key: cord-0946921-79gp4rrx
authors: Fan, Eddy; Beitler, Jeremy R; Brochard, Laurent; Calfee, Carolyn S; Ferguson, Niall D; Slutsky, Arthur S; Brodie, Daniel
title: COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted?
date: 2020-07-06
journal: Lancet Respir Med
DOI: 10.1016/s2213-2600(20)30304-0
sha: fa7798c4c35ca7e64820da0497ee1f3145f0c506
doc_id: 946921
cord_uid: 79gp4rrx

The COVID-19 pandemic has seen a surge of patients with acute respiratory distress syndrome (ARDS) in intensive care units across the globe. As experience of managing patients with COVID-19-associated ARDS has grown, so too have efforts to classify patients according to respiratory system mechanics, with a view to optimising ventilatory management. Personalised lung-protective mechanical ventilation reduces mortality and has become the mainstay of treatment in ARDS. In this Viewpoint, we address ventilatory strategies in the context of recent discussions on phenotypic heterogeneity in patients with COVID-19-associated ARDS. Although early reports suggested that COVID-19-associated ARDS has distinctive features that set it apart from historical ARDS, emerging evidence indicates that the respiratory system mechanics of patients with ARDS, with or without COVID-19, are broadly similar. In the absence of evidence to support a shift away from the current paradigm of ventilatory management, we strongly recommend adherence to evidence-based management, informed by bedside physiology, as resources permit.

The global experience of managing patients with COVID-19-associated acute respiratory distress syndrome (ARDS) is rapidly expanding, along with an increasing number of reports on respiratory system mechanics and ventilatory management. 1-6 Over the past two decades, the heterogeneity of ARDS has increasingly been recognised, and efforts have been made to describe subgroups of patients with different clinical and biological characteristics, clinical outcomes, and treatment responses. 7,8 As hospitals have faced a surge of patients with COVID-19 and health-care professionals have worked under enormous pressure, often with limited resources, to save the lives of patients with ARDS, obser vations of hetero geneity in both the clinical features and clinical course of COVID-19-associated ARDS have led to proposals for different management strategies on the basis of described pheno types. 9-11 Phenotypic heterogeneity is an important concept, but there is a risk of overinterpretation or inappropriate application of these prin ciples, which can have detrimental implications for outcomes of ventilatory manage ment. Given the importance of lung-protective mechan ical ventilation in ARDS, in this Viewpoint we address ventilatory strategies in the context of recent reports that discussed phenotypic heterogeneity in patients with COVID-19-associated ARDS. 9-11 Without a strong evidence base to guide a shift from the current paradigm of patient management, we strongly recommend adherence to evidence-based management, 12 informed by bedside physi ology, and supported by current data.

In a case series of 16 mechanically ventilated patients with COVID-19, Gattinoni and colleagues 9 described severe hypoxaemia despite relatively normal lung compliance-an unusual finding in patients with severe ARDS. In eight patients, blood gases and CT scans revealed a large shunt fraction despite relatively small amounts of gasless tissue, suggesting hyperperfusion of poorly ventilated lung regions. Because the lungs appeared relatively open, they recommended a lower positive end-expiratory pressure (PEEP) strategy, as well as avoidance of prone positioning, especially because of potential limitations in human resources during the pandemic.

In a second report, 10 the authors highlighted the nonuniformity of patients with COVID-19-associated ARDS and proposed the existence of two primary phenotypes: type L (low values of elastance, pulmonary ventilation/ perfusion ratio, lung weight, and recruit ability) and type H (high values of elastance, right-to-left shunt, lung weight, and recruitability), with the latter being more consistent with what they describe as typical severe ARDS. Gattinoni and colleagues proposed that most patients present early with type L, and that some transition to type H, potentially

