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Objective: To review the use of airway pressure release ventilation (APRV) in the treatment of acute lung injury/acute respiratory distress syndrome.Data Source: Published animal studies, human studies, and review articles of APRV.Data Summary: APRV has been successfully used in neonatal, pediatric, and adult forms of respiratory failure. Experimental and clinical use of APRV has been shown to facilitate spontaneous breathing and is associated with decreased peak airway pressures and improved oxygenation/ventilation when compared with conventional ventilation. Additionally, improvements in hemodynamic parameters, splanchnic perfusion, and reduced sedation/neuromuscular blocker requirements have been reported.Conclusion: APRV may offer potential clinical advantages for ventilator management of acute lung injury/acute respiratory distress syndrome and may be considered as an alternative "open lung approach" to mechanical ventilation. Whether APRV reduces mortality or increases ventilator-free days compared with a conventional volume-cycled "lung protective" strategy will require future randomized, controlled trials. [ABSTRACT FROM AUTHOR]

Backgroud: Lung volume measurements are important for monitoring functional aeration and recruitment and may help guide adjustments in ventilator settings. The expiratory phase of airway pressure release ventilation (APRV) may provide physiologic information about lung volume based on the expiratory flow-time slope, angle, and time to approach a no-flow state (expiratory time [T E ]). We hypothesized that expiratory flow would correlate with estimated lung volume (ELV) as measured using a modified nitrogen washout/washin technique in a large-animal lung injury model., Methods: Eight pigs (35.2 ± 1.0 kg) were mechanically ventilated using an Engström Carescape R860 on the APRV mode. All settings were held constant except the expiratory duration, which was adjusted based on the expiratory flow curve. Abdominal pressure was increased to 15 mm Hg in normal and injured lungs to replicate a combination of pulmonary and extrapulmonary lung injury. ELV was estimated using the Carescape FRC INview tool. The expiratory flow-time slope and T E were measured from the expiratory flow profile., Results: Lung elastance increased with induced lung injury from 29.3 ± 7.3 cm H 2 O/L to 39.9 ± 15.1cm H 2 O/L, and chest wall elastance increased with increasing intra-abdominal pressures (IAPs) from 15.3 ± 4.1 cm H 2 O/L to 25.7 ± 10.0 cm H 2 O/L in the normal lung and 15.8 ± 6.0 cm H 2 O/L to 33.0 ± 6.2 cm H 2 O/L in the injured lung ( P = .39). ELV decreased from 1.90 ± 0.83 L in the injured lung to 0.67 ± 0.10 L by increasing IAP to 15 mm Hg. This had a significant correlation with a T E decrease from 2.3 ± 0.8 s to 1.0 ± 0.1 s in the injured group with increasing insufflation pressures (ρ = 0.95) and with the expiratory flow-time slope, which increased from 0.29 ± 0.06 L/s 2 to 0.63 ± 0.05 L/s 2 (ρ = 0.78)., Conclusions: Changes in ELV over time, and the T E and flow-time slope, could be used to demonstrate evolving lung injury during APRV. Using the slope to infer changes in functional lung volume represents a unique, reproducible, real-time, bedside technique that does not interrupt ventilation and may be used for clinical interpretation., Competing Interests: Dr Kollisch-Singule discloses a relationship with Dräger Medical Systems. Dr Habashi is the founder of ICON, of which Ms Andrews is an employee. Dr Habashi holds patents on a method of initiating, managing, and/or weaning airway pressure release ventilation, as well as controlling a ventilator in accordance with the same. Drs Kaczka and Herrmann are co-founders and shareholders of OscillaVent, and are co-inventors on a patent involving multifrequency oscillatory ventilation. Drs Kaczka and Herrmann disclose a relationship with ZOLL Medical. Dr Kaczka discloses a relationship with Lungpacer Medical. The remaining authors have disclosed no conflicts of interest. The authors maintain that industry had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; nor the preparation, review, or approval of the manuscript., (Copyright © 2024 by Daedalus Enterprises.)

Competing Interests: Dr. Habashi disclosed that he has patents in the field of mechanical ventilation and airway pressure release ventilation. Dr. Bates’ institution received funding from the National Institutes of Health (NIH) (HL142702); he received funding from Oscillavent, Respiratory Sciences, and Johnson & Johnson; he disclosed that he is co-inventor on patents (US7945303 B2, WO2015127377 A1, and 20160007882 A1) and that he has a patent pending (PCT/US21/24537). Dr. Bates and Nieman received support for article research from the NIH. Dr. Nieman’s institution received funding from Drager Medical; he received support for article research from the Congressionally Directed Medical Research Programs Department of Defense. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Airway pressure release ventilation (APRV) is a protective mechanical ventilation mode for patients with acute respiratory distress syndrome (ARDS) that theoretically may reduce ventilator-induced lung injury (VILI) and ARDS-related mortality. However, there is no standard method to set and adjust the APRV mode shown to be optimal. Therefore, we performed a meta-regression analysis to evaluate how the four individual APRV settings impacted the outcome in these patients. Methods: Studies investigating the use of the APRV mode for ARDS patients were searched from electronic databases. We tested individual settings, including (1) high airway pressure (P High ); (2) low airway pressure (P Low ); (3) time at high airway pressure (T High ); and (4) time at low pressure (T Low ) for association with PaO 2 /FiO 2 ratio and ICU length of stay. Results: There was no significant difference in PaO 2 /FiO 2 ratio between the groups in any of the four settings (P High difference -12.0 [95% CI -100.4, 86.4]; P Low difference 54.3 [95% CI -52.6, 161.1]; T Low difference -27.19 [95% CI -127.0, 72.6]; T High difference -51.4 [95% CI -170.3, 67.5]). There was high heterogeneity across all parameters (P hHgh I 2 = 99.46%, P Low I 2 = 99.16%, T Low I 2 = 99.31%, T High I 2 = 99.29%). Conclusions: None of the four individual APRV settings independently were associated with differences in outcome. A holistic approach, analyzing all settings in combination, may improve APRV efficacy since it is known that small differences in ventilator settings can significantly alter mortality. Future clinical trials should set and adjust APRV based on the best current scientific evidence available.

