A, In vivo photomicrographs at inspiration and expiration prior to coloring and for positive end-expiratory pressure (PEEP) of 5 cm H2O, airway pressure release ventilation (APRV) ratio of termination of peak expiratory flow rate (T-PEFR) to peak expiratory flow rate (PEFR) of 10%, PEEP of 16 cm H2O, and APRV T-PEFR to PEFR ratio of 75% (original magnification ×10). Alveoli are colored in yellow; nonalveolar tissue, red. B, Alveolar air space occupancy is expressed as a percentage of the photomicrograph containing inflated alveoli (yellow in A) at inspiration and expiration. Data are shown as the mean; error bars indicate standard error of the mean.
aP < .05 for PEEP of 5 cm H2O vs APRV T-PEFR to PEFR ratio of 10%.
bP < .05 for PEEP of 16 cm H2O vs APRV T-PEFR to PEFR ratio of 75%.
A, Microstrain vs alveolar air space occupancy at inspiration. Dashed line indicates difference in alveolar air space occupancy between airway pressure release ventilation (APRV) and controlled mandatory ventilation. B, Normalized pressure-time profile (pressure time integral [PTI] · f) over a minute vs alveolar air space occupancy at inspiration. PEEP indicates positive end-expiratory pressure. Percentages for APRV indicate the APRV ratio of termination of peak expiratory flow rate to peak expiratory flow rate.
A, Alveolar microstrain vs alveolar tidal volume in APRV. Decreasing the time at low pressure (Tlow) (or increasing the ratio of termination of peak expiratory flow rate [T-PEFR] to peak expiratory flow rate [PEFR] from 10% to 75%) resulted in both reduced microstrain and alveolar tidal volume. B, Alveolar microstrain vs alveolar tidal volume in CMV. Increasing positive end-expiratory pressure from 5 to 16 cm H2O reduced microstrain and alveolar tidal volume. C, Mean tracheal vs alveolar tidal volume with decreasing Tlow in APRV. Error bars indicate standard error of the mean. D, Mean tracheal vs alveolar tidal volume with increasing positive end-expiratory pressure in CMV. Error bars indicate standard error of the mean.
Positive end-expiratory pressure (PEEP) of 16 cm H2O had no difference between microstrain and macrostrain. However, PEEP of 5 cm H2O and airway pressure release ventilation (APRV) ratios of termination of peak expiratory flow rate (T-PEFR) to peak expiratory flow rate (PEFR) of 10% and 75% demonstrated significant differences between microstrain and macrostrain. Error bars indicate standard error of the mean.
aP < .05 between microstrain and macrostrain.
bP < .05 between PEEP of 5 cm H2O and APRV T-PEFR to PEFR ratio of 10%.
eTable 1. The relationships among micro-strain (μ-strain) and Macro-Strain (M-Strain), total alveolar area at inspiration (Ins %) and expiration (Exp %), and the number of inflated alveoli (# of Alveoli) in CMV and APRV
eTable 2. Components of the Mechanical Breath Profile with APRV versus CMV Settings
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Kollisch-Singule M, Emr B, Smith B, et al. Mechanical Breath Profile of Airway Pressure Release Ventilation: The Effect on Alveolar Recruitment and Microstrain in Acute Lung Injury. JAMA Surg. 2014;149(11):1138–1145. doi:10.1001/jamasurg.2014.1829
Improper mechanical ventilation settings can exacerbate acute lung injury by causing a secondary ventilator-induced lung injury. It is therefore important to establish the mechanism by which the ventilator induces lung injury to develop protective ventilation strategies. It has been postulated that the mechanism of ventilator-induced lung injury is the result of heterogeneous, elevated strain on the pulmonary parenchyma. Acute lung injury has been associated with increases in whole-lung macrostrain, which is correlated with increased pathology. However, the effect of mechanical ventilation on alveolar microstrain remains unknown.
To examine whether the mechanical breath profile of airway pressure release ventilation (APRV), consisting of a prolonged pressure-time profile and brief expiratory release phase, reduces microstrain.