• During an outbreak such as the COVID-19 pandemic, it is important to balance the rapidly evolving and initially low-level evidence-largely case series, case reports, and anecdotes-with the scientific rigour needed to support any necessary shifts in the current paradigm of patient management • The notion that acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome is a ubiquitous finding as old as the concept of ARDS itself, contributing substantially to the complexity of its management; heterogeneity is most relevant when linked to differential treatment effects, which have been shown to improve outcomes • Reports of phenotypic heterogeneity in patients with COVID-19-associated ARDS, although interesting, could easily be overinterpreted or inappropriately applied in the intensive care unit, potentially leading to detrimental ventilatory management strategies in these patients • Large observational studies suggest that patients with COVID-19-associated ARDS have similar respiratory system mechanics to patients with ARDS from other causes and that, for most patients, COVID-19-associated ARDS is, in the end, ARDS • We strongly recommend adherence to evidence-based management, informed by bedside physiology, and supported by outcome data; this approach includes lungprotective mechanical ventilation, individualised positive end-expiratory pressure, prone positioning, and venovenous extracorporeal membrane oxygenationas suggested by international guidelines for ARDS, and as resources permit due to the synergistic effects of worsening COVID-19 pneumonia and patient self-inflicted lung injury. 13 Therefore, the authors 10 ad vocated early endotracheal intubation in patients with excessive inspiratory efforts, and stated that once "…deeply sedated, the Type L patients, if hypercapnic, can be ventilated with volumes greater than 6 mL/kg (up to 8-9 mL/kg) predicted body weight, as the high compliance results in tolerable strain without the risk of VILI [ventilator-induced lung injury]". 10 A third report on this subject re-emphasised these key points. 11 We are at an early stage in understanding the heterogeneity of COVID-19-associated ARDS (eg, pathophysiological features, clinical course, biomarkers, and phenotypes based on respiratory mechanics). The rigorous identification of phenotypes could ultimately help to guide the management of patients who are critically ill with COVID-19. At present, we argue that an evidence-based approach informed by decades of research in ARDS is needed.

The notion that ARDS is a heterogeneous syndromepresenting with variable mechanical and gas exchange disturbances-is an important but ubiquitous finding and as old as the concept of ARDS itself. This clinical and biological heterogeneity contributes substantially to the complexity of managing the syndrome. Heterogeneity is clinically relevant when linked to differential treatment effects. For example, hyperinflammatory versus hypoinflammatory subphenotypes might respond differ ently to PEEP levels and fluid management. 14,15 Identifying recruitability with a simple bedside technique could help to tailor ventilatory management in patients with ARDS, including those with COVID-19. 1,16 However, the application of such a tailored physiological approach does not necessarily equate to improved outcomes with that treatment. Similarly, an atypical presentation of ARDS does not necessarily mean that the patient will respond differently to a typical treatment regimen. 3 In this context, we propose recommendations for the treatment of COVID-19-associated ARDS, from both a practical and theoretical perspective. First, lung protection with volume-limited and pressure-limited ventilation was initially shown to be effective in a heterogeneous ARDS population with a wide range of physiological parameters, including static compliance, plateau pres sure, and the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen 17 Similar to patients with COVID-19 with the proposed L phenotype, patients with mild ARDS typically have higher respiratory system compliance than do those with more severe ARDS. Some data suggest that a lung-protective strategy can be beneficial even in patients with relatively low plateau pressures. 18 Moreover, a number of studies have shown that using lung-protective ventilation in patients who have relatively normal lungs is associated with fewer pulmonary compli cations, including decreased progression to ARDS, and improved clinical outcomes. 19 Patients with the robust inflam matory response common in COVID-19 are prob ably biologically primed to develop ventilation-induced lung injury. 20 The respiratory system mechanics and risk of lung strain in these patients might worsen quickly, especially with the resumption of spontaneous efforts to breathe. 21 Therefore, liberalising tidal volumes in these patients might be associated with worse outcomes, even if they do not have what might be regarded as typical ARDS.

Gattinoni and colleagues 10 recommended the use of tidal volumes greater than 6 mL/kg predicted bodyweight for patients with type L COVID-19-associated ARDS who develop hypercapnia. Because of the potential for greater ventilator-induced lung injury with higher tidal volumes, we suggest that clinicians first address common treatable causes of hypercapnia before resorting to the use of higher tidal volumes. These causes might include the following: inadequate respiratory rate; increased dead space from a heat and moisture exchange filter at the Y-connector, 22 which might be used out of an abundance of caution to prevent cross-contamination, instead of a heated humidifier; or ventilators used without the circuit compliance compensation turned on, reducing the volumes delivered to patients. 23 Meticulous attention to these details, before consideration of ab normal vascular components of dead space as a cause of hypercapnia, is strongly encouraged before increasing the tidal volume above 6 mL/kg predicted bodyweight.