Purpose of Review: Airway pressure release ventilation (APRV) is a modality of ventilation in which high inspiratory continuous positive airway pressure (CPAP) alternates with brief releases. In this review, we will discuss the rationale for APRV as a lung protective strategy and then provide a practical introduction to initiating APRV using the time-controlled adaptive ventilation (TCAV) method., Recent Findings: APRV using the TCAV method uses an extended inspiratory time and brief expiratory release to first stabilize and then gradually recruit collapsed lung (over hours/days), by progressively 'ratcheting' open a small volume of collapsed tissue with each breath. The brief expiratory release acts as a 'brake' preventing newly recruited units from re-collapsing, reversing the main drivers of ventilator-induced lung injury (VILI). The precise timing of each release is based on analysis of expiratory flow and is set to achieve termination of expiratory flow at 75% of the peak expiratory flow. Optimization of the release time reflects the changes in elastance and, therefore, is personalized (i.e. conforms to individual patient pathophysiology), and adaptive (i.e. responds to changes in elastance over time)., Summary: APRV using the TCAV method is a paradigm shift in protective lung ventilation, which primarily aims to stabilize the lung and gradually reopen collapsed tissue to achieve lung homogeneity eliminating the main mechanistic drivers of VILI., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Acute respiratory distress syndrome (ARDS) alters the dynamics of lung inflation during mechanical ventilation. Repetitive alveolar collapse and expansion (RACE) predisposes the lung to ventilator-induced lung injury (VILI). Two broad approaches are currently used to minimize VILI: (1) low tidal volume (LV T ) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LV T approach attempts to protect already open lung tissue from overdistension, while simultaneously resting collapsed tissue by excluding it from the cycle of mechanical ventilation. By contrast, the OLA attempts to reinflate potentially recruitable lung, usually over a period of seconds to minutes using higher PEEP used to prevent progressive loss of end-expiratory lung volume (EELV) and RACE. However, even with these protective strategies, clinical studies have shown that ARDS-related mortality remains unacceptably high with a scarcity of effective interventions over the last two decades. One of the main limitations these varied interventions demonstrate to benefit is the observed clinical and pathologic heterogeneity in ARDS. We have developed an alternative ventilation strategy known as the Time Controlled Adaptive Ventilation (TCAV) method of applying the Airway Pressure Release Ventilation (APRV) mode, which takes advantage of the heterogeneous time- and pressure-dependent collapse and reopening of lung units. The TCAV method is a closed-loop system where the expiratory duration personalizes V T and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (C RS ) measured by the slope of the expiratory flow curve during passive exhalation. Two potentially beneficial features of TCAV are: (i) the expiratory duration is personalized to a given patient's lung physiology, which promotes alveolar stabilization by halting the progressive collapse of alveoli, thereby minimizing the time for the reopened lung to collapse again in the next expiration, and (ii) an extended inspiratory phase at a fixed inflation pressure after alveolar stabilization gradually reopens a small amount of tissue with each breath. Subsequently, densely collapsed regions are slowly ratcheted open over a period of hours, or even days. Thus, TCAV has the potential to minimize VILI, reducing ARDS-related morbidity and mortality., (© 2024. The Author(s).)

Patients with acute respiratory distress syndrome (ARDS) have few treatment options other than supportive mechanical ventilation. The mortality associated with ARDS remains unacceptably high, and mechanical ventilation itself has the potential to increase mortality further by unintended ventilator-induced lung injury (VILI). Thus, there is motivation to improve management of ventilation in patients with ARDS. The immediate goal of mechanical ventilation in ARDS should be to prevent atelectrauma resulting from repetitive alveolar collapse and reopening. However, a long-term goal should be to re-open collapsed and edematous regions of the lung and reduce regions of high mechanical stress that lead to regional volutrauma. In this paper, we consider the proposed strategy used by the full-term newborn to open the fluid-filled lung during the initial breaths of life, by ratcheting tissues opened over a series of initial breaths with brief expirations. The newborn's cry after birth shares key similarities with the Airway Pressure Release Ventilation (APRV) modality, in which the expiratory duration is sufficiently short to minimize end-expiratory derecruitment. Using a simple computational model of the injured lung, we demonstrate that APRV can slowly open even the most recalcitrant alveoli with extended periods of high inspiratory pressure, while reducing alveolar re-collapse with brief expirations. These processes together comprise a ratchet mechanism by which the lung is progressively recruited, similar to the manner in which the newborn lung is aerated during a series of cries, albeit over longer time scales., Competing Interests: MK-S has received a Research Grant and has received equipment loans and NH has received an Unrestricted Educational Grant from Drager Medical Systems, Inc. MK-S and NH have presented and received honoraria and/or travel reimbursement at event(s) sponsored by Drager Medical Systems, Inc., outside of the published work. GN and MK-S have lectured for Intensive Care Online Network, Inc. (ICON). NH holds patents on a method of initiating, managing and/or weaning airway pressure release ventilation, as well as controlling a ventilator in accordance with the same, but these patents are not commercialized, licensed, or royalty-producing. DK and JH are co-founders and shareholders of OscillaVent, Inc., and are co-inventors on a patent involving multi-frequency oscillatory ventilation. DK and JH also receive research support from ZOLL Medical Corporation. JB is a consultant to and shareholder of OscillaVent, Inc., and has two patents pending in the field of mechanical ventilation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Nieman, Herrmann, Satalin, Kollisch-Singule, Andrews, Habashi, Tingay, Gaver, Bates and Kaczka.)

Acute respiratory distress syndrome (ARDS) is associated with a heterogeneous pattern of injury throughout the lung parenchyma that alters regional alveolar opening and collapse time constants. Such heterogeneity leads to atelectasis and repetitive alveolar collapse and expansion (RACE). The net effect is a progressive loss of lung volume with secondary ventilator-induced lung injury (VILI). Previous concepts of ARDS pathophysiology envisioned a two-compartment system: a small amount of normally aerated lung tissue in the non-dependent regions (termed "baby lung"); and a collapsed and edematous tissue in dependent regions. Based on such compartmentalization, two protective ventilation strategies have been developed: (1) a "protective lung approach" (PLA), designed to reduce overdistension in the remaining aerated compartment using a low tidal volume; and (2) an "open lung approach" (OLA), which first attempts to open the collapsed lung tissue over a short time frame (seconds or minutes) with an initial recruitment maneuver, and then stabilize newly recruited tissue using titrated positive end-expiratory pressure (PEEP). A more recent understanding of ARDS pathophysiology identifies regional alveolar instability and collapse (i.e., hidden micro-atelectasis) in both lung compartments as a primary VILI mechanism. Based on this understanding, we propose an alternative strategy to ventilating the injured lung, which we term a "stabilize lung approach" (SLA). The SLA is designed to immediately stabilize the lung and reduce RACE while gradually reopening collapsed tissue over hours or days. At the core of SLA is time-controlled adaptive ventilation (TCAV), a method to adjust the parameters of the airway pressure release ventilation (APRV) modality. Since the acutely injured lung at any given airway pressure requires more time for alveolar recruitment and less time for alveolar collapse, SLA adjusts inspiratory and expiratory durations and inflation pressure levels. The TCAV method SLA reverses the open first and stabilize second OLA method by: (i) immediately stabilizing lung tissue using a very brief exhalation time (≤0.5 s), so that alveoli simply do not have sufficient time to collapse. The exhalation duration is personalized and adaptive to individual respiratory mechanical properties (i.e., elastic recoil); and (ii) gradually recruiting collapsed lung tissue using an inflate and brake ratchet combined with an extended inspiratory duration (4-6 s) method. Translational animal studies, clinical statistical analysis, and case reports support the use of TCAV as an efficacious lung protective strategy.

