Air Care Series: Refractory Hypoxemia & ARDS

Introduction

Refractory hypoxemia is a complex clinical challenge, often occurring in the context of acute respiratory distress syndrome (ARDS). Accumulating evidence suggests that patients with severe hypoxia on mechanical ventilation may benefit from referral to specialized centers, including those with ECMO capabilities (1-3). As such, critical care transport providers can expect to be increasingly responsible for managing these patients while bringing them to central tertiary care centers. These transports represent a tenuous time in the patient’s course and are often associated with worsening lung injury (4). It is essential that critical care transport teams be familiar with the evidence surrounding ARDS management and adept at supporting these patients to ensure safe delivery to their destination. Data informing ARDS management in the pre-hospital arena is relatively sparse, thus the vast majority of this discussion will be based in studies conducted in the emergency department (ED), intensive care unit (ICU), and other hospital-based settings.

The Basics

Table 1. The Berlin Criteria. ARDS diagnosis requires all four criteria to be met. *Chest radiograph of computed tomography (CT), not fully explained by underlying pleural effusion, collapse, or pulmonary nodules.

A unifying formal definition of refractory hypoxemia is elusive. Pragmatically, patients who remain relatively hypoxemic despite mechanical ventilation with appropriate settings (i.e. FiO2 ≥ 50%, PEEP ≥ 5 cm H2O) should be considered refractory. Prior data suggest that patients requiring FiO2 greater than 50% prior to transfer are at the highest risk of decompensation in transport (4). ARDS criteria are historically more formalized – see Table 1 (5).

While a direct assessment of PaO2 (via arterial blood gas) is the gold standard, peripheral oxygen saturation (SpO2), can be utilized in the transport setting to estimate the severity of lung injury (6). PaO2 can be roughly estimated from SpO2, as seen in Table 2, assuming no significant known confounders (i.e. severe shock, hypothermia, peripheral vascular disease) (7).

Ventilator Management

Table 2: PaO2’s rough relation to peripheral oxygen saturation (SpO2)..

The goals of mechanical ventilation in ARDS are summarized by the following mantra: first, do no harm. In transport we should aim to minimize the various forms of lung trauma incurred by mechanical ventilation (see Figure 1). At the turn of the 21st century, the ARMA trial demonstrated that patients suffering from ARDS managed with low-tidal volume ventilation, targeting volumes of 4 – 8mL/kg of ideal body weight (IBW), were more likely to survive to hospital discharge than those receiving larger volumes (8). Given the impressive reduction in mortality (absolute risk reduction – 8.9%; number needed to treat - 11.4), lung protective ventilation (LPV) using lower tidal volume is now a cornerstone of ARDS management. Subsequent meta-analyses performed by the Cochrane Collaboration confirmed the observed mortality reduction, most recently in 2013 (9).

As the pathophysiologic basis of ARDS was elucidated, it became clear that application of positive end-expiratory pressure (PEEP) was essential for minimizing repetitive alveolar collapse and subsequent shunt. The optimal positive end-expiratory pressure (PEEP) for patients with ARDS remains an individualized decision based on the particular patient and pathology. Numerous trials have attempted to discern the potential benefit of a high or low PEEP strategy, with no clear answer (See Table 3 for low and high PEEP tables according to ARDSnet). The ARDSnet follow up to the ARMA trial ended early when an interim analysis showed no change to mortality in patients managed with higher PEEP (10). However, several limiting factors in the trial, including significant differences between groups at baseline and changes to protocol during the trial, led to persistent equipoise regarding optimal PEEP in ARDS (11). Follow up studies included recruitment maneuvers – application of high PEEP for short periods of time (i.e. constant pressure of 40cm H2O for 40 seconds, followed by reduction to 20cm H2O and incremental reduction to pre-determined baseline) – paired with higher PEEP, giving rise to the term “lung open ventilation”. While this strategy failed to demonstrate an effect on mortality, it was associated with fewer deaths related to hypoxemia and less frequent rescue therapy utilization in at least one large multicenter trial (12). A recently published multidisciplinary guideline for ARDS management created by the American Thoracic Society (ATS), European Society of Intensive Care Medicine (ESICM), and Society for Critical Care Medicine (SCCM) conditionally recommends higher PEEP and recruitment maneuvers for patients with moderate to severe ARDS based on meta-analysis level data (30, 37).