Second, what level of hypercapnia is tolerable? Permitting hypercapnia with the use of lower tidal volumes might mitigate the initial risk of ventilator-induced lung injury and be well tolerated. But it is also associated with a number of detrimental effects such as: facilitating bacterial growth in the lung; inhibiting alveolar wound repair, reabsorption of alveolar fluid, and alveolar cell proliferation; and increasing pulmonary hypertension. 24 The acceptable degree of hypercapnia in a patient will depend in part on any associated metabolic acidosis or haemo dynamic instability. 25 Third, the proposed temporal evolution of the type L and type H subtypes, in contrast to previous reports in patients with ARDS, 26 raises the important question of whether the proposed subtypes merely reflect the natural evolution of ARDS. This issue is particularly relevant in patients with COVID-19-associated ARDS who might have been intubated earlier in the disease course than is usually the case. Comparison of data between reports is difficult because the decision to intubate might have been made at distinctly different timepoints in the course of patients' illness at different centres due to resource limitations. All of this raises the difficult question of the optimal point at which to intubate a given patient, because we know that the window can be narrow and that the consequences of intubating too early or too late could be substantial. 27 Data are n (%) or median (IQR), unless otherwise indicated. ECMO=extracorporeal membrane oxygenation. FiO 2 =fraction of inspired oxygen. HFNC=high-flow nasal cannula. PaO 2 =partial pressure of arterial oxygen. PBW=predicted bodyweight. PEEP=positive end-expiratory pressure. *Some patients received more than one type of respiratory support. †Mean (SD). ‡Denominator is 18 for the group that had invasive mechanical ventilation. §It is not explicitly stated in the manuscript why the denominators are different, although they might represent the group of patients for which these data were collected and available at the time of analysis.

• No high-quality clinical trial evidence addressing optimal timing of intubation in ARDS is available • Intubation might be beneficial in patients with high respiratory drive and at high risk of patient self-inflicted lung injury 13 • Non-invasive ventilation has been associated with worse outcomes when PaO 2 /FiO 2 ratio <150 in ARDS 39 • Detrimental consequences of intubation and invasive ventilation (eg, related to sedation, paralysis, and endotracheal tube complications) might outweigh benefits, especially in patients with mild hypoxaemia and without high respiratory drive or work of breathing; consequences for other patients because of bed and ventilator shortages in the ICU should be considered 

• Higher PEEP might be beneficial in patients with high recruitability, with better gas exchange and reduced risk of ventilator-induced lung injury • Higher PEEP can be harmful in patients with low recruitability, who have hypoxaemia due largely to pulmonary vascular pathology; high PEEP can lead to adverse haemodynamic effects or barotrauma • Improvement in partial pressure of arterial oxygen with increased PEEP can be misleading • Individualise PEEP; 28 consider higher PEEP in patients with evidence of higher potential for recruitment (eg, as suggested by CT scan or recruitment to inflation index 16 ) or with a body habitus or clinical exam that suggests high pleural pressures are likely • Evaluate response to changes in PEEP at the bedside 43 Prone positioning • Prone positioning is associated with improved outcomes in patients with moderate or severe ARDS, with improved ventilation or perfusion matching, more homogeneous distribution of ventilation, and reduced risk of ventilator-induced lung injury 44 • Staffing and resource demands can limit feasibility during surges in case volume • Efficacy and safety of prone positioning in awake, non-intubated patients remain unclear [45] [46] [47] and are being evaluated in clinical trials in patients with COVID-19 (NCT04350723, NCT04347941, NCT04365959)

• In the absence of contraindications, use prone positioning in mechanically ventilated patients with PaO 2 /FiO 2 ratio <150 48

Venovenous ECMO

• Patients can develop refractory hypoxaemia or have mechanics leading to potentially injurious levels of mechanical ventilation, despite optimisation of conventional measures • Staffing and resource demands can limit feasibility during an increase in the number of cases • Consider venovenous ECMO in patients with refractory hypoxaemia or high driving pressures or respiratory acidosis despite conventional lung-protective measures (eg, higher PEEP or prone positioning) 49 ARDS=acute respiratory distress syndrome. ECMO=extracorporeal membrane oxygenation. FiO 2 =fraction of inspired oxygen. ICU=intensive care unit. PaO 2 =partial pressure of arterial oxygen. PBW=predicted bodyweight. PEEP=positive end-expiratory pressure. 

Fourth, the question of what PEEP levels to use is more complex than the previous discussion on the management of tidal volume. Previous data already suggest that the same PEEP should not be applied to all patients with ARDS; 28 individual isation is needed because the response to PEEP differs on the basis of individual respiratory mechanics. The seminal studies of Suter and colleagues 29 and Dantzker and colleagues 30 showed that PEEP can improve hypoxaemia while reducing tissue oxygen delivery. If, in fact, there is a subphenotype in which vascular derangement is the major mechanism for the hypoxaemia (eg, loss of pulmonary vasoconstriction, or pulmonary emboli or thrombi), then increasing PEEP might not improve hypoxaemia. Therefore, PEEP should be targeted to improve oxygen delivery while mitigating the risk of ventilator-induced lung injury and patient selfinflicted lung injury, depending on the clinical context. This titration remains complicated to achieve in patients with ARDS with or without COVID-19.