Ventilator-induced lung injury (VILI) is a significant risk for patients with acute respiratory distress syndrome (ARDS). Management of the patient with ARDS is currently dominated by the use of low tidal volume mechanical ventilation, the presumption being that this mitigates overdistension (OD) injury to the remaining normal lung tissue. Evidence exists, however, that it may be more important to avoid cyclic recruitment and derecruitment (RD) of lung units, although the relative roles of OD and RD in VILI remain unclear. Forty pigs had a heterogeneous lung injury induced by Tween instillation and were randomized into four groups ( n = 10 each) with higher (↑) or lower (↓) levels of OD and/or RD imposed using airway pressure release ventilation (APRV). OD was increased by setting inspiratory airway pressure to 40 cmH 2 O and lessened with 28 cmH 2 O. RD was attenuated using a short duration of expiration (∼0.45 s) and increased with a longer duration (∼1.0 s). All groups developed mild ARDS following injury. RD ↑ OD↑ caused the greatest degree of lung injury as determined by [Formula: see text]/[Formula: see text] ratio (226.1 ± 41.4 mmHg). RD ↑ OD↓ ([Formula: see text]/[Formula: see text]= 333.9 ± 33.1 mmHg) and RD ↓ OD↑ ([Formula: see text]/[Formula: see text] = 377.4 ± 43.2 mmHg) were both moderately injurious, whereas RD ↓ OD↓ ([Formula: see text]/[Formula: see text] = 472.3 ± 22.2 mmHg; P < 0.05) was least injurious. Both tidal volume and driving pressure were essentially identical in the RD ↑ OD↓ and RD ↓ OD↑ groups. We, therefore, conclude that considerations of expiratory time may be at least as important as pressure for safely ventilating the injured lung. NEW & NOTEWORTHY In a large animal model of ARDS, recruitment/derecruitment caused greater VILI than overdistension, whereas both mechanisms together caused severe lung damage. These findings suggest that eliminating cyclic recruitment and derecruitment during mechanical ventilation should be a preeminent management goal for the patient with ARDS. The airway pressure release ventilation (APRV) mode of mechanical ventilation can achieve this if delivered with an expiratory duration (T Low ) that is brief enough to prevent derecruitment at end expiration.

A hallmark of ARDS is progressive shrinking of the 'baby lung,' now referred to as the ventilator-induced lung injury (VILI) 'vortex.' Reducing the risk of the VILI vortex is the goal of current ventilation strategies; unfortunately, this goal has not been achieved nor has mortality been reduced. However, the temporal aspects of a mechanical breath have not been considered. A brief expiration prevents alveolar collapse, and an extended inspiration can recruit the atelectatic lung over hours. Time-controlled adaptive ventilation (TCAV) is a novel ventilator approach to achieve these goals, since it considers many of the temporal aspects of dynamic lung mechanics., (© 2022. The Author(s).)

In the pursuit of science, competitive ideas and debate are necessary means to attain knowledge and expose our ignorance. To quote Murray Gell-Mann (1969 Nobel Prize laureate in Physics): "Scientific orthodoxy kills truth". In mechanical ventilation, the goal is to provide the best approach to support patients with respiratory failure until the underlying disease resolves, while minimizing iatrogenic damage. This compromise characterizes the philosophy behind the concept of "lung protective" ventilation. Unfortunately, inadequacies of the current conceptual model-that focuses exclusively on a nominal value of low tidal volume and promotes shrinking of the "baby lung" - is reflected in the high mortality rate of patients with moderate and severe acute respiratory distress syndrome. These data call for exploration and investigation of competitive models evaluated thoroughly through a scientific process. Airway Pressure Release Ventilation (APRV) is one of the most studied yet controversial modes of mechanical ventilation that shows promise in experimental and clinical data. Over the last 3 decades APRV has evolved from a rescue strategy to a preemptive lung injury prevention approach with potential to stabilize the lung and restore alveolar homogeneity. However, several obstacles have so far impeded the evaluation of APRV's clinical efficacy in large, randomized trials. For instance, there is no universally accepted standardized method of setting APRV and thus, it is not established whether its effects on clinical outcomes are due to the ventilator mode per se or the method applied. In addition, one distinctive issue that hinders proper scientific evaluation of APRV is the ubiquitous presence of myths and misconceptions repeatedly presented in the literature. In this review we discuss some of these misleading notions and present data to advance scientific discourse around the uses and misuses of APRV in the current literature., Competing Interests: NH has patents in the field of mechanical ventilation including APRV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Andrews, Shiber, Madden, Nieman, Camporota and Habashi.)

Pediatric acute respiratory distress syndrome (PARDS) remains a significant cause of morbidity and mortality, with mortality rates as high as 50% in children with severe PARDS. Despite this, pediatric lung injury and mechanical ventilation has been poorly studied, with the majority of investigations being observational or retrospective and with only a few randomized controlled trials to guide intensivists. The most recent and universally accepted guidelines for pediatric lung injury are based on consensus opinion rather than objective data. Therefore, most neonatal and pediatric mechanical ventilation practices have been arbitrarily adapted from adult protocols, neglecting the differences in lung pathophysiology, response to injury, and co-morbidities among the three groups. Low tidal volume ventilation has been generally accepted for pediatric patients, even in the absence of supporting evidence. No target tidal volume range has consistently been associated with outcomes, and compliance with delivering specific tidal volume ranges has been poor. Similarly, optimal PEEP has not been well-studied, with a general acceptance of higher levels of F i O 2 and less aggressive PEEP titration as compared with adults. Other modes of ventilation including airway pressure release ventilation and high frequency ventilation have not been studied in a systematic fashion and there is too little evidence to recommend supporting or refraining from their use. There have been no consistent outcomes among studies in determining optimal modes or methods of setting them. In this review, the studies performed to date on mechanical ventilation strategies in neonatal and pediatric populations will be analyzed. There may not be a single optimal mechanical ventilation approach, where the best method may simply be one that allows for a personalized approach with settings adapted to the individual patient and disease pathophysiology. The challenges and barriers to conducting well-powered and robust multi-institutional studies will also be addressed, as well as reconsidering outcome measures and study design., Competing Interests: PA, GN, MK-S, and NH have presented and received honoraria and/or travel reimbursement at event(s) sponsored by Dräger Medical Systems, Inc. outside of the published work. PA, GN, MK-S, LG, and NH have lectured for Intensive Care Online Network, Inc. (ICON). NH is the founder of ICON, of which PA is an employee. NH holds patents on a method of initiating, managing and/or weaning airway pressure release ventilation, as well as controlling a ventilator in accordance with the same, but these patents are not commercialized, licensed or royalty-producing. AB is the founder and CEO of CircuitLife™. MK-S has received a research grant from Dräger Medical Systems, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kollisch-Singule, Ramcharran, Satalin, Blair, Gatto, Andrews, Habashi, Nieman and Bougatef.)