Figure 1. Ventilator-induced lung injury, starting with a resting alveolus. A – atelectrauma, damage due to repetitive opening and closing of groups of alveoli. B – volutrauma, damage due to over-distension or stretching of lung units. C – barotrauma, damage resulting from overdistension leading to frank alveolar rupture, considered a subtype of volutrauma.

Historically, supplemental oxygen has often been applied using a one-size-fits- all strategy: when some is good, more is better. While oxygen was recognized as potentially harmful essentially upon discovery, the true threshold at which oxygen toxicity should become a concern remains a bit of a mystery (13). Large scale investigations assessing appropriate SpO2 targets for patients treated in the ICU have produced conflicting data (14,15). The most recent randomized trial assessing optimal oxygenation in ARDS, conducted across 13 ICU’s in France, was stopped early due to a signal of harm in the conservative arm, which targeted PaO2 55-70 and SpO2 88-92% between ABG draws (16). Specifically, the LOCO2 trial found that 90-day mortality was 44% in the conservative oxygen arm, versus 30% in the liberal arm. Further, five patients in the conservative group suffered episodes of mesenteric ischemia, compared to none in the liberal group. A new retrospective examination of two large electronic medical record databases suggested an optimal SpO2 between 94 – 98% in ICU patients requiring supplemental oxygen (17). Unsurprisingly, the clinical data suggest that unnatural perturbations of oxygen are harmful at either extreme. In the absence of a clear history of chronic obstructive pulmonary disease, ensuring an SpO2 between 94 and 98% during transport seems reasonable.

Table 3. ARDSnet PEEP table – high PEEP and low PEEP arms.

Non-ventilator management

Ensuring patient comfort during mechanical ventilation and optimizing patient interaction with the ventilator are key in managing respiratory failure, particularly so in ARDS. Administering appropriate analgesia and sedation (in tandem termed analgosedation) is not only clinically beneficial, but morally essential. Provision of analgesia has been shown to reduce global metabolic demand, and thus preserve circulating oxygen (18). Data regarding sedation in the ICU are plentiful, yet specific trials in the ARDS population are less common. In transport, the immediate safety of the crew and patient come first, thus level of sedation should be titrated first and foremost to the comfort of the crew and patient. Outside of additional indications (concomitant alcohol withdrawal, sympathomimetic toxicity, NMB), midazolam, lorazepam, and other benzodiazepines should be avoided when possible, due to the known associations with delirium, prolonged ICU stay, and other adverse events (19).

Fluid administration should be minimized in patients suffering from refractory hypoxemia. Sepsis is a common cause of ARDS, and with the most recent Surviving Sepsis Campaign recommending an initial crystalloid bolus of 30mL/kg, it stands to reason that many patients being transferred for specialty care will have already received a significant fluid challenge (20). These patients are also likely to be receiving a number of supportive medications (analgesia, sedatives, antimicrobials, anticoagulation, etc.) contributing to a net positive fluid balance. There are data that argue a conservative fluid strategy for patients in ARDS decreases ventilator and ICU days, although it may not affect mortality (21). Transport management should include judicious fluid use, with special attention to the almost reflexive response of a fluid bolus to ameliorate intermittent hypotension.

Adjunct Therapies

Ventilator modes

Figure 2. APRV pressure time wave form. The majority of the respiratory cycle occurs at Phigh, with intermittent, short release periods (Tlow) at Plow. Note that the patient should be able to breath spontaneously, as APRV in a paralyzed patient represents inverse ratio ventilation.

While low tidal volume ventilation, via the volume- or pressure-controlled modes, has been established as the foundation of ARDS management, alternative modes have shown promise, most notably airway pressure release ventilation (APRV). In contrast to volume control, when using APRV, operator inputs include a pair of pressures and times, with a high and low value for each input. The goal of APRV is to create a primarily high-pressure environment in the lungs, maximizing alveolar recruitment, while maintaining a safe plateau pressure and permitting spontaneous respiration throughout the cycle (See Figure 2). Plateau pressure is quantified using an alternative mode, and then used as the upper limit for the high pressure (Phigh). The time spent (Thigh) at Phigh occupies a majority of the cycle, up to 95%, keeping the lung units inflated. Thigh periods are interspersed with release periods at the low pressure (Plow) that are quite short, with the release time (Tlow) usually being around 0.6 – 0.8 seconds. These release periods augment spontaneous ventilation of the patient, although a volume of air will remain in the lungs, predisposing to generation of auto-PEEP (22). Auto-PEEP can be anticipated and manipulated to prevent total collapse of vulnerable alveoli during Tlow, hopefully minimizing ventilator-induced lung injury.