Design, Setting, and Participants
In a randomized, nonblinded laboratory animal study, rats were randomized into a controlled mandatory ventilation group (n = 3) and an APRV group (n = 3). Lung injury was induced by polysorbate lavage. A thoracotomy was performed and an in vivo microscope was placed on the lungs to measure alveolar mechanics.
Main Outcomes and Measures
In the controlled mandatory ventilation group, multiple levels of positive end-expiratory pressure (PEEP; 5, 10, 16, 20, and 24 cm H2O) were tested. In the APRV group, decreasing durations of expiratory release (time at low pressure [Tlow]) were tested. The Tlow was set to achieve ratios of termination of peak expiratory flow rate (T-PEFR) to peak expiratory flow rate (PEFR) of 10%, 25%, 50%, and 75% (the smaller this ratio is [ie, 10%], the more time the lung is exposed to low pressure during the release phase, which decreases end-expiratory lung volume and potentiates derecruitment). Alveolar perimeters were measured at peak inspiration and end expiration using digital image analysis, and strain was calculated by normalizing the change in alveolar perimeter length to the original length. Macrostrain was measured by volume displacement.
Higher PEEP (16-24 cm H2O) and a brief Tlow (APRV T-PEFR to PEFR ratio of 75%) reduced microstrain. Microstrain was minimized with an APRV T-PEFR to PEFR ratio of 75% (mean [SEM], 0.05 [0.03]) and PEEP of 16 cm H2O (mean [SEM], 0.09 [0.08]), but an APRV T-PEFR to PEFR ratio of 75% also promoted alveolar recruitment compared with PEEP of 16 cm H2O (mean [SEM] total inspiratory area, 52.0% [2.9%] vs 29.4% [4.3%], respectively; P < .05). Whole-lung strain was correlated with alveolar microstrain in tested settings (P < .05) except PEEP of 16 cm H2O (P > .05).
Conclusions and Relevance
Increased positive-end expiratory pressure and reduced time at low pressure (decreased Tlow) reduced alveolar microstrain. Reduced microstrain and improved alveolar recruitment using an APRV T-PEFR to PEFR ratio of 75% may be the mechanism of lung protection seen in previous clinical and animal studies.
In patients with acute lung injury, mechanical ventilation is a lifesaving treatment. However, mechanical ventilation may cause a secondary ventilator-induced lung injury (VILI) exacerbating the original acute lung injury. Several mechanisms of VILI have been described, including pressure gradient–induced tissue trauma from repetitive alveolar collapse and expansion, also known as atelectrauma1,2 and alveolar overdistention (volutrauma).3 Alveolar heterogeneity and instability exacerbate these mechanisms. Despite implementation of ventilation strategies to protect against both atelectrauma and volutrauma, mortality from acute respiratory distress syndrome (ARDS) remains unacceptably high.4,5 Protti et al6 developed a technique of measuring whole-lung stress or strain and demonstrated that dynamic lung strain was more injurious than static strain. Their data suggest a novel method of determining the effects of the different components that compose the mechanical breath profile (MBP), including volumes, flows, pressures, rates, and the time that these forces are applied, on lung pathology. This knowledge may be used to optimize protective ventilation and reduce VILI.7 However, acute lung injury causes a heterogeneous injury such that whole-lung strain may not accurately reflect regional lung strain given the interdependence of alveolar architecture.8
Whole-lung stress and strain describe the global deformation of the lung but do not characterize the effect and distribution of forces generated by mechanical ventilation on lung microanatomy, including the alveoli and alveolar ducts. This is of particular importance in the injured lung because derecruitment may reduce the effective size of the lung so that overdistention occurs at lower tidal volumes.9,10 Studying lung strain at this microanatomical level has been impeded by the complex geometry of the alveolar and conducting airway network.8 An understanding of microventilation, the forces imparted to lung tissues at the microanatomical level, may provide insight into the development of optimal macroventilation strategies.3 To better classify the strain associated with mechanical ventilation at the microanatomical level, we investigated alveolar microstrain using in vivo microscopy of subpleural alveoli during dynamic inflation and deflation. We hypothesized that whole-lung macrostrain is not correlated with alveolar microstrain for a given mechanical breath in the acutely injured lung. We further hypothesized that the MBP of airway pressure release ventilation (APRV), with a prolonged time at the plateau pressure (Phigh) and minimal time at end-expiratory release pressure (Plow), minimizes microstrain.