The time-controlled adaptive ventilation (TCAV) method attenuates lung damage in acute respiratory distress syndrome. However, so far, no study has evaluated the impact of the TCAV method on ventilator-induced lung injury (VILI) and cardiac function in emphysema. We hypothesized that the use of the TCAV method to achieve an expiratory flow termination/expiratory peak flow (E FT /E PF ) of 25% could reduce VILI and improve right ventricular function in elastase-induced lung emphysema in rats. Five weeks after the last intratracheal instillation of elastase, animals were anesthetized and mechanically ventilated for 1 h using TCAV adjusted to either E FT /E PF 25% or E FT /E PF 75%, the latter often applied in acute respiratory distress syndrome (ARDS). Pressure-controlled ventilation (PCV) groups with positive end-expiratory pressure levels similar to positive end-release pressure in TCAV with E FT /E PF 25% and E FT /E PF 75% were also analyzed. Echocardiography and lung ultrasonography were monitored. Lung morphometry, alveolar heterogeneity, and biological markers related to inflammation [interleukin 6 (IL-6), CINC-1], alveolar pulmonary stretch (amphiregulin), lung matrix damage [metalloproteinase 9 (MMP-9)] were assessed. E FT /E PF 25% reduced respiratory system peak pressure, mean linear intercept, B lines at lung ultrasonography, and increased pulmonary acceleration time/pulmonary ejection time ratio compared with E FT /E PF 75%. The volume fraction of mononuclear cells, neutrophils, and expression of IL-6, CINC-1, amphiregulin, and MMP-9 were lower with E FT /E PF 25% than with E FT /E PF 75%. In conclusion, TCAV with E FT /E PF 25%, compared with E FT /E PF 75%, led to less lung inflammation, hyperinflation, and pulmonary arterial hypertension, which may be a promising strategy for patients with emphysema. NEW & NOTEWORTHY The TCAV method reduces lung damage in ARDS. However, so far, no study has evaluated the impact of the TCAV method on ventilator-induced lung injury and cardiac function in experimental emphysema. The TCAV method at E FT /E PF ratio of 25%, compared with E FT /E PF of 75% (frequently used in ARDS), reduced lung inflammation, alveolar heterogeneity and hyperinflation, and pulmonary arterial hypertension in elastase-induced emphysema. TCAV may be a promising and personalized ventilation strategy for patients with emphysema.

The worldwide pandemic caused by the SARS-CoV-2 virus has resulted in over 84,407,000 cases, with over 1,800,000 deaths when this paper was submitted, with comorbidities such as gender, race, age, body mass, diabetes, and hypertension greatly exacerbating mortality. This review will analyze the rapidly increasing knowledge of COVID-19-induced lung pathophysiology. Although controversial, the acute respiratory distress syndrome (ARDS) associated with COVID-19 (CARDS) seems to present as two distinct phenotypes: type L and type H. The "L" refers to low elastance, ventilation/perfusion ratio, lung weight, and recruitability, and the "H" refers to high pulmonary elastance, shunt, edema, and recruitability. However, the LUNG-SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) and ESICM (European Society of Intensive Care Medicine) Trials Groups have shown that ∼13% of the mechanically ventilated non-COVID-19 ARDS patients have the type-L phenotype. Other studies have shown that CARDS and ARDS respiratory mechanics overlap and that standard ventilation strategies apply to these patients. The mechanisms causing alterations in pulmonary perfusion could be caused by some combination of 1 ) renin-angiotensin system dysregulation, 2 ) thrombosis caused by loss of endothelial barrier, 3 ) endothelial dysfunction causing loss of hypoxic pulmonary vasoconstriction perfusion control, and 4 ) hyperperfusion of collapsed lung tissue that has been directly measured and supported by a computational model. A flowchart has been constructed highlighting the need for personalized and adaptive ventilation strategies, such as the time-controlled adaptive ventilation method, to set and adjust the airway pressure release ventilation mode, which recently was shown to be effective at improving oxygenation and reducing inspiratory fraction of oxygen, vasopressors, and sedation in patients with COVID-19.

Objectives: Elucidate how the degree of ventilator-induced lung injury due to atelectrauma that is produced in the injured lung during mechanical ventilation is determined by both the timing and magnitude of the airway pressure profile., Design: A computational model of the injured lung provides a platform for exploring how mechanical ventilation parameters potentially modulate atelectrauma and volutrauma. This model incorporates the time dependence of lung recruitment and derecruitment, and the time-constant of lung emptying during expiration as determined by overall compliance and resistance of the respiratory system., Setting: Computational model., Subjects: Simulated scenarios representing patients with both normal and acutely injured lungs., Measurements and Main Results: Protective low-tidal volume ventilation (Low-Vt) of the simulated injured lung avoided atelectrauma through the elevation of positive end-expiratory pressure while maintaining fixed tidal volume and driving pressure. In contrast, airway pressure release ventilation avoided atelectrauma by incorporating a very brief expiratory duration () that both prevents enough time for derecruitment and limits the minimum alveolar pressure prior to inspiration. Model simulations demonstrated that has an effective threshold value below which airway pressure release ventilation is safe from atelectrauma while maintaining a tidal volume and driving pressure comparable with those of Low-Vt. This threshold is strongly influenced by the time-constant of lung-emptying., Conclusions: Low-Vt and airway pressure release ventilation represent markedly different strategies for the avoidance of ventilator-induced lung injury, primarily involving the manipulation of positive end-expiratory pressure and , respectively. can be based on exhalation flow values, which may provide a patient-specific approach to protective ventilation., Competing Interests: Dr. Bates is a consultant for and shareholder in Oscillavent and LLC (Iowa), and a coapplicant on the patent “Variable ventilation as a diagnostic tool for assessing lung mechanical function” PCT Application WO2015127377 A1, Filed on February 23, 2014 (C538); Mr. Nieman has an Unrestricted Educational Grant from Dräger Medical; Dr. Habashi is founder of Intensive Care On-line Network, lectured at symposia sponsored in part by an unrestricted educational grant from Dräger Medical, holds patents that have not been commercialized, licensed or produced royalties on a method of initiating, managing and/or weaning airway pressure release ventilation, and controlling a ventilator in accordance with the same. Dr. Gaver has disclosed that he does not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Protective ventilation strategies for the injured lung currently revolve around the use of low Vt, ostensibly to avoid volutrauma, together with positive end-expiratory pressure to increase the fraction of open lung and reduce atelectrauma. Protective ventilation is currently applied in a one-size-fits-all manner, and although this practical approach has reduced acute respiratory distress syndrome deaths, mortality is still high and improvements are at a standstill. Furthermore, how to minimize ventilator-induced lung injury (VILI) for any given lung remains controversial and poorly understood. Here we present a hypothesis of VILI pathogenesis that potentially serves as a basis upon which minimally injurious ventilation strategies might be developed. This hypothesis is based on evidence demonstrating that VILI begins in isolated lung regions manifesting a Permeability-Originated Obstruction Response (POOR) in which alveolar leak leads to surfactant dysfunction and increases local tissue stresses. VILI progresses topographically outward from these regions in a POOR-get-POORer fashion unless steps are taken to interrupt it. We propose that interrupting the POOR-get-POORer progression of lung injury relies on two principles: 1 ) open the lung to minimize the presence of heterogeneity-induced stress concentrators that are focused around the regions of atelectasis, and 2 ) ventilate in a patient-dependent manner that minimizes the number of lung units that close during each expiration so that they are not forced to rerecruit during the subsequent inspiration. These principles appear to be borne out in both patient and animal studies in which expiration is terminated before derecruitment of lung units has enough time to occur.