Theoretical benefits of APRV include reducing peak pressure while maintaining plateau pressure, allowing for diaphragm activity to continue during LPV, and improving ventilation and perfusion matching compared to traditional modes (23). Theoretical benefits may translate to clinical outcomes in the surgical population – a systematic review comparing polytrauma patients with ALI/ARDS managed with APRV at a single academic center to those managed with other ventilator modes at other trauma centers (24). Patients managed at the publishing center were less likely to progress to ARDS (1.3 vs 14%), and more likely to survive to discharge (96.1% vs 85.9%). While this review was comprised of strictly observational studies, APRV has been analyzed in at least one prospective investigation. A randomized trial of 138 patients in a single medical ICU in China showed that APRV reduced ventilator and ICU days, with a non-significant signal of improved mortality (19.7% vs 34.3%, p = 0.053), compared to traditional LPV (25).

While these data are intriguing, both trials are generally limited. Large scale, prospective randomized studies will be needed to establish a clear link between APRV and improved outcomes. Further, transport of an ARDS patient is not the time to trial a new ventilator mode. The philosophic underpinnings of APRV are entirely different than volume control, and it requires expertise to employ. Without a clear understanding of the physiology, enhanced by a well-established base of experience, it should not be considered for ARDS patients in the transport setting. For a more thorough discussion of APRV please refer to the reviews in the references (22, 23).

Neuromuscular blockade (NMB)

Like many therapies in modern critical care, NMB has data both supporting and refuting its use. The ARDS et Curarisation Systematique (ACURASYS) trial, a multicenter investigation from France published in 2010, demonstrated that patients suffering from moderate to severe ARDS were more likely to survive if treated with a continuous infusion of cisatracurium, compared to those treated with deep sedation alone (26). These results stand in contrast to the more recently conducted Reevaluation of Systematic Early Neuromuscular Blockade (ROSE) trial. In ROSE, there was no mortality difference, in hospital or at 90 days, nor a change to any of the secondary outcomes assessed, including ventilator-, ICU- and hospital-free days (27). There were several differences between the protocols that may have contributed to the osberved differences. ROSE utilized a higher PEEP strategy (all patients enrolled received ≥ 8 cm H2O) and the control arm received light sedation, while ACURASYS employed a deep sedation strategy in each group.

Given the ACURASYS data and strong physiologic basis, paralysis remains a consideration for refractory hypoxemia in ARDS when patient-ventilator dyssynchrony prevents delivery of appropriate LPV. After ensuring adequate sedation, based on a structured neurologic assessment, a trial of NMB with a short acting agent (i.e. succinylcholine or vecuronium) is reasonable. If the transport team notes an improvement in objective measures, including SpO2 or plateau pressure, a longer acting agent or infusion could be considered.

Prone positioning

Supine lungs are generally less happy lungs. When patients are placed in the prone position the heart becomes dependent, lung units in the posterior fields receive improved ventilation, and perfusion is more evenly distributed (28). These physiologic benefits appear to translate to clinical outcomes – patients randomized to a prone ventilation strategy in the Proning Severe ARDS Patients (PROSEVA) trial were about twice as likely to survive to hospital discharge (29). While this trial represented a relatively selected population, due to a long list of contraindications and a pre-specified period of stability prior to randomization, the mortality benefit, along with support from other more recently conducted trials, was cited by the ATS/EISCM/SCCM guidelines as justification for a strong recommendation for patients with severe ARDS (30).

Recent case reports suggest that although transport of the prone patient is no small feat, it is feasible with adequate preparation and available expertise. A small case series of seven patients transported for ECMO evaluation, all with severe ARDS (mean PaO2/FiO2 <100), paralyzed, and proned, had no significant decompensation in flight (31). An additional case report includes a detailed checklist, which ensures appropriate patient position, securing of equipment, and continuous monitoring (32).

Transport of the prone patient is undoubtedly high risk, and while these reports provide some evidence that a mortality-reducing intervention can be provided by sufficiently trained critical care transport teams, this is not an intervention to be trialed on a whim. Similar to other high-risk interventions performed in transport, prone ventilation should only be performed after appropriate preparation at both the organizational and individual level, including crew education, high-fidelity simulation, and on-going quality assurance.