All experiments were performed in accordance with National Institutes of Health guidelines in the use of laboratory animals and approved by the State University of New York Upstate Medical University Institutional Animal Care and Use Committee. Male Sprague-Dawley rats (450-500 g) were anesthetized with a mixture of ketamine hydrochloride (90 mg/mL) and xylazine hydrochloride (10 mg/mL) dosed at 0.1 mg/kg of ketamine. Animals were intubated via tracheostomy with a 2.5-mm tracheal cannula (Harvard Apparatus), then placed on mechanical ventilation (Dräger Evita Infinity V500) with a positive end-expiratory pressure (PEEP) of 5 cm H2O and a tracheal tidal volume (Vt) of 6 mL/kg, where tracheal Vt defines the whole-lung Vt measured by the ventilator at the level of the trachea. The carotid artery was cannulated with silastic tubing for hemodynamic monitoring and the external jugular vein was cannulated for fluid and medication administration. Surfactant deactivation was induced by intratracheal installation of 0.2% polysorbate 20 in normal saline (5 mL/kg, with half this volume into each lung). Rats were rotated into the right and left lateral decubitus positions for bilateral polysorbate distribution. Animals were then subjected to high Vt (tracheal Vt 16 mL/kg) and PEEP of 0 cm H2O for 10 minutes. Peak airway pressures reached approximately 35 to 40 cm H2O during this injurious mechanical ventilation. Prior to randomization, injury was verified by demonstrating regional and alveolar instability by gross observation and with in vivo microscopy.
The right lung was exposed via thoracotomy for in vivo assessment. A microscopic coverslip was lowered onto the pleural surface and the lung was held in place by gentle suction (5 cm H2O) for in vivo video microscopy (epi-objective microscope with epi-illumination; Olympus America Inc) as previously described.11 Animals were randomized into 2 treatment groups: controlled mandatory ventilation (CMV) (n = 3) and APRV (n = 3).
Rats were maintained on low tracheal Vt ventilation (tracheal Vt 6 mL/kg) with a respiratory rate of 55 breaths/min and PEEP of 5 cm H2O with incrementally increasing PEEP (10, 16, 20, and 24 cm H2O). Animals were ventilated at each setting for 5 minutes to acclimate and standardize the volume history. The in vivo microscope was placed as described and videos were recorded with a high-definition video camera (Allied Visions Stingray F-145C) for 5 ventilator cycles at each ventilation setting.
Rats were maintained at a Phigh of 35 to 40 cm H2O for a time (Thigh) of 1.9 to 2.0 seconds, which was set to occupy approximately 90% of the ventilator cycle. The release pressure (Plow = 0 cm H2O) was applied for a time (Tlow) between 0.13 and 0.40 second. The peak expiratory flow rate (PEFR) is defined as the greatest absolute flow rate during the release from Phigh. The flow rate at the termination of PEFR (T-PEFR) was altered by varying the Tlow to set the ratio between T-PEFR and PEFR to be 10%, 25%, 50%, or 75%. Rats were acclimated to each ventilator setting for 5 minutes prior to having in vivo microscopic fields recorded for 5 ventilator cycles.
Microscopic images of alveoli were recorded for analysis using StreamPix 5 (Norpix Inc). The dynamic changes in alveolar size during ventilation were determined by outlining individual alveoli at both peak inspiration and end expiration (Figure 1A) using PhotoShop CS6 (Adobe Inc). Individual alveolar perimeters and areas were quantified using Image-Pro Plus (MediaCybernetics). Individual alveolar area and total alveolar air space area were calculated as a percentage of total frame area. For each ventilation mode, the mean and standard deviation of the individual alveolar area were calculated. Change in individual alveolar area between inspiration and expiration, representing a surrogate for alveolar Vt, was then calculated and the number of pixels along the perimeter of each alveolus was measured to analyze microstrain. Alveoli that were visually lost between inspiration and expiration were assumed to have totally collapsed and were designated values of 0% for area and 0 pixels for perimeter.
