key: cord-0972902-degybvgy
authors: Coleman, Melissa H.; Aldrich, J. Matthew
title: Acute Respiratory Distress Syndrome: Ventilator Management and Rescue Therapies
date: 2021-05-27
journal: Crit Care Clin
DOI: 10.1016/j.ccc.2021.05.008
sha: 6e62327926c7884e28d8559b620782c0e470d8d7
doc_id: 972902
cord_uid: degybvgy

This review describes the management of mechanical ventilation in patients with acute respiratory distress syndrome, including in those with COVID-19. Low tidal volume ventilation with moderate to high positive end expiratory pressure (PEEP) remains the foundation of an evidence-based approach. We consider strategies for setting PEEP levels, the use of recruitment maneuvers, and the potential role of driving pressure. Rescue therapies including prone positioning and extracorporeal membrane oxygenation are also discussed.

Critical care providers are frequently confronted with the challenges of managing patients with acute respiratory distress syndrome (ARDS). While in some cases, non-invasive options like high flow nasal oxygen (HFNO) are appropriate for select patients with mild ARDS, many will ultimately require intubation and mechanical ventilation. The purpose of this review is to describe an evidence-based approach to ventilatory management that avoids exacerbation of lung injury and offers the best hope for good outcomes-ICU and hospital survival but also reduced length of stay, days on the ventilator, and avoidance and minimization of the cognitive, physical and psychological impairments that are common to patients with ARDS and severe critical illness. We will review the major advances in lung protective ventilation (LPV) with a focus on low tidal ventilation and optimal use of positive end-expiratory pressure (PEEP). We will explore the conflicting and sometimes controversial literature with regard to recruitment maneuvers (RMs) and driving pressure as a goal and prognostic factor for patients with ARDS.

Since many patients will still deteriorate despite lung protective ventilation, we will discuss rescue strategies including prone positioning and extracorporeal membrane oxygenation (ECMO). Lastly, given the extraordinary situation created by the COVID-19 pandemic and the high volume of patients with severe disease and ARDS, we discuss the evidence for ventilatory management of these patients as well as the burgeoning literature regarding ECMO strategies and outcomes. adults, intensivists and respiratory therapists have used varied approaches to mechanical ventilation of patients with ARDS. Much of the initial focus during this era, both in the operating room and ICU, was on optimization of gas exchange and higher tidal volumes were common. 2, 3 Researchers, however, demonstrated that mechanical ventilation, especially with high tidal volumes, could cause or exacerbate lung injury. 4 In 1990, Hickling and colleagues demonstrated that a mechanical ventilatory strategy that reduced peak inspiratory pressure and tolerated hypercapnia could improve mortality in a cohort of patients with ARDS. 5 Over the next decade, several randomized controlled trials investigated lung protective approaches, with mixed but mostly negative results. [6] [7] [8] [9] In 2000, the landmark ARMA trial 10 of patients with ARDS compared a traditional ventilatory approach of 12 ml/kg of predicated body weight with plateau pressure less than 50 cm H 2 O with a lung protective approach of 6 ml/kg with a plateau pressure target of less than 30 cm H 2 O. The trial was halted early after 861 patients were randomized due to an absolute mortality benefit of 9 percentage points: 31% vs. 40% mortality prior to hospital discharge. While this trial established LPV with low tidal volumes and a FiO 2 /PEEP scale as the standard ventilatory approach to patients with ARDS 11 , implementation and compliance continued to vary over the next 20 years.

LUNG SAFE-a large multinational prospective cohort study of severe respiratory failuredemonstrated both an underdiagnosis of ARDS and widespread non-compliance with lung protective ventilation: less than two-thirds of patients with ARDS received < 8 ml/kg of PBW. 12 J o u r n a l P r e -p r o o f