Rescue Therapies

Inhaled pulmonary vasodilators

Despite aggressive adherence to LPV, treatment of the underlying insult, and individualized care by diligent critical care teams, ARDS remains a highly morbid illness. As such, rescue therapies are frequently employed to attempt to salvage patients who continue to decline. Inhaled pulmonary vasodilators, compounds that improve ventilation-perfusion matching by selectively vasodilating vessels approximating well ventilated alveoli, can be considered for refractory hypoxemia. Inhaled nitric oxide (iNO) acts on smooth musculature surrounding pulmonary vessels, activating cyclic GMP, reducing intracellular calcium, and promoting vasodilation. Numerous randomized studies have demonstrated that although addition of iNO can temporarily increase PaO2 in acute lung injury, this does not translate to a mortality benefit (33). Epoprostenol, a prostaglandin that accomplishes vasodilation via a separate G-protein mediated pathway, is also frequently utilized to reduce pulmonary vascular resistance in a variety of clinical settings. A systematic review and meta-analysis of 25 studies in patients with ARDS, primarily observational and case series, suggests that inhaled prostaglandin use is associated with improvement in oxygenation as well as lower mean pulmonary artery pressure (34). Due to significant heterogeneity and a lack of clinical outcome data in the available literature, effect on mortality is unknown. From a practical standpoint, there are data to inform clinicians when choosing between iNO and inhaled epoprostenol: a single center retrospective review suggested that while outcomes were similar between the medications, the cost of epoprostenol was significantly lower (35). Given this difference, systems may stock a single agent to cut down on associated cost at the organizational level.

Inhaled pulmonary vasodilator therapy has been utilized in at least one published report of an inter-hospital transfer for consideration of VV-ECMO (36). While published data are sparse, there are logistical considerations regarding continuation or initiation of inhaled therapies in transport. If the referring facility has placed the patient on iNO, this requires specialized equipment to ensure appropriate titration, which the transport crew may not be able to accommodate. Prostaglandins can be administered by nebulization similar to many other inhaled therapies (i.e. albuterol, ipratropium, etc.), and thus do not require additional specialized equipment for single doses –although continuous administration requires a capable intravenous pump. As most transport crews will not carry prostaglandins, this would need to be obtained from the referring facility and reconstituted prior to administration. Teams should be aware that due to prolonged half-life, epoprostenol can theoretically cause systemic hypotension (34). Further, if the team is unable to continue inhaled therapy in flight, be prepared for the possibility of rebound hypoxemia as the pulmonary vasculature re-equilibrates.

Extracorporeal membrane oxygenation (ECMO)

Maximal support of pulmonary function via VV-ECMO is an option for patients meeting certain criteria. Please refer to the post authored by Ms. Garber, Dr.’s Powell and Gottula for further information (http://www.tamingthesru.com/blog/air-care-series/vv-ecmo).

Summary

Transport of the ARDS patient is fraught with risk. These patients are at high risk of decompensation, which can be disastrous in the back of an ambulance or helicopter. The primary goal for critical care transport teams should be safe arrival of both the crew and patient to their destination. As such, if patients are achieving an adequate oxygen saturation at the referring facility, the better part of valor is to continue the current course, even if the crew believes that ventilator settings are suboptimal. If ventilator changes need to be made due to inadequate oxygenation, ventilation, or other factors, strong consideration should be given to LPV settings. Of note, ventilator settings utilized in an emergency department setting have been strongly correlated with the settings used in the ICU, and changes designed to encourage adherence to LPV have been associated with reduced incidence of ARDS and even mortality (38). It is reasonable to assume that this therapeutic momentum may apply in the inter-facility setting. Any ventilator changes should be made prior to loading the patient to ensure a period of stability and to ensure the availability of extra staff if decompensation does occur. NMB can be considered for patient who remain dyssynchronous with the ventilator despite appropriate analgosedation. Adjunct therapies, including APRV or proning, should only be considered by appropriately experienced teams after rigorous preparation, including high-fidelity simulation. Given the increasing use of ECMO in the United States, it is reasonable to assume that transport of these patients will become increasingly common (39). It is imperative that critical care transport teams be familiar with the data informing management of these patients, to ensure that we continue to deliver definitive care outside the walls of the hospital.

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AUTHORED BY Christopher shaw, MD (@cshaw1026)

Dr. Shaw is a third-year Emergency Medicine resident at the University of Cincinnati with an interest in critical care.

