventilation strategy to the T/HS population.

The need for a preventive approach

Two recent reviews of therapeutic clinical trials for ARDS spanning three decades show that LTV is the only treatment strategy that can be recommended (5, 20). However, this current standard of care for management of ARDS, ventilation with LTV, has recently been shown to still have an unacceptably high mortality (40%–60%) (2). In addition, longitudinal study of ARDS survivors has revealed that they suffer debilitating lifelong sequelae including function-limiting pulmonary, psychological (4), and neurologic (21) dysfunction. Because no treatment has been shown effective for established ARDS (5, 20), including LTV (2), and many patients who do survive have lifelong disabilities (4, 21), preventing ARDS development would have a tremendous positive impact on patient care.

Successful prevention of ARDS requires a temporal “window of opportunity” during disease onset in which treatment strategies can interrupt disease progression. However, the current perception is that ARDS is a binary construct, the disease seen as either present or absent. The patient’s lungs are considered “healthy” before the diagnosis of ARDS and “sick” thereafter (8). Therefore, treatment of ARDS often does not begin until the disease is fully developed (22). However, the recent shift in ARDS definition by the Berlin Conference suggests a staged disease with mild, moderate, or severe ARDS (23). Our group has suggested an even earlier stage, before the development of clinical symptoms, and has termed this the occult stage (10). This novel reconception of ARDS as a progressive injury is supported by the finding that ARDS is rarely present at the time of hospital admission but rather develops over a period of hours to days in the hospital (24). Furthermore, the findings of Shari et al. (24) suggest a “window of opportunity” exists during which application of preventive strategies may block progression from occult lung injury to ARDS. Experimental data from our group including the present study support this hypothesis, demonstrating that an appropriate ventilator technique targeting early pathologic mechanisms during this occult stage can prevent disease progression to established ARDS (10, 11).

Pressure/time profile

The key early event in the pathogenesis of ARDS is the increase in vascular permeability that results from massive systemic inflammation (6). Increased permeability leads to proteinaceous edema fluid flooding the alveolar space, which deactivates surfactant. Application of mechanical ventilation to the lung in the context of this pathologic milieu results in alveolar instability with associated mechanical and biological trauma (6). Ventilation with extended P/TP appears to block the increase in permeability, thereby blocking the subsequent downstream events that would lead to ARDS.

There are four basic components that can be manipulated during the mechanical breath: time (TI) and pressure (PI) at inspiration and time (TE) and pressure (PE) at expiration along with the transition time between inspiration and expiration (ΔPI/PE). Airway P/TP represents the integration of these quantities, as calculated by Eq. 1 and therefore reflects the forces applied at the alveolar surface by the ventilator. The impact of P/TP on lung fluid balance (i.e., pulmonary edema), surfactant function, and alveolar stability is the proposed mechanism of preemptive extended airway P/TP-induced lung protection. Our study supports early physiology literature that studied the effect of increased PEEP on lung fluid balance and showed that PEEP-induced modification of the Starling forces is the likely mechanism of edema prevention (25–35).

P/TP and edema

The literature investigating the effect of airway P/TP on lung fluid balance has almost exclusively focused on only one of the four P/TP components—the pressure at expiration (i.e., PEEP). It has been shown that if PEEP is applied following lung injury, then the accumulated edema is not decreased but rather redistributed within the lung (36, 37). However, if preemptive PEEP is applied to the normal lung before the insult has been applied, the development of pulmonary edema will be significantly reduced (25–35). These data demonstrate that elevated P/TP in the form of PEEP prevents development of pulmonary edema if applied to the normal lung. The technique of APRV used in the present study significantly extends P/TP by sustaining a relatively constant airway pressure (Phigh) for greater than 90% of the duration of the breath (Thigh) with a subsecond release (Tlow) to allow for CO2 clearance. We postulate that it is this sustained pressure on the pulmonary interstitium that is the key mechanism of reduced pulmonary edema in the APRV group. This study demonstrates that an extended airway P/TP applied early can be protective; additional studies are underway to further analyze each component of the airway P/TP and identify, which are critical to lung protection.

Critique of the study

This pilot study demonstrates that preemptive application of APRV will prevent ARDS development in a rat T/HS model. These data combined with the results from our sepsis and a gut I/R model (10, 11) suggest that ARDS can be prevented regardless if the origin of lung injury is T/HS or sepsis. One limitation of this study is that we did not include a control ventilator-only group. The reason for not including a ventilator-only group was that this preliminary study was not designed to differentiate between the degree of lung injury caused by systemic inflammation (i.e., T/HS) and the lung injury caused directly by mechanical ventilation. Future studies in which rats are mechanically ventilated but not subjected to T/HS and rats subjected to T/HS without mechanical ventilation will be necessary to obtain this information. The data from this study are still highly significant because they show that preemptive application of a protective mechanical ventilation strategy following systemic inflammation (T/HS) but before the beginning of lung injury will block disease progression and prevent ARDS. These data suggest that ARDS may be prevented in patients at risk.

Nor was this study designed to compare multiple preemptive ventilator strategies, but rather to show that progression of lung injury could be blocked with an appropriate mechanical ventilation strategy secondary to reduction in the four key drivers of ARDS pathophysiology (i.e., increased permeability, alveolar edema, surfactant deactivation, and alveolar instability). We chose the ventilator settings in the VC group to be similar to those often used in surgery patients (12–15) because our model of T/HS simulates the trauma patient who would often undergo surgery and subsequently be treated in the surgical intensive care unit. However, it is very possible that preemptive application of VC with a low Vt and higher PEEP might also prevent ARDS development, similar to APRV. Further research is necessary before the optimal mechanical breath P/TP necessary to prevent ARDS is determined.


This study suggests that T/HS-induced ARDS can be prevented by preemptive application of a mechanical breath with an extended airway pressure P/TP delivered via the APRV mode. This pilot study demonstrates proof of concept that prevention of progressive lung injury is possible in the T/HS setting. To our knowledge, this is the first T/HS-induced lung injury model in a rat, which demonstrates that ARDS can be prevented with appropriate preemptive mechanical ventilation. These data expand on prior work from our laboratory, which showed the effectiveness of early APRV in preventing PS + I/R–induced ARDS and thus extends the applicability of a preemptive ventilation strategy to the trauma population. Having established this small animal T/HS-induced ARDS model, and proof of concept of prevention, future studies will focus on optimizing a variety of preemptive ventilation strategies. This novel therapeutic approach, if successful in humans, would change the clinical paradigm from treating to preventing ARDS. Indeed, Villar and Slutsky (38) recently commented that “ARDS is no longer a syndrome that must be treated, but is a syndrome that should be prevented.”


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Acute respiratory distress syndrome; ventilator-induced lung injury; airway pressure release ventilation; hemorrhagic shock rat model

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