Use and adjustment of moderate to high PEEP is a standard approach to the management of ARDS and severe hypoxemia. However, there is considerable variability among clinicians in the use of PEEP strategies. 12 As mentioned above, the ARMA trial used a FiO 2 /PEEP table to set PEEP levels. Subsequent trials over the next decade investigated the potential benefits of higher levels of PEEP in patients receiving low tidal volume ventilation. Brower and colleagues in the ALVEOLI trial found no difference in mortality or unassisted breathing in their comparison of LPV using low vs. high PEEP/FiO 2 tables; mean PEEP values were 8 vs. 13. 13 The LOVS trial in 2008 examined an "open lung" approach of higher PEEP and recruitment maneuvers and found no improvement in mortality compared to a standard LPV approach similar to the ARMA protocol. The study did demonstrate, however, improvements in secondary outcomes, including hypoxemia and need for rescue therapies. 14 The third major study of PEEP in the management of ARDS-the EXPRESS trial 15 -compared a "minimal distention" approach with an "increased recruitment" approach that maximized PEEP while maintaining plateau pressures less than 28-30. This trial did not demonstrate any mortality benefits but patients in the intervention arm did have more ventilator-and organ failure-free days. A subsequent systematic review and metaanalysis of the three aforementioned trials confirmed the absence of benefit of higher PEEP with regards to hospital mortality among all patients. 16 This meta-analysis highlighted the critique that PEEP trials have failed to detect potential benefits to sub-groups with severe ARDS. Therefore, despite these large, well-designed trials, considerable uncertainty remains about the best approach to PEEP management. Some clinicians favor an individualized approach to PEEP J o u r n a l P r e -p r o o f titration based on data showing that the amount recruitable lung is highly variable 17 and low tidal volume ventilation without appropriate PEEP adjustment can result in significant alveolar decruitment. 18 One common approach is the use of esophageal pressure (P ES ) monitoring as a surrogate for pleural pressure and calculating transpulmonary pressure (P L = P alveolar -P pleural ) ( Figure 1 ). PEEP is usually set to achieve a P L above zero at end expiration. 19 In the single-center EPVent study, Talmor and colleagues randomized patients with acute lung injury or ARDS to an esophageal pressure-guided approach or a conventional approach of PEEP adjustment using the standard ARDSNet PEEP/FiO 2 scale. 20 This resulted in significant PEEP differences between the groups-17 +/-6 vs. 10 +/-4, P < 0.001-and higher P/F ratios and respiratory system compliance in the esophageal P group. There was no statistically significant difference in mortality although adjustment for severity of illness did result in a significant reduction in 28day mortality. The follow up multi-center study-EPVent2 21 -also investigated a P ES guided approach but compared it to a higher PEEP-FiO2 table with a maximum PEEP of 24. This trial found no significant difference in the primary endpoint of death and days free from mechanical ventilation though day 28. Even though this was a negative trial, there still may be rationale for some intensivists using esophageal pressure measurements to guide PEEP therapy, especially in patients with elevated BMI or abdominal compression from ascites or other intra-abdominal processes.

In addition to PEEP, and often used as a combined approach, recruitment maneuvers (RM) are a commonly used strategy of applying sustained pressure for a set period of time to open collapsed lung segments and improve oxygenation. 22, 23 One challenge in evaluating outcomes is the significant variability in approaches described in different trials both in terms of the actual RM and how the strategy is used with PEEP adjustment. 24 Medicine guideline provided a conditional recommendation for RMs in patients with ARDS. 11 More recently, however, the multi-center, multi-national ART study of greater than 1000 patients investigated a combined RM and decremental PEEP trial approach compared with a standard ARDSNet low PEEP strategy. The intervention was complex: neuromuscular blockade was initiated and then patients were placed on pressure-control ventilation with a driving pressure of 15 

Driving pressure is commonly defined as airway plateau pressure (P plat -PEEP), or the ratio of tidal volume to respiratory system compliance (Vt/C rs ). Among the earliest considerations of driving pressure as a concept was as a component of a lung protective intervention in a small 1998 trial. 6 In 2015, Amato and colleagues analyzed nine previous RCTs of various mechanical ventilation interventions in patients with ARDS and concluded that driving pressure was the independent variable most strongly associated with survival. Other variables like reduction in tidal volume and increases in PEEP only demonstrated benefit if associated with reductions in driving pressure. Another secondary analysis of driving pressure also found it to be a risk factor for mortality with higher survival when driving pressure was less than 13 cm H 2 O at day one of mechanical ventilation. 29 This study, however, did not find as strong a correlation with mortality as the Amato study, and determined that driving pressure added little additional value when compared with P plat and respiratory system compliance. More recently, a systematic review and meta-analysis of seven studies and > 6000 patients receiving mechanical ventilation for ARDS demonstrated that higher driving pressure is associated with higher mortality. 30 The authors concluded that a driving pressure of less than 13-15 cm H 2 O could be a target for clinicians.