Morbidity and mortality associated with lung injury remains disappointingly unchanged over the last two decades, in part due to the current reliance on lung macro-parameters set on the ventilator instead of considering the micro-environment and the response of the alveoli and alveolar ducts to ventilator adjustments. The response of alveoli and alveolar ducts to mechanical ventilation modes cannot be predicted with current bedside methods of assessment including lung compliance, oxygenation, and pressure-volume curves. Alveolar tidal volumes (Vt) are less determined by the Vt set on the mechanical ventilator and more dependent on the number of recruited alveoli available to accommodate that Vt and their heterogeneous mechanical properties, such that high lung Vt can lead to a low alveolar Vt and low Vt can lead to high alveolar Vt. The degree of alveolar heterogeneity that exists cannot be predicted based on lung calculations that average the individual alveolar Vt and compliance. Finally, the importance of time in promoting alveolar stability, specifically the inspiratory and expiratory times set on the ventilator, are currently under-appreciated. In order to improve outcomes related to lung injury, the respiratory physiology of the individual patient, specifically at the level of the alveolus, must be targeted. With experimental data, this review highlights some of the known mechanical ventilation adjustments that are helpful or harmful at the level of the alveolus., (Copyright © 2020 Kollisch-Singule, Satalin, Blair, Andrews, Gatto, Nieman and Habashi.)

Acute respiratory distress syndrome (ARDS) causes a heterogeneous lung injury and remains a serious medical problem, with one of the only treatments being supportive care in the form of mechanical ventilation. It is very difficult, however, to mechanically ventilate the heterogeneously damaged lung without causing secondary ventilator-induced lung injury (VILI). The acutely injured lung becomes time and pressure dependent, meaning that it takes more time and pressure to open the lung, and it recollapses more quickly and at higher pressure. Current protective ventilation strategies, ARDSnet low tidal volume (LVt) and the open lung approach (OLA), have been unsuccessful at further reducing ARDS mortality. We postulate that this is because the LVt strategy is constrained to ventilating a lung with a heterogeneous mix of normal and focalized injured tissue, and the OLA, although designed to fully open and stabilize the lung, is often unsuccessful at doing so. In this review we analyzed the pathophysiology of ARDS that renders the lung susceptible to VILI. We also analyzed the alterations in alveolar and alveolar duct mechanics that occur in the acutely injured lung and discussed how these alterations are a key mechanism driving VILI. Our analysis suggests that the time component of each mechanical breath, at both inspiration and expiration, is critical to normalize alveolar mechanics and protect the lung from VILI. Animal studies and a meta-analysis have suggested that the time-controlled adaptive ventilation (TCAV) method, using the airway pressure release ventilation mode, eliminates the constraints of ventilating a lung with heterogeneous injury, since it is highly effective at opening and stabilizing the time- and pressure -dependent lung. In animal studies it has been shown that by "casting open" the acutely injured lung with TCAV we can (1) reestablish normal expiratory lung volume as assessed by direct observation of subpleural alveoli; (2) return normal parenchymal microanatomical structural support, known as alveolar interdependence and parenchymal tethering, as assessed by morphometric analysis of lung histology; (3) facilitate regeneration of normal surfactant function measured as increases in surfactant proteins A and B; and (4) significantly increase lung compliance, which reduces the pathologic impact of driving pressure and mechanical power at any given tidal volume., (Copyright © 2020 Nieman, Al-Khalisy, Kollisch-Singule, Satalin, Blair, Trikha, Andrews, Madden, Gatto and Habashi.)

Mortality in acute respiratory distress syndrome (ARDS) remains unacceptably high at approximately 39%. One of the only treatments is supportive: mechanical ventilation. However, improperly set mechanical ventilation can further increase the risk of death in patients with ARDS. Recent studies suggest that ventilation-induced lung injury (VILI) is caused by exaggerated regional lung strain, particularly in areas of alveolar instability subject to tidal recruitment/derecruitment and stress-multiplication. Thus, it is reasonable to expect that if a ventilation strategy can maintain stable lung inflation and homogeneity, regional dynamic strain would be reduced and VILI attenuated. A time-controlled adaptive ventilation (TCAV) method was developed to minimize dynamic alveolar strain by adjusting the delivered breath according to the mechanical characteristics of the lung. The goal of this review is to describe how the TCAV method impacts pathophysiology and protects lungs with, or at high risk of, acute lung injury. We present work from our group and others that identifies novel mechanisms of VILI in the alveolar microenvironment and demonstrates that the TCAV method can reduce VILI in translational animal ARDS models and mortality in surgical/trauma patients. Our TCAV method utilizes the airway pressure release ventilation (APRV) mode and is based on opening and collapsing time constants, which reflect the viscoelastic properties of the terminal airspaces. Time-controlled adaptive ventilation uses inspiratory and expiratory time to (1) gradually "nudge" alveoli and alveolar ducts open with an extended inspiratory duration and (2) prevent alveolar collapse using a brief (sub-second) expiratory duration that does not allow time for alveolar collapse. The new paradigm in TCAV is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. This novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. The outcome of this approach is an open and stable lung with reduced regional strain and greater lung protection.

Background: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units. Distal airway mucus clearance has been shown to reduce VAP incidence. Studies suggest that mucus clearance is enhanced when the rate of expiratory flow is greater than inspiratory flow. The time-controlled adaptive ventilation (TCAV) protocol using the airway pressure release ventilation (APRV) mode has a significantly increased expiratory relative to inspiratory flow rate, as compared with the Acute Respiratory Distress Syndrome Network (ARDSnet) protocol using the conventional ventilation mode of volume assist control (VAC). We hypothesized the TCAV protocol would be superior to the ARDSnet protocol at clearing mucus by a mechanism of net flow in the expiratory direction., Methods: Preserved pig lungs fitted with an endotracheal tube (ETT) were used as a model to study the effect of multiple combinations of peak inspiratory (I PF ) and peak expiratory flow rate (E PF ) on simulated mucus movement within the ETT. Mechanical ventilation was randomized into 6 groups (n = 10 runs/group): group 1-TCAV protocol settings with an end-expiratory pressure (P Low ) of 0 cmH 2 O and P High 25 cmH 2 O, group 2-modified TCAV protocol with increased P Low 5 cmH 2 O and P High 25 cmH 2 O, group 3-modified TCAV with P Low 10 cmH 2 O and P High 25 cmH 2 O, group 4-ARDSnet protocol using low tidal volume (LTV) and PEEP 0 cmH 2 O, group 5-ARDSnet protocol using LTV and PEEP 10 cmH 2 O, and group 6-ARDSnet protocol using LTV and PEEP 20 cmH 2 O. PEEP of ARDSnet is analogous to P Low of TCAV. Proximal (towards the ventilator) mucus movement distance was recorded after 1 min of ventilation in each group., Results: The TCAV protocol groups 1, 2, and 3 generated significantly greater peak expiratory flow (E PF 51.3 L/min, 46.8 L/min, 36.8 L/min, respectively) as compared to the ARDSnet protocol groups 4, 5, and 6 (32.9 L/min, 23.5 L/min, and 23.2 L/min, respectively) (p < 0.001). The TCAV groups also demonstrated the greatest proximal mucus movement (7.95 cm/min, 5.8 cm/min, 1.9 cm/min) (p < 0.01). All ARDSnet protocol groups (4-6) had zero proximal mucus movement (0 cm/min)., Conclusions: The TCAV protocol groups promoted the greatest proximal movement of simulated mucus as compared to the ARDSnet protocol groups in this excised lung model. The TCAV protocol settings resulted in the highest E PF and the greatest proximal movement of mucus. Increasing P Low reduced proximal mucus movement. We speculate that proximal mucus movement is driven by E PF when E PF is greater than I PF , creating a net force in the proximal direction.