The primary outcome of interest was microstrain, which was calculated as the change in length of the alveolar wall normalized by the original length12: microstrain = ∆LP/LPe, where ∆LP is the change in perimeter length between inspiration and expiration and LPe is the original perimeter length at expiration.
As previously described, the pressure-time integral (PTI) was calculated using direct measurements from the ventilator.13 The PTI calculates the degree of pressure applied to the lung over a given ventilator cycle (inspiration plus expiration or expiratory release). It describes 1 ventilator cycle but does not take into account the difference between total cycle times in the 2 ventilator modes. To account for the ventilation frequency f, we define a normalized PTI over a minute, PTI · f.
To define macrostrain for similar treatment conditions, another group of rats was randomized to CMV (n = 3) or APRV (n = 3). Rats were anesthetized and surfactant deactivation was induced via intratracheal polysorbate instillation as described earlier.
Macrostrain was calculated as the relative change in total lung volume14: macrostrain = ∆V/V0, where ∆V represents the change in lung volume between inspiration and expiration and V0 represents the end-expiratory lung volume (EELV).
Lungs were excised via thoracotomy. Macrostrain for the settings with the least microstrain (PEEP 16 cm H2O; APRV T-PEFR to PEFR ratio 75%) and greatest microstrain (PEEP 5 cm H2O; APRV T-PEFR to PEFR ratio 10%) within each group was assessed. The excised lungs were ventilated for 5 minutes and then the trachea was clamped at peak inspiration (Vi) and end expiration (V0). The volumes were measured by the volume of water displaced in a graduated cylinder so that ∆V = Vi − V0.
Results are reported as mean (standard error of the mean). Continuous variables were analyzed using analysis of variance within each group and Tukey test was used for post hoc multiple comparisons. The settings within each group that yielded the greatest and least microstrain were compared pairwise using t test. All tests were 2-tailed and P ≤ .05 was considered statistically significant. We used Prism version 5.0 statistical software for analysis (GraphPad Software, Inc).
Changing both PEEP and Tlow dramatically affected alveolar recruitment at both peak inspiratory pressure and end-expiratory pressure (Figure 1). The APRV T-PEFR to PEFR ratios of both 10% and 75% caused greater alveolar recruitment at peak inspiratory pressure compared with CMV at PEEPs of 5 and 16 cm H2O (Figure 1). The largest expiratory derecruitment was seen with PEEP of 5 cm H2O and an APRV T-PEFR to PEFR ratio of 10%. An APRV T-PEFR to PEFR ratio of 75% caused maximal inspiratory recruitment and minimal expiratory derecruitment (Figure 1).
The values of microstrain and macrostrain, the percentage of the photomicrograph occupied by alveoli (total alveolar area), the alveolar Vt, the number of alveoli, and PTI · f are listed in the Table and eTable 1 in the Supplement. A PEEP of 16 cm H2O and an APRV T-PEFR to PEFR ratio of 75% resulted in minimal microstrain (mean SEM, 0.09 [0.08] and 0.05 [0.03], respectively) and caused minimal change in alveolar Vt (mean [SEM], 0.06% [0.07%] and 0.07% [0.03%], respectively). With APRV, a greater number of alveoli were recruited at inspiration with all Tlow settings (ie, a large percentage of total alveolar area and number of alveoli). The PTI · f value was higher in APRV compared with CMV at all ventilator settings. The APRV T-PEFR to PEFR ratio of 75% had the highest PTI · f (mean [SEM], 34.46 [0.94] cm H2O · breaths/min), the greatest total alveolar area at both inspiration (mean [SEM], 52.0% [2.9%]) and expiration (mean [SEM], 49.6% [3.2%]), and the lowest microstrain (mean [SEM], 0.05 [0.03]) and alveolar Vt (mean [SEM], 0.07% [0.03%]) of all ventilator settings within APRV.