While some argue that driving pressure should be routinely monitored in clinical practice 19 , we agree with the conclusion of others that more research is needed to both confirm its role as a predictor of mortality and determine how to best incorporate it into a clinical protocol. 31 J o u r n a l P r e -p r o o f Other areas of recent investigation with regard to management of mechanical ventilation include patient self-inflicted lung injury (P-SILI) and conservative oxygen strategies. P-SILI, a term coined by Brochard and colleagues in 2017 32 , describes the clinical condition in which spontaneous breathing during mechanical ventilation may result in lung injury through a variety of mechanisms: unintended high tidal volumes, high transpulmonary pressure swings due to vigorous efforts with creation of a "pendelluft" phenomenon, and negative alveolar pressures with concomitant development of lung edema. While investigators recognize that spontaneous breathing during mechanical ventilation can confer benefits including maintenance of respiratory muscle function, improved gas exchange and lighter sedation requirements, there is increasing concern that spontaneous breathing can contribute to lung injury especially in severe ARDS. 33, 34 However, data from the observational LUNG SAFE study indicates that spontaneous breathing is common early in the course of ARDS, not associated with increased mortality and may result in decreased ICU LOS and earlier liberation from mechanical ventilation. 35 The authors nonetheless urge caution in interpretating the study's results given the higher use of controlled ventilation in severe disease and the absence of measurements of respiratory effort that may provide a better indication of potential harm. There needs to be further study of a structured approach to spontaneous breathing during mechanical ventilation, such as use of a higher PEEP strategy that could confer benefit and avoid some of the harms described above. 36 Hyperoxia is common in the management of early stage ARDS, with a prevalence of 30% on day one in the LUNG SAFE study. Two recent randomized controlled studies-LOCO2 37 and ICU ROX 38 -investigated whether a conservative oxygen strategy could improve outcomes. LOCO2, which enrolled only patients with ARDS, did not result in improved 28-day survival and the J o u r n a l P r e -p r o o f study was stopped early due to safety concerns. ICU ROX included a broader range of patients requiring mechanical ventilation but also did not show any benefit in the primary outcome of ventilator free days. We agree with the conclusion of the accompanying editorial that hyperoxia is unnecessary and should be avoided but the lower threshold of 88% used in LOCO2 may be harmful in patients with ARDS. 39

Airway pressure release ventilation (APRV) Airway pressure release ventilation is a ventilatory strategy first described by Stock and Downs in 1987, which allows a patient to breathe spontaneously while providing CPAP with a short, periodic release phase. 40, 41 (Figure 2 ). This mode of ventilation uses CPAP to promote and maintain alveolar recruitment with a partial release phase for ventilation. Implementation of APRV can vary considerably, which poses a significant challenge when evaluating studies comparing its use to conventional mechanical ventilation for patients with ARDS. The duration of the release phase may be fixed or it may be adjusted based on changes in a patient's respiratory mechanics. 41 To date there is only one randomized control trial that compares APRV to low tidal volume mechanical ventilation for patients with ARDS. 42 in the APRV group and 34.3% in the LTV group, however this was not statistically significant (P = 0.053). This study had several limitations including small sample size and investigation only at a single center. Notably, despite randomization, patients in the low tidal volume group had more comorbidities than patients in the APRV group. Currently there are no large, multi-center RCTS that demonstrate an improvement in patient outcomes with the use of APRV versus low tidal volume ventilation for ARDS. Thus, APRV should not be implemented in standard clinical practice until more evidence is provided for its benefits.

High-Frequency Oscillatory Ventilation (HFOV) is a mode of ventilation that was developed after an incidental finding in 1972, when CO 2 was detected at the mouthpiece of an experimental circuit developed to measure the effects of neuromuscular blockade on lung impedance under anesthesia. 44, 45 This observation lead to the development of HFOV in which ventilation can modulated by oscillation frequency. HFOV delivers very small tidal volumes that should, in theory, make this method of lung protective ventilation well-suited for patients with ARDS. In 2013, two multicenter randomized control trials of HFOV versus standard mechanical ventilation were reported. The OSCILLATE trial concluded that HFOV, when compared to low tidal volume ventilation and high PEEP, did not reduce in-hospital mortality. 46 The OSCAR trial showed no significant difference in 30-day mortality between HFOV and standard ventilatory management for patients with ARDS. 47 A subsequent meta-analysis of six randomized control J o u r n a l P r e -p r o o f trials showed HFOV was not associated with improved survival in patients with ARDS. 48 At this time HFOV is not widely recommended for the management of adult patients with ARDS. 49

Prone positioning is associated with improved oxygenation due to improved ventilationperfusion ratio in the setting of recruitment of dependent portions of the lung with more homogenous ventilation distribution, increase in lung volume, and improved redistribution of perfusion. 50 In the prone position the effect of compression from the heart, gravity and the chest wall are decreased for portions of the lung which are dependent in the supine position. 51 While prone positioning had previously been utilized for patients with ARDS, initial trials failed to show an association with improvement in patient outcomes. [52] [53] [54] [55] In 

The results of the initial randomized control trials for ECMO for ARDS did not support the use of ECMO for severe ARDS. 58, 59 In 2009, the Conventional ventilation or ECMO for Severe Adult Respiratory failure (CEASAR) trial was conducted in the UK to re-evaluate the use of ECMO for ARDS in the setting of modern ventilation strategies and improved patient selection. 60 In this multi-centered, randomized control trial, 180 patients were enrolled and randomly assigned to either conventional management or consideration for VV-ECMO. Of the 90 patients randomized to the ECMO arm of the trial, 85 were successfully transferred to a center with ECMO capability and 75% ultimately underwent VV-ECMO cannulation. The primary endpoint of survival to 6 months after randomization was achieved by 63% of patients within the ECMO consideration group and 47% patients within conventional management group.