POSTED BY ADAM GOTTULA, MD (@laertezz)

Dr. Gottula is a third-year Emergency Medicine resident at the University of Cincinnati with an interest in critical care and HEMS.

FACULTY EDITORS William Knight, MD (@waknight4)

William Knight, MD is an attending in the Department of Emergency Medicine, Neuroscience ICU and Stroke Team Member at the University of Cincinnati.

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References:

1. Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A (H1N1). JAMA. 2011;306(15): 1659-1668.

2. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilator support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomized controlled trial.

3. Wilcox, S. R., Richards, J. B., Genthon, A., Saia, M. S., Waden, H., Gates, J. D., ... & Wedel, S. K. (2018). Mortality and resource utilization after critical care transport of patients with hypoxemic respiratory failure. Journal of intensive care medicine, 33(3), 182-188.

4. Marx, G., Vangerow, B., Hecker, H., Leuwer, M., Jankowski, M., Piepenbrock, S., & Rueckoldt, H. (1998). Predictors of respiratory function deterioration after transfer of critically ill patients. Intensive care medicine, 24(11), 1157-1162.

5. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526–2533.

6. Rice, T. W., Wheeler, A. P., Bernard, G. R., Hayden, D. L., Schoenfeld, D. A., Ware, L. B., ... & National Institutes of Health. (2007). Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest, 132(2), 410-417.

7. Jubran, A. (2015). Pulse oximetry. Critical Care, 19(1), 272.

8. Acute Respiratory Distress Syndrome Network. (2000). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine, 342(18), 1301-1308.

9. De Feo, C., & Petrucci, N. (2013). Lung protective ventilation strategy for the acute respiratory distress syndrome. The Cochrane Database of Systematic Reviews, 2013(2).

10. National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. (2004). Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. New England Journal of Medicine, 351(4), 327-336.

11. Levy, M. M. (2004). PEEP in ARDS--how much is enough?. New England Journal of Medicine, 351(4), 389-390.

12. Meade, M. O., Cook, D. J., Guyatt, G. H., Slutsky, A. S., Arabi, Y. M., Cooper, D. J., ... & Austin, P. (2008). Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. Jama, 299(6), 637-645.

13. Kallet, R. H., & Matthay, M. A. (2013). Hyperoxic acute lung injury. Respiratory care, 58(1), 123-141.

14. Girardis, M., Busani, S., Damiani, E., Donati, A., Rinaldi, L., Marudi, A., ... & Singer, M. (2016). Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial. Jama, 316(15), 1583-1589.

15. Mackle, D. M., Bailey, M. J., Beasley, R. W., Bellomo, R., Bennett, V., Deane, A., ... & McArthur, C. J. (2018). Protocol summary and statistical analysis plan for the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX). Critical Care and Resuscitation, 20(1), 22.

16. Barrot, L., Asfar, P., Mauny, F., Winiszewski, H., Montini, F., Badie, J., ... & Souweine, B. (2020). Liberal or conservative oxygen therapy for acute respiratory distress syndrome. New England Journal of Medicine, 382(11), 999-1008.

17. van den Boom, W., Hoy, M., Sankaran, J., Liu, M., Chahed, H., Feng, M., & See, K. C. (2020). The search for optimal oxygen saturation targets in critically ill patients: observational data from large ICU databases. Chest, 157(3), 566-573.

18. Swinamer, D. L., Phang, P. T., Jones, R. L., Grace, M., & King, E. G. (1988). Effect of Routine Administration of Analgesia on Energy Expenditure in Critically III Patients. Chest, 93(1), 4-10.

19. Devlin, J. W., Skrobik, Y., Gélinas, C., Needham, D. M., Slooter, A. J., Pandharipande, P. P., ... & Balas, M. C. (2018). Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical care medicine, 46(9), e825-e873.

20. Rhodes, A., Evans, L. E., Alhazzani, W., Levy, M. M., Antonelli, M., Ferrer, R., ... & Rochwerg, B. (2017). Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive care medicine, 43(3), 304-377.

21. Network, A. R. D. S., Wheeler, A. P., Bernard, G. R., Thompson, B. T., Hayden, D., & DeBoisblanc, B. (2006). Comparison of two fluid-management strategies in acute lung injury. N Engl j Med, 354(24), 2564-2575.