The relationship between the alveolar air space occupancy at inspiration (which represents the combined effects of alveolar recruitment and alveolar Vt) and the microstrain and PTI · f are shown in Figure 2. Figure 2B indicates that high PTI · f, which occurred in all APRV modes, was associated with alveolar recruitment. High PEEP (16 to 24 cm H2O) reduced microstrain but recruited fewer alveoli than APRV (mean [SEM] total inspiratory area, 52.0% [2.9%] for APRV T-PEFR to PEFR ratio of 75% vs 29.4% [4.3%] for PEEP of 16 cm H2O; P < .05). The APRV T-PEFR to PEFR ratio of 75% was optimal at both recruiting alveoli and minimizing microstrain (Figure 2A).
Alveolar Vt (the change in the size of individual alveoli during ventilation) and microstrain both decreased in response to reductions in Tlow (T-PEFR to PEFR ratios increased from 10% to 75%) (Figure 3A). Increasing PEEP from 5 to 16 cm H2O also decreased both alveolar Vt and microstrain, which did not change significantly with further increases in PEEP (Figure 3B). Tracheal Vt decreased during APRV with reduced Tlow (T-PEFR to PEFR ratio increased from 10% to 75%) (Figure 3C). Increasing PEEP with a set tracheal Vt reduced alveolar Vt from PEEP of 5 to 16 cm H2O; however, minimal changes were seen with further PEEP increases (Figure 3D).
There was a significant difference in mean (SEM) macrostrain between PEEP of 5 cm H2O (0.15 [0.03]) and an APRV T-PEFR to PEFR ratio of 10% (0.33 [0.07]) (P < .05), which was not reflected in the microstrain (Figure 4). Mean (SEM) macrostrain and microstrain were also significantly different within both PEEP of 5 cm H2O (macrostrain, 0.15 [0.03]; microstrain, 0.84 [0.09]; P < .05) and an APRV T-PEFR to PEFR ratio of 10% (macrostrain, 0.33 [0.07]; microstrain, 0.66 [0.10]; P < .05). Likewise, there was a significant difference between mean (SEM) microstrain and macrostrain with an APRV T-PEFR to PEFR ratio of 75% (macrostrain, 0.14 [0.07]; microstrain, 0.05 [0.03]; P < .05); however, this difference was not present with a CMV PEEP of 16 cm H2O (macrostrain, 0.10 [0.04]; microstrain, 0.09 [0.08]; P > .05) (Figure 4).
Details of the mechanical breath profile settings for both CMV and APRV are shown in eTable 2 in the Supplement.
This study provides novel insights into the effect of mechanical ventilation on dynamic alveolar strain in the acutely injured lung using in vivo microscopy. We have shown that alveoli can be stabilized and microstrain reduced by either setting PEEP in CMV above alveolar critical closing pressure or by setting a sufficiently brief Tlow in APRV to maintain the end-expiratory release pressure above alveolar critical closing pressure. We have also found that an APRV T-PEFR to PEFR ratio of 75% optimized both alveolar recruitment and alveolar stability (ie, minimized microstrain) compared with all other groups. In addition, we have shown that whole-lung measurements such as the delivered Vt and macrostrain are not always adequate markers of the regional microenvironment, as described by alveolar Vt and microstrain. Moreover, APRV represents a low alveolar Vt ventilation strategy despite greater tracheal Vt. This study suggests that the appropriately adjusted APRV MBP (APRV T-PEFR to PEFR ratio of 75%) may be optimal (of the MBPs tested in this study) to protect the acutely injured lung because it results in maximal alveolar recruitment and minimal alveolar microstrain.