Due to the fact that only 75% of the patients within the ECMO consideration arm actually received VV-ECMO, the study investigators did not specifically recommend ECMO for severe J o u r n a l P r e -p r o o f ARDS, but instead recommended that these patients be transferred to a center with ECMO capability. These regional centers may have more expertise in applying lung protective ventilation effectively. Important limitations of the CESAR trial include the use of greater than recommended tidal volumes in the control group and the significant number of patients randomized to the ECMO arm who did not undergo ECMO cannulation. 61 In an effort to address the limitations of prior VV-ECMO for ARDS trials, the international, randomized ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial was conducted to study the efficacy of early VV-ECMO versus standard lung protective ventilation for patients with severe ARDS. 62 Early cannulation was defined as endotracheal intubation with less than 7 days of mechanical ventilation. The 60-day morality rate was 35% for the VV-ECMO group and 46% for the control group (P=0.09). 62 The investigators concluded that the mortality at 60 days was not significantly different between patients treated with early VV-ECMO and those treated with conventional management. Of note, the study was stopped early and there was crossover between the VV-ECMO and control group.

Within the control group, 35 (28%) patients underwent VV-ECMO cannulation. For these 35 patients, the time of VV-ECMO cannulation was 6.5 ± 9.7 after randomization and 60-day mortality was 57%. Though there was no statistically significant difference in mortality the study did suggest a potential mortality benefit. Further, when considering the secondary outcomes, there was a statistically significant decrease in the number of days of prone positioning and days of renal-replacement therapy for patient in the ECMO group. While this trial did not appear to definitively support the use of VV-ECMO for ARDS, the potential for mortality benefit seen with regard to secondary outcomes has supported the continued use in selected patients. Based J o u r n a l P r e -p r o o f on these studies, the Extracorporeal Life Support Organization (ELSO), an international consortium of institutions focusing on providing advanced therapies for organ failure, published guidelines for the use of ECMO for respiratory failure. 63 (Table 1) While many studies focus on the short-term outcomes of ECMO for ARDS there are fewer studies that focus on long-term outcomes. A retrospective review of patients in the ELSO registry from 2012 to 2017 who were cannulated for VV-ECMO and successfully weaned was performed to examine long-term outcomes. 64 In this study, 6,536 patients were identified and 89.7% survived to discharge. The patients were divided into two groups, complete recovery and partial recovery. Complete recovery was defined as discharge to home and partial recovery was defined as ongoing need for hospitalization, transfer to a referral hospital, or discharged to a location other than home. The factors which were noted to have a negative impact on the achievement of complete recovery were age  65, cardiac arrest prior to VV-ECMO cannulation, use of vasopressors, use of neuromuscular blocking agents, renal replacement therapy prior to VV-ECMO cannulation, ECMO cannulation  2 weeks and the development of an ECMOrelated complication. 64

Since the beginning of the pandemic there has been considerable, and at times, heated debate about the best approach to ventilator management. Several early studies from China, Italy and J o u r n a l P r e -p r o o f the United States described very high mortality in patients requiring mechanical ventilation [65] [66] [67] [68] [69] , and mainstream and social media accounts of ICU outcomes were often grim. All of this likely contributed to the belief among some clinicians that mechanical ventilation should be avoided at all costs. 70 Further adding to the debate and confusion, some argued that COVID-19 causes a unique type of lung injury and requires a different approach to ventilator management than standard evidence-based lung protective ventilation. 71 In contrast, major guidelines from the Society of Critical Care Medicine, World Health