22. Modrykamien, A., Chatburn, R. L., & Ashton, R. W. (2011). Airway pressure release ventilation: an alternative mode of mechanical ventilation in acute respiratory distress syndrome. Cleve Clin J Med, 78(2), 101-110.

23. Fredericks, A. S., Bunker, M. P., Gliga, L. A., Ebeling, C. G., Ringqvist, J. R., Heravi, H., ... & Romito, B. T. (2020). Airway Pressure Release Ventilation: A Review of the Evidence, Theoretical Benefits, and Alternative Titration Strategies. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, 14, 1179548420903297.

24. Andrews, P. L., Shiber, J. R., Jaruga-Killeen, E., Roy, S., Sadowitz, B., O’Toole, R. V., ... & Habashi, N. M. (2013). Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature. Journal of Trauma and Acute Care Surgery, 75(4), 635-641.

25. Zhou, Y., Jin, X., Lv, Y., Wang, P., Yang, Y., Liang, G., ... & Kang, Y. (2017). Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive care medicine, 43(11), 1648-1659.

26. Papazian, L., Forel, J. M., Gacouin, A., Penot-Ragon, C., Perrin, G., Loundou, A., ... & Constantin, J. M. (2010). Neuromuscular blockers in early acute respiratory distress syndrome. New England Journal of Medicine, 363(12), 1107-1116.

27. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. (2019). Early neuromuscular blockade in the acute respiratory distress syndrome. New England Journal of Medicine, 380(21), 1997-2008.

28. Gattinoni, L., Taccone, P., Carlesso, E., & Marini, J. J. (2013). Prone position in acute respiratory distress syndrome. Rationale, indications, and limits. American journal of respiratory and critical care medicine, 188(11), 1286-1293.

29. Guérin, C., Reignier, J., Richard, J. C., Beuret, P., Gacouin, A., Boulain, T., ... & Clavel, M. (2013). Prone positioning in severe acute respiratory distress syndrome. New England Journal of Medicine, 368(23), 2159-2168.

30. Fan, Eddy, et al. "An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome." American journal of respiratory and critical care medicine 195.9 (2017): 1253-1263.

31. DellaVolpe, J. D., Lovett, J., Martin‐Gill, C., & Guyette, F. X. (2016). Transport of mechanically ventilated patients in the prone position. Prehospital Emergency Care, 20(5), 643-647.

32. Hersey, D., Witter, T., & Kovacs, G. (2018). Transport of a Prone Position Acute Respiratory Distress Syndrome Patient. Air medical journal, 37(3), 206-210.

33. Taylor, R. W., Zimmerman, J. L., Dellinger, R. P., Straube, R. C., Criner, G. J., Davis Jr, K., ... & Inhaled Nitric Oxide in ARDS Study Group. (2004). Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. Jama, 291(13), 1603-1609.

34. Fuller, B. M., Mohr, N. M., Skrupky, L., Fowler, S., Kollef, M. H., & Carpenter, C. R. (2015). The use of inhaled prostaglandins in patients with ARDS. Chest, 147(6), 1510-1522.

35. Torbic, H., Szumita, P. M., Anger, K. E., Nuccio, P., LaGambina, S., & Weinhouse, G. (2013). Inhaled epoprostenol vs inhaled nitric oxide for refractory hypoxemia in critically ill patients. Journal of critical care, 28(5), 844-848.

36. Schili, J., Tilney, P. V., Gutsche, J. T., & Cohen, J. (2016). A 63-Year-Old Male Interfacility Transfer for Extracorporeal Membrane Oxygenation Evaluation. Air medical journal, 35(5), 261-264.

37. Briel, M., Meade, M., Mercat, A., Brower, R. G., Talmor, D., Walter, S. D., ... & Brochard, L. (2010). Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. Jama, 303(9), 865-873.

38. Fuller, B. M., Ferguson, I. T., Mohr, N. M., Drewry, A. M., Palmer, C., Wessman, B. T., ... & Kolomiets, A. A. (2017). Lung-protective ventilation initiated in the emergency department (LOV-ED): a quasi-experimental, before-after trial. Annals of emergency medicine, 70(3), 406-418.

39. McCarthy, F. H., McDermott, K. M., Kini, V., Gutsche, J. T., Wald, J. W., Xie, D., ... & Desai, N. D. (2015, June). Trends in US extracorporeal membrane oxygenation use and outcomes: 2002-2012. In Seminars in thoracic and cardiovascular surgery (Vol. 27, No. 2, pp. 81-88). WB Saunders.