Brunner and Wysocki15 developed a stress-strain index to determine the optimal MBP to minimize both stress and strain. Using a computational model, they determined that the stress-strain index increased markedly when EELV is reduced. Reducing EELV presumably increased alveolar tidal recruitment and derecruitment, suggesting that the larger the change in lung volume is with each breath, the higher the stress-strain index is. Corroborating these findings in a porcine model, Protti et al6 induced dynamic strain by decreasing the level of PEEP (reducing EELV) and increasing the tracheal Vt. The study by Protti and colleagues clearly demonstrated that dynamic strain significantly increased VILI compared with static strain, even though the global strain was identical. Tschumperlin et al16 described similar findings using an in vitro model in which alveolar epithelial type II cells were exposed to identical degrees of peak deformation but varying degrees of static or dynamic deformation. They showed that large deformation amplitudes increased cell death, and minimizing these amplitudes improved alveolar epithelial cell viability. This study combined with those by Brunner and Wysocki15 and Protti et al6 support the hypothesis that dynamic strain causes more pulmonary injury than the same level of static strain.16 Our study builds on the work of these investigations by elucidating the features of the MBP that minimize lung volume loss at end expiration, thereby reducing microstrain. Specifically, we demonstrate that reducing EELV by either increasing Tlow (T-PEFR to PEFR ratio of 10%) in the APRV group or decreasing PEEP (5 cm H2O) in the CMV group significantly increased microstrain.
To recruit the lung and maintain recruitment,17 inspiratory pressures must be greater than the critical opening pressure and PEEP must be set above the critical closing pressure to prevent derecruitment.18,19 In addition, there is latency to both recruitment and derecruitment such that a finite period is necessary for an alveolus to close when the airway pressure falls below the critical closing pressure.19,20 In a randomized trial of 20 patients, Hodgson et al21 assessed critical closing pressure by a stepwise reduction in PEEP until a decrease in oxygen saturation occurred. Patients ventilated with PEEP above critical closing pressure demonstrated a trend toward shorter duration of mechanical ventilation, intensive care unit stay, and hospital stay.21 These results follow an earlier randomized trial by Villar et al22 of 95 patients in whom PEEP was set just above the critical closing pressure as determined by the lower inflection point of the pressure and volume curve. Patients randomized to PEEP set with this strategy, as compared with a lower PEEP scale, demonstrated lower intensive care unit and hospital mortality and fewer ventilator-free days by day 28. In our study, PEEP set below the critical closing pressure demonstrated greater microstrain. Similarly, we have shown that extending Tlow during APRV to yield an inappropriate T-PEFR to PEFR ratio is correlated with an increase in microstrain (Table), which has been shown to cause lung damage. In addition, APRV set with a longer Tlow allows the lungs to deflate to airway pressures below critical closing pressure.6,15,16 These data provide mechanistic support for prior assertions that the technique of APRV application (ie, appropriate titration of the release phase) is essential to achieving the lung-protective outcomes described in prior articles.23
All settings of the APRV MBP used in our study demonstrated a greater number of open alveoli at inspiration compared with all CMV settings. We hypothesize that the observed improvements in alveolar recruitment occurred because of the increased time at the plateau pressure and reduced time at the release phase (increased PTI).20,24 The plateau pressures of APRV and high PEEP (20 and 24 cm H2O) were similar but the time over which plateau pressure was applied was up to 5 times longer in the APRV group, yielding an increased PTI · f. There is a strong time dependence to alveolar reopening as demonstrated by continued recruitment over a 40-second period of sustained plateau pressure in a rat saline lung lavage–induced acute lung injury.20 Therefore, APRV favors recruitment due to sustained plateau pressures, which facilitate reopening, and brief excursions to low pressure that do not allow time for the recruited units to close.