Organization and National Institutes of Health recommend an evidence-based approach of lung protective ventilation for COVID-19 induced ARDS, including low tidal volume ventilation, maintaining plateau pressure less than 30 cm H 2 O, and consideration of higher PEEP in those with moderate to severe ARDS. [72] [73] [74] Prone positioning for 12-16 hours/day is recommended by all guidelines for those with severe ARDS and refractory hypoxemia. We strongly agree with the perspective that in a time of great challenge and uncertainty, we should follow the evidencebased recommendations of these guidelines. 70, 75, 76 For those with COVID-19 and acute hypoxemic respiratory failure but not requiring mechanical ventilation, we favor HFNO as the initial approach, largely based on prior institutional experience and strong evidence from non-COVID causes of hypoxemic respiratory failure. 77 There are conflicting studies regarding the role of non-invasive ventilation, either with continuous positive airway pressure (CPAP) or Bilevel positive airway pressure (BPAP). [78] [79] [80] Helmet non-invasive ventilation has been of particular interest during the pandemic, and several studies prior to COVID-19 did demonstrate favorable outcomes compared to face mask non-J o u r n a l P r e -p r o o f invasive ventilation 81 , standard supplemental oxygen 82 , and HFNO. 83 The degree of aerosolization with either HFNO or NIV techniques remains unclear. 84 Regardless of the approach, patients should be monitored closely and an experienced airway provider immediately available if urgent intubation is required.

The experience regarding the use of ECMO for COVID-19 in France is captured by a retrospective cohort study of patients within the Paris-Sorbonne ECMO-COVID University Hospital Network. 85 In this study, 492 patients with COVID-19 were treated in the ICU between March 8 and May 2, 2020. Patients were considered eligible for ECMO if they had ARDS and despite optimum ventilator management met specific criteria for respiratory failure severity (Table 2) . Eighty-three (16.9%) of these patients underwent ECMO cannulation; 98% with V-V.

The median age of COVID patients cannulated for ECMO was 49 years with a median Simplified Acute Physiology Score (SAPS) II of 45. Median time from intubation to ECMO cannulation was four days and the median duration of ECMO support was 20 days. The authors noted that prone positioning after ECMO cannulation was recommended and this was used in 67 (81%) patients in this cohort. The probability of 60-day mortality for COVID patients treated with ECMO was estimated to be 31%.

A recent ELSO registry review investigated ECMO outcomes for COVID patients between January 16 and May 1, 2020. 86 This cohort study included a total of 1,035 patients from 36 J o u r n a l P r e -p r o o f countries and 213 hospitals. Of note, 779 (75%) of these patients were reported to have ARDS.

Consistent with the Paris experience, the median time from intubation to ECMO cannulation was 4 days with 94% of the patients receiving VV-ECMO. The median duration of ECMO cannulation was 13.9 days and the 90-day in-hospital mortality for patients with ARDS cannulated for VV-ECMO was found to be 38%.

The initial experience with ECMO for ARDS due to COVID-19 was associated with high mortality and called into question the use of VV-ECMO as a rescue strategy. The Paris and ELSO registry data suggest improved mortality outcomes, however, questions remain as to role of VV-ECMO during the COVID-19 pandemic. 87 With median duration of cannulation ranging from 14 to 20 days, it is important to consider if the use of VV-ECMO significantly reduces illness duration and if it is an appropriate use of critical resources for many institutions and health systems. While patient selection and timing of ECMO cannulation are important factors, careful consideration of the use of such a resource intensive treatment during a global pandemic is crucial.

The use of low tidal volume ventilation has been consistently shown to be the cornerstone of the management of patients with ARDS. Additionally, evidence-based ARDS management supports the use of rescue strategies including neuromuscular blockade and early prone positioning.

Utilization of VV-ECMO for severe ARDS has evolved and increased in the wake of the H1N1 pandemic. As we consider the ongoing use of VV-ECMO for ARDS, now with the growing J o u r n a l P r e -p r o o f experience in patients with ARDS due to COVID-19 infection, it is critical to focus on patient selection, resource allocation and early referral to specialized ECMO centers. Indications ARDS Criteria 86,87 plus optimal ventilator management (FiO2  80%, tidal volume 6mL/kg of predicated body weight, PEEP  10 cm of water) and one of the following: 1. PaO2 to FiO2 ratio < 50 mmHg for > 3 hours 2. PaO2 to FiO2 ratio < 80 mmHg for > 6 hours 3. Arterial blood pH < 7.25 and PaCO2  60 mmHg for Alveolar Pressure (P alv ) ≈ Airway Pressure (P aw ) Pleural Pressure (P pl ) ≈ Esophageal Pressure (P es ) Transpulmonary Pressure (P tp ) ≈ P alv -P pl ≈ P aw -P es Figure 1 . Transpulmonary pressure (P tp ) is the difference between airway and esophageal pressures measured at two points in the respiratory cycle: end-inspiration and end-expiration. It is recommended to set PEEP such that end-inspiratory P tp is < 25 cm H 2 O and end-expiratory P tp is > 0 cm H 2 O. 

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