Airway pressure release ventilation (APRV) is a ventilator mode that has previously been considered a rescue mode, but has gained acceptance as a primary mode of ventilation. In clinical series and experimental animal models of extrapulmonary acute respiratory distress syndrome (ARDS), the early application of APRV was able to prevent the development of ARDS. Recent experimental evidence has suggested mechanisms by which APRV, using the time-controlled adaptive ventilation (TCAV) protocol, may reduce lung injury, including: 1) an improvement in alveolar recruitment and homogeneity; 2) reduction in alveolar and alveolar duct micro-strain and stress-risers; 3) reduction in alveolar tidal volumes; and 4) recruitment of the chest wall by combating increased intra-abdominal pressure. This review examines these studies and discusses our current understanding of the pleiotropic mechanisms by which TCAV protects the lung. APRV set according to the TCAV protocol has been misunderstood and this review serves to highlight the various protective physiological and mechanical effects it has on the lung, so that its clinical application may be broadened., Competing Interests: Conflict of interest: M. Kollisch-Singule reports grants from NIH during the conduct of the study, and other funding from Dräger Medical Systems, Inc. and the Intensive Care On-line Network, Inc. (ICON), outside the submitted work. Conflict of interest: P. Andrews has presented and received honoraria and travel reimbursement at events sponsored by Dräger Medical outside of the submitted work. She is employed by the Intensive Care On-line Network (ICON). Conflict of interest: J. Satalin has nothing to disclose. Conflict of interest: L.A. Gatto reports being listed as co-inventor in U.S. Patent No. 5 977 091 issued to the Research Foundation of SUNY (no related funds or royalties). Conflict of interest: G.F. Nieman reports grants from Drager Medical, outside the submitted work. In addition, He has patents issued on the method of preventing acute lung injury, the method of treating sepsis-induced ARDS, the novel method of assessing alveolar inflation, the method of reducing blood loss associated with cardiopulmonary bypass, minimally invasive suction and treatment device (MIST), and apparatus system and method for assessing alveolar inflation issued. Conflict of interest: N.M. Habashi has presented and received honoraria and travel reimbursement at events sponsored by Dräger Medical outside of the submitted work. He holds patents in the area of mechanical ventilation and is the founder of the Intensive Care On-line Network (ICON)., (Copyright ©ERS 2019.)

The pathophysiology of acute respiratory distress syndrome (ARDS) results in heterogeneous lung collapse, edema-flooded airways and unstable alveoli. These pathologic alterations in alveolar mechanics (i.e. dynamic change in alveolar size and shape with each breath) predispose the lung to secondary ventilator-induced lung injury (VILI). It is our viewpoint that the acutely injured lung can be recruited and stabilized with a mechanical breath until it heals, much like casting a broken bone until it mends. If the lung can be "casted" with a mechanical breath, VILI could be prevented and ARDS incidence significantly reduced.

It has been shown that mechanical ventilation in patients with, or at high-risk for, the development of acute respiratory distress syndrome (ARDS) can be a double-edged sword. If the mechanical breath is improperly set, it can amplify the lung injury associated with ARDS, causing a secondary ventilator-induced lung injury (VILI). Conversely, the mechanical breath can be adjusted to minimize VILI, which can reduce ARDS mortality. The current standard of care ventilation strategy to minimize VILI attempts to reduce alveolar over-distension and recruitment-derecruitment (R/D) by lowering tidal volume (Vt) to 6 cc/kg combined with adjusting positive-end expiratory pressure (PEEP) based on a sliding scale directed by changes in oxygenation. Thus, Vt is often but not always set as a "one-size-fits-all" approach and although PEEP is often set arbitrarily at 5 cmH 2 O, it may be personalized according to changes in a physiologic parameter, most often to oxygenation. However, there is evidence that oxygenation as a method to optimize PEEP is not congruent with the PEEP levels necessary to maintain an open and stable lung. Thus, optimal PEEP might not be personalized to the lung pathology of an individual patient using oxygenation as the physiologic feedback system. Multiple methods of personalizing PEEP have been tested and include dead space, lung compliance, lung stress and strain, ventilation patterns using computed tomography (CT) or electrical impedance tomography (EIT), inflection points on the pressure/volume curve (P/V), and the slope of the expiratory flow curve using airway pressure release ventilation (APRV). Although many studies have shown that personalizing PEEP is possible, there is no consensus as to the optimal technique. This review will assess various methods used to personalize PEEP, directed by physiologic parameters, necessary to adaptively adjust ventilator settings with progressive changes in lung pathophysiology.

Background: Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH 2 O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain)., Methods: Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + H DS , n = 6) and (2) over-distension + low dynamic strain (OD + L DS , n = 6). OD was caused by setting the inspiratory pressure at 40 cmH 2 O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy., Results: In normal tissue (N T ), OD + L DS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + H DS . In acutely injured tissue (ALI T ), OD + L DS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + H DS ., Conclusions: Both N T and ALI T are resistant to VILI caused by OD alone, but when combined with a H DS , significant tissue injury develops.

Acute respiratory distress syndrome (ARDS) remains a serious clinical problem with the main treatment being supportive in the form of mechanical ventilation. However, mechanical ventilation can be a double-edged sword: if set improperly, it can exacerbate the tissue damage caused by ARDS; this is known as ventilator-induced lung injury (VILI). To minimize VILI, we must understand the pathophysiologic mechanisms of tissue damage at the alveolar level. In this Physiology in Medicine paper, the dynamic physiology of alveolar inflation and deflation during mechanical ventilation will be reviewed. In addition, the pathophysiologic mechanisms of VILI will be reviewed, and this knowledge will be used to suggest an optimal mechanical breath profile (MB P : all airway pressures, volumes, flows, rates, and the duration that they are applied at both inspiration and expiration) necessary to minimize VILI. Our review suggests that the current protective ventilation strategy, known as the "open lung strategy," would be the optimal lung-protective approach. However, the viscoelastic behavior of dynamic alveolar inflation and deflation has not yet been incorporated into protective mechanical ventilation strategies. Using our knowledge of dynamic alveolar mechanics (i.e., the dynamic change in alveolar and alveolar duct size and shape during tidal ventilation) to modify the MB P so as to minimize VILI will reduce the morbidity and mortality associated with ARDS., (Copyright © 2017 the American Physiological Society.)