Previous studies demonstrated that APRV yields an increase in tracheal Vt over time, raising concerns that APRV is not a low Vt ventilation strategy.13,25,26 These findings bring to light the important distinction between macroventilation and microventilation. The Vt measured at the endotracheal tube may not accurately reflect distribution of volume over the alveolar units. For example, a lung with 50% derecruitment ventilated at 6 mL/kg may have greater localized distention than an open lung ventilated at 10 mL/kg owing to the reduced number of ventilated alveoli in the collapsed lung. In our study, alveolar Vt was similar between an APRV T-PEFR to PEFR ratio of 75% and PEEP of 16 cm H2O, but the APRV T-PEFR to PEFR ratio of 75% had a significantly greater tracheal Vt (Figure 3). We postulate that this discordance occurred because the APRV T-PEFR to PEFR ratio of 75% increased the number of alveoli over which the tracheal Vt was distributed. When describing volutrauma as a potential source of VILI, it is important to recognize that volutrauma does not describe the topographical distribution of regional Vt. Volume distribution is strongly dependent on derecruitment. Therefore, regional or alveolar volutrauma may be a more important indicator of lung injury than whole-lung volume.3,6,27
Calculating the distribution of stresses and strains in a living, 3-dimensional system with interdependence of the pulmonary units is extremely complex. Protti et al6 have pioneered a method for approximating global pulmonary stress and strain using transpulmonary pressure and volume change, respectively. Unfortunately, this technique does not provide insight into regional microstress and microstrain experienced by individual alveoli due to volutrauma and atelectrauma. As we have shown in this study, macrostrain is not indicative of microstrain at the alveolar level. For instance, small global strain in lungs may lead to significantly larger local strains owing to the heterogeneity and complex interdependence of alveoli, particularly in the injured lung.6,8,28,29 Current clinical management relies on global parameters even though these may not reflect the regional lung micromechanics.30 This approach does not explicitly account for regional heterogeneity; it does, however, represent the best possible approach given the limitations of current clinical diagnostic tools.
The importance of maintaining patency using techniques such as APRV is highlighted by Mead et al,29 who demonstrated that simulations of nonuniform alveoli result in a 13% increase in stress compared with a uniform system. Similarly, Rausch et al8 determined that local strains could achieve levels up to 4 times that of the global strain in rat lungs using image-based 3-dimensional finite-element simulations. It is clear that use of global parameters to manage protective mechanical ventilation in patients may be inaccurate and knowledge of the effect of any MBP at the microanatomical level is essential. We have confirmed that there is a significant difference between measured microstrain and macrostrain in the heterogeneously injured lung.
We have found that an APRV T-PEFR to PEFR ratio of 75% was the most effective MBP at both minimizing microstrain and maximizing alveolar recruitment (Figure 2A). Because others have shown that reduced dynamic strain decreases VILI,6,15 our data suggest that of the MBPs considered herein, an APRV T-PEFR to PEFR ratio of 75% is the MBP most effective at minimizing lung injury caused by mechanical ventilation and optimizing the surface area available for oxygen exchange. These findings support our previous studies showing that preemptive application of an APRV T-PEFR to PEFR ratio of 75% significantly reduced lung damage in a retrospective data analysis of severely injured trauma patients,31 a porcine sepsis and gut ischemia- and reperfusion-induced ARDS model,13,26 a rat VILI model,25 and a hemorrhagic shock–induced ARDS model.32
Our in vivo video microscopy shows that to understand the potential protective or deleterious properties of any MBP, it must be examined at the microanatomical level. Calculation of whole-lung stress and strain is limited in accurately determining the optimal MBP because it does not always correlate with the physical forces at the alveolar level (ie, the microanatomical environment). The importance of the time that the airway pressure is applied on alveolar recruitment and stabilization was also demonstrated in this study. An APRV T-PEFR to PEFR ratio of 75% had a mean plateau pressure less than that of PEEP of 16 cm H2O but still recruited more alveoli, presumably owing to the application of plateau pressure for much longer during each breath. Because these factors may not be captured using current whole-lung stress and strain calculations, it is clear that further analysis of the time dependence of recruitment and derecruitment will be necessary to devise optimal MBPs.
Low Vt ventilation with PEEP adjusted to maintain satisfactory blood oxygen saturation is the current clinical standard-of-care ventilation for patients with established ARDS.4 The rationale for this strategy is that low tracheal Vt with adequate PEEP will minimize repetitive alveolar collapse and expansion, prevent atelectrauma, and protect the lung from VILI.4 The ARDS Network ventilation strategy allows much of the lung to collapse and attempts to ventilate and protect only the “baby lung” that remains relatively healthy.33 However, it has been shown that the combination of optimizing alveolar recruitment and minimizing alveolar instability reduces mechanical trauma to pulmonary tissue and inactivation of surfactant.3 The increased recruitment, reduced microstrain, and improved alveolar stability afforded by an APRV T-PEFR to PEFR ratio of 75% suggest that this MBP may offer optimal protection from VILI.