Purpose: Preterm infants are prone to respiratory distress syndrome (RDS), with severe cases requiring mechanical ventilation for support. However, there are no clear guidelines regarding the optimal ventilation strategy. We hypothesized that airway pressure release ventilation (APRV) would mitigate lung injury in a preterm porcine neonatal model., Methods: Preterm piglets were delivered on gestational day 98 (85% of 115day term), instrumented, and randomized to volume guarantee (VG; n=10) with low tidal volumes (5.5cm 3 kg -1 ) and PEEP 4cmH 2 O or APRV (n=10) with initial ventilator settings: P High 18cmH 2 O, P Low 0cmH 2 O, T High 1.30s, T Low 0.15s. Ventilator setting changes were made in response to clinical parameters in both groups. Animals were monitored continuously for 24hours., Results: The mortality rates between the two groups were not significantly different (p>0.05). The VG group had relatively increased oxygen requirements (F i O 2 50%±9%) compared with the APRV group (F i O 2 28%±5%; p>0.05) and a decrease in PaO 2 /FiO 2 ratio (VG 162±33mmHg; APRV 251±45mmHg; p<0.05). The compliance of the VG group (0.51±0.07L·cmH 2 O -1 ) was significantly less than the APRV group (0.90±0.06L·cmH 2 O -1 ; p<0.05)., Conclusion: This study demonstrates that APRV improves oxygenation and compliance as compared with VG. This preliminary work suggests further study into the clinical uses of APRV in the neonate is warranted., Level of Evidence: Not Applicable (Basic Science Animal Study)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Airway pressure release ventilation (APRV) was first described in 1987 and defined as continuous positive airway pressure (CPAP) with a brief release while allowing the patient to spontaneously breathe throughout the respiratory cycle. The current understanding of the optimal strategy to minimize ventilator-induced lung injury is to "open the lung and keep it open". APRV should be ideal for this strategy with the prolonged CPAP duration recruiting the lung and the minimal release duration preventing lung collapse. However, APRV is inconsistently defined with significant variation in the settings used in experimental studies and in clinical practice. The goal of this review was to analyze the published literature and determine APRV efficacy as a lung-protective strategy. We reviewed all original articles in which the authors stated that APRV was used. The primary analysis was to correlate APRV settings with physiologic and clinical outcomes. Results showed that there was tremendous variation in settings that were all defined as APRV, particularly CPAP and release phase duration and the parameters used to guide these settings. Thus, it was impossible to assess efficacy of a single strategy since almost none of the APRV settings were identical. Therefore, we divided all APRV studies divided into two basic categories: (1) fixed-setting APRV (F-APRV) in which the release phase is set and left constant; and (2) personalized-APRV (P-APRV) in which the release phase is set based on changes in lung mechanics using the slope of the expiratory flow curve. Results showed that in no study was there a statistically significant worse outcome with APRV, regardless of the settings (F-ARPV or P-APRV). Multiple studies demonstrated that P-APRV stabilizes alveoli and reduces the incidence of acute respiratory distress syndrome (ARDS) in clinically relevant animal models and in trauma patients. In conclusion, over the 30 years since the mode's inception there have been no strict criteria in defining a mechanical breath as being APRV. P-APRV has shown great promise as a highly lung-protective ventilation strategy.

Lungs stored ahead of transplant surgery experience ischemia. Pulmonary ischemia differs from ischemia in the systemic organs in that stop of blood flow in the lung leads to loss of shear alone because the lung parenchyma does not rely on blood flow for its cellular oxygen requirements. Our earlier studies on the ischemia-induced mechanosignaling cascade showed that the pulmonary endothelium responds to stop of flow by production of reactive oxygen species (ROS). We hypothesized that ROS produced in this way led to induction of proinflammatory mediators. In this study, we used lungs or cells subjected to various periods of storage and evaluated the induction of several proinflammatory mediators. Isolated murine, porcine and human lungs in situ showed increased expression of cellular adhesion molecules; the damage-associated molecular pattern protein high-mobility group box 1 and the corresponding pattern recognition receptor, called the receptor for advanced glycation end products; and induction stabilization and translocation of hypoxia-inducible factor 1α and its downstream effector VEGFA, all of which are participants in inflammation. We concluded that signaling with lung preservation drives expression of inflammatory mediators that potentially predispose the donor lung to an inflammatory response after transplant., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Importance: Ventilator-induced lung injury may arise from heterogeneous lung microanatomy, whereby some alveoli remain collapsed throughout the breath cycle while their more compliant or surfactant-replete neighbors become overdistended, and this is called dynamic alveolar heterogeneity., Objective: To determine how dynamic alveolar heterogeneity is influenced by 2 modes of mechanical ventilation: low tidal-volume ventilation (LTVV) and airway pressure release ventilation (APRV), using in vivo microscopy to directly measure alveolar size distributions., Design, Setting, and Participants: In a randomized, nonblinded laboratory animal study conducted between January 2013 and December 2014, 14 rats (450-500 g in size) were randomized to a control group with uninjured lungs (n = 4) and 2 experimental groups with surfactant deactivation induced by polysorbate lavage: the LTVV group (n = 5) and the APRV group (n = 5). For all groups, a thoracotomy and in vivo microscopy were performed. Following lung injury induced by polysorbate lavage, the LTVV group was ventilated with a tidal volume of 6 mL/kg and progressively higher positive end-expiratory pressure (PEEP) (5, 10, 16, 20, and 24 cm H2O). Following lung injury induced by polysorbate lavage, the APRV group was ventilated with a progressively shorter time at low pressure, which increased the ratio of the end-expiratory flow rate (EEFR) to the peak expiratory flow rate (PEFR; from 10% to 25% to 50% to 75%)., Main Outcomes and Measures: Alveolar areas were quantified (using PEEP and EEFR to PEFR ratio) to determine dynamic heterogeneity., Results: Following lung injury induced by polysorbate lavage, a higher PEEP (20-24 cm H2O) with LTVV resulted in alveolar occupancy (reported as percentage of total frame area) at inspiration (39.9%-42.2%) and expiration (35.9%-38.7%) similar to that in the control group (inspiration 53.3%; expiration 50.3%; P > .01). Likewise, APRV with an increased EEFR to PEFR ratio (50%-75%) resulted in alveolar occupancy at inspiration (46.7%-47.9%) and expiration (40.2%-46.6%) similar to that in the control group (P > .01). At inspiration, the distribution of the alveolar area of the control group was similar to that of the APRV group (P > .01) (but not to that of the LTVV group [P < .01]). A lower PEEP (5-10 cm H2O) and a decreased EEFR to PEFR ratio (≤50%) demonstrated dynamic heterogeneity between inspiration and expiration (P < .01 for both) with a greater percentage of large alveoli at expiration. Dynamic alveolar homogeneity between inspiration and expiration occurred with higher PEEP (16-24 cm H2O) (P > .01) and an increased EEFR to PEFR ratio (75%) (P > .01)., Conclusions and Relevance: Increasing PEEP during LTVV increased alveolar recruitment and dynamic homogeneity but had a significantly different alveolar size distribution compared with the control group. By comparison, reducing the time at low pressure (EEFR to PEFR ratio of 75%) in the APRV group provided dynamic homogeneity and a closer approximation of the dynamics observed in the control group.