This study demonstrates that changes in the MBP in both CMV and APRV modes can dramatically affect the degree of alveolar recruitment and stability in the heterogeneously injured lung. Our findings highlight the limitations of using whole-lung strain to identify the effect of the MBP on lung physiology. Because of the heterogeneous nature of the injured lung, alveolar microstrain provides a superior assessment of the injurious mechanical forces that cause VILI. We postulate that adjusting the MBP directed by microanatomical changes would assist in the development of the optimally protective mechanical breaths, potentially reducing VILI morbidity and mortality.
Corresponding Author: Joshua Satalin, BS, Department of General Surgery, State University of New York Upstate Medical University, 750 E Adams St, Syracuse, NY 13210 (firstname.lastname@example.org).
Accepted for Publication: May 27, 2014.
Correction: This article was corrected online September 7, 2016, to include potential conflicts of interest that had been omitted.
Published Online: September 17, 2014. doi:10.1001/jamasurg.2014.1829
Author Contributions: Dr Kollisch-Singule and Mr Satalin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kollisch-Singule, Emr, Roy, Jain, Satalin, Andrews, Habashi, Bates, Marx, Nieman, Gatto.
Acquisition, analysis, or interpretation of data: Kollisch-Singule, Smith, Roy, Satalin, Snyder, Andrews, Habashi, Nieman, Gatto.
Drafting of the manuscript: Kollisch-Singule, Andrews, Habashi, Bates, Marx, Nieman, Gatto.
Critical revision of the manuscript for important intellectual content: Emr, Smith, Roy, Jain, Satalin, Snyder, Andrews, Habashi, Bates, Marx, Nieman, Gatto.
Statistical analysis: Kollisch-Singule, Satalin, Andrews, Habashi.
Obtained funding: Nieman.
Administrative, technical, or material support: Kollisch-Singule, Emr, Smith, Jain, Satalin, Snyder, Gatto.
Study supervision: Emr, Roy, Satalin, Marx, Nieman.
Conflict of Interest Disclosures: Dr Habashi reports presenting at conferences sponsored by or in part by Dräger Medical between 2010 and 2015 for which he received remuneration for honoraria and travel. He is also a founder of Intensive Care On-line Network (ICON) and presented webinars hosted by ICON between 2010 and 2015 and continues to present such webinars and assist clinicians with questions, without any remuneration received. Dr Habashi also reports that he has been issued 2 patents for a ventilation method related to initiating, managing, and/or weaning airway pressure release ventilation and controlling a ventilator in accordance with this method. To date, the patents have not been licensed to any manufacturer and no monetary gain has resulted from the patents. Ms Andrews reports presenting at conferences sponsored by or in part by Dräger Medical between 2010 and 2015 for which she received remuneration for honoraria and travel. She also presented webinars hosted by ICON between 2010 and 2015, with no remuneration received. Ms Andrews also reports being employed by ICON since 2001. Mr Nieman reports presenting at conferences sponsored by or in part by Dräger Medical between 2010 and 2015 for which he received remuneration for honoraria and travel. He also presented webinars hosted by ICON between 2013 and 2015, with no remuneration received. Mr Nieman also reports holding multiple patents for methods to prevent, assess, or treat acute lung injury, sepsis-induced multiple organ dysfunction syndrome, or blood loss associated with cardiopulmonary bypass surgery. Dr Kollisch-Singule reports having lectured at an event sponsored by Dräger Medical in 2014. Dr Bates reports having filed a patent for variable ventilation as a diagnostic tool for assessing lung mechanical function. No other disclosures were reported.
Funding/Support: This work was supported by a seed grant from the AMA Foundation.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentation: This paper was presented at the 2014 Annual Meeting of the Association of VA Surgeons; April 6, 2014; New Haven, Connecticut.
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