The earliest description of what is now known as the acute respiratory distress syndrome (ARDS) was a highly lethal double pneumonia. Ashbaugh and colleagues (Ashbaugh DG, Bigelow DB, Petty TL, Levine BE Lancet 2: 319-323, 1967) correctly identified the disease as ARDS in 1967. Their initial study showing the positive effect of mechanical ventilation with positive end-expiratory pressure (PEEP) on ARDS mortality was dampened when it was discovered that improperly used mechanical ventilation can cause a secondary ventilator-induced lung injury (VILI), thereby greatly exacerbating ARDS mortality. This Synthesis Report will review the pathophysiology of ARDS and VILI from a mechanical stress-strain perspective. Although inflammation is also an important component of VILI pathology, it is secondary to the mechanical damage caused by excessive strain. The mechanical breath will be deconstructed to show that multiple parameters that comprise the breath-airway pressure, flows, volumes, and the duration during which they are applied to each breath-are critical to lung injury and protection. Specifically, the mechanisms by which a properly set mechanical breath can reduce the development of excessive fluid flux and pulmonary edema, which are a hallmark of ARDS pathology, are reviewed. Using our knowledge of how multiple parameters in the mechanical breath affect lung physiology, the optimal combination of pressures, volumes, flows, and durations that should offer maximum lung protection are postulated., (Copyright © 2015 the American Physiological Society.)

Trauma, hemorrhagic shock, or sepsis can incite systemic inflammatory response syndrome, which can result in early acute lung injury (EALI). As EALI advances, improperly set mechanical ventilation (MV) can amplify early injury into a secondary ventilator-induced lung injury that invariably develops into overt ARDS. Once established, ARDS is refractory to most therapeutic strategies, which have not been able to lower ARDS mortality below the current unacceptably high 40%. Low tidal volume ventilation is one of the few treatments shown to have a moderate positive impact on ARDS survival, presumably by reducing ventilator-induced lung injury. Thus, there is a compelling case to be made that the focus of ARDS management should switch from treatment once this syndrome has become established to the application of preventative measures while patients are still in the EALI stage. Indeed, studies have shown that ARDS incidence is markedly reduced when conventional MV is applied preemptively using a combination of low tidal volume and positive end-expiratory pressure in both patients in the ICU and in surgical patients at high risk for developing ARDS. Furthermore, there is evidence from animal models and high-risk trauma patients that superior prevention of ARDS can be achieved using preemptive airway pressure release ventilation with a very brief duration of pressure release. Preventing rather than treating ARDS may be the way forward in dealing with this recalcitrant condition and would represent a paradigm shift in the way that MV is currently practiced.

Background: Lung injury is often studied without consideration for pathologic changes in the chest wall. In order to reduce the incidence of lung injury using preemptive mechanical ventilation, it is important to recognize the influence of altered chest wall mechanics on disease pathogenesis. In this study, we hypothesize that airway pressure release ventilation (APRV) may be able to reduce the chest wall elastance associated with an extrapulmonary lung injury model as compared with low tidal volume (LVt) ventilation., Methods: Female Yorkshire pigs were anesthetized and instrumented. Fecal peritonitis was established, and the superior mesenteric artery was clamped for 30 min to induce an ischemia/reperfusion injury. Immediately following injury, pigs were randomized into (1) LVt (n = 3), positive end-expiratory pressure (PEEP) 5 cmH2O, V t 6 cc kg(-1), FiO2 21 %, and guided by the ARDSnet protocol or (2) APRV (n = 3), P High 16-22 cmH2O, P Low 0 cmH2O, T High 4.5 s, T Low set to terminate the peak expiratory flow at 75 %, and FiO2 21 %. Pigs were monitored continuously for 48 h. Lung samples and bronchoalveolar lavage fluid were collected at necropsy., Results: LVt resulted in mild acute respiratory distress syndrome (ARDS) (PaO2/FiO2 = 226.2 ± 17.1 mmHg) whereas APRV prevented ARDS (PaO2/FiO2 = 465.7 ± 66.5 mmHg; p < 0.05). LVt had a reduced surfactant protein A concentration and increased histologic injury as compared with APRV. The plateau pressure in APRV (34.3 ± 0.9 cmH2O) was significantly greater than LVt (22.2 ± 2.0 cmH2O; p < 0.05) yet transpulmonary pressure between groups was similar (p > 0.05). This was because the pleural pressure was significantly lower in LVt (7.6 ± 0.5 cmH2O) as compared with APRV (17.4 ± 3.5 cmH2O; p < 0.05). Finally, the elastance of the lung, chest wall, and respiratory system were all significantly greater in LVt as compared with APRV (all p < 0.05)., Conclusions: APRV preserved surfactant and lung architecture and maintenance of oxygenation. Despite the greater plateau pressure and tidal volumes in the APRV group, the transpulmonary pressure was similar to that of LVt. Thus, the majority of the plateau pressure in the APRV group was distributed as pleural pressure in this extrapulmonary lung injury model. APRV maintained a normal lung elastance and an open, homogeneously ventilated lung without increasing lung stress.

Background: Improperly set mechanical ventilation (MV) with normal lungs can advance lung injury and increase the incidence of acute respiratory distress syndrome (ARDS). A key mechanism of ventilator-induced lung injury (VILI) is an alteration in alveolar mechanics including alveolar instability or recruitment/derecruitment (R/D). We hypothesize that R/D cannot be identified by PaO2 (masking occult VILI), and if protective ventilation is not applied, ARDS incidence will increase., Methods: Sprague-Dawley rats (n = 8) were anesthetized, surgically instrumented, and placed on MV. A thoracotomy was performed and an in vivo microscope attached to the pleural surface of the lung with baseline dynamic changes in alveolar size during MV recorded. Alveolar instability was induced by intra-tracheal instillation of Tween and alveolar R/D identified as a marked change in alveolar size from inspiration to expiration with increases in positive end-expiratory pressure (PEEP) levels., Results: Despite maintaining a clinically acceptable PaO2 (55-80 mmHg), the alveoli remained unstable with significant R/D at low PEEP levels. Although PaO2 consistently increased with an increase in PEEP, R/D did not plateau until PEEP was >9 cmH2O., Conclusions: PaO2 remained clinically acceptable while alveolar instability persisted at all levels of PEEP (especially PEEP <9 cmH2O). Therefore, PaO2 levels cannot be used reliably to guide protective MV strategies or infer that VILI is not occurring. Using PaO2 to set a PEEP level necessary to stabilize the alveoli could underestimate the potential for VILI. These findings highlight the need for more accurate marker(s) of alveolar stability to guide protective MV necessary to prevent VILI.

Background: Adult respiratory distress syndrome is often refractory to treatment and develops after entering the health care system. This suggests an opportunity to prevent this syndrome before it develops. The objective of this study was to demonstrate that early application of airway pressure release ventilation in high-risk trauma patients reduces hospital mortality as compared with similarly injured patients on conventional ventilation., Methods: Systematic review of observational data in patients who received conventional ventilation in other trauma centers were compared with patients treated with early airway pressure release ventilation in our trauma center. Relevant studies were identified in a PubMed and MEDLINE search from 1995 to 2012 and included prospective and retrospective observational and cohort studies enrolling 100 or more adult trauma patients with reported adult respiratory distress syndrome incidence and mortality data., Results: Early airway pressure release ventilation as compared with the other trauma centers represented lower mean adult respiratory distress syndrome incidence (14.0% vs. 1.3%) and in-hospital mortality (14.1% vs. 3.9%)., Conclusion: These data suggest that early airway pressure release ventilation may prevent progression of acute lung injury in high-risk trauma patients, reducing trauma-related adult respiratory distress syndrome mortality., Level of Evidence: Systematic review, level IV.

Object: Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN)., Methods: The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data., Results: In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades., Conclusions: The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation-II score had no relationship to pulmonary complications.