Nearly a third of patients in the reports by Gattinoni and colleagues 9,10 had severe (proposed type H) ARDS, consistent with previously reported patients with ARDS. 31, 32 In two reports of patients receiving mechanical ventilation for COVID-19-associated ARDS from New York City, NY, USA, 4,5 the median respiratory system compliances were 28 mL/cm H 2 O and 26 mL/cm H 2 O, not unusual for patients with ARDS. Similar values of compliance were reported in two smaller studies from Seattle, WA, USA 33 and Boston, MA, USA 2 (median compliances of 29 mL/cm H 2 O and 35 mL/cm H 2 O, respectively; table 1). These data do not preclude the existence of subphenotypes with high respiratory system compliance. However, they do suggest that, on average, patients with COVID-19-associated ARDS probably have similar respiratory system mechanics to patients with ARDS from other causes and that, for most patients, COVID-19-associated ARDS is, in the end, ARDS. 35 Viewing COVID-19-associated ARDS as a different entity suggests the need to abandon current treatment principles in favour of a new approach. Without robust evidence to the contrary, a new approach should not be considered because of risks of harm. Patients with moderate-to-severe COVID-19-associated ARDS should receive prone positioning and patients with severe ARDS might need venovenous extracorporeal membrane oxygenation, as indicated in international guidelines for ARDS, [36] [37] [38] and as resources permit.

What does all of this mean for how we should ventilate patients with ARDS due to COVID-19? Table 2 outlines our recom mendations to help set ventilatory strategy based on underlying pulmonary pathophysiology in patients with COVID-19. We suggest that the focus should be on using our existing ARDS ventilation evidence base to guide therapy, [36] [37] [38] while adjusting as necessary based on individual patient-specific issues. For example, apparent heterogeneity might be due to the fact that there is a distinct underlying pathological process contributing to hypoxaemia in some patients, which requires nonventilatory therapy (eg, increased prevalence of thromboembolic compli cations in COVID-19). 50 Of course, if such a patient requires mechanical ventilation, it is not appropriate to use a ventilatory strategy that largely targets fluid-filled, atelectatic lungs. Clinicians should adapt their manage ment plan to each patient, accounting for their individual characteristics, as well as their preferences and values-the advice is not a one-size-fits-all approach.

In the midst of a pandemic, we can serve our patients best by organising and participating in collaborative research programmes to facilitate learning while caring for patients, to better inform the management of critically ill patients with COVID-19. 51, 52 Particularly in this era of social media, we need to balance anecdotes and case reports 53 with the scientific rigour needed to support any necessary shifts in the current paradigm of patient management. 54 Until such new data emerge, we should continue to manage patients with ARDS from COVID-19 pneumonia with our current evidence-based practices, 7 informed by bedside physiology.

EF and DB conceived the manuscript. EF conducted the search and drafted the manuscript. All authors critically revised the manuscript and accepted the final version for publication.

EF is supported by a New Investigator Award from the Canadian Institutes of Health Research, and receives personal fees from ALung Technologies, Fresenius Medical Care, and MC3 Cardiopulmonary, all outside of the submitted work. JRB receives grants from the US National Institutes of Health (K23-HL133489, R21-HL145506), and reports personal fees from Hamilton Medical and Sedana Medical, outside of the submitted work. LB's laboratory has received research grants and equipment form Medtronic Covidien, Fisher Paykel, Air Liquide, Philips, and Sentec; and has a patent with General Electric. CSC is supported through grants from the National Institutes of Health (HL140026); she also receives research support from Roche and Genentech and has previously received research support from Bayer; she reports personal fees from Quark and Gen1e, outside of the submitted work. NDF reports personal fees from Getinge and Xenios, outside of the

We searched PubMed for articles published in English between Jan 1, 1950, and June 8, 2020, using combinations of the terms "coronavirus", "COVID-19", "SARS-CoV-2", "nCoV", "acute respiratory distress syndrome", "mechanical ventilation", "critical care", and "intensive care". We determined which articles were relevant on the basis of the article's title and citations. We also found articles through searches of the authors' personal files and reviewed relevant references cited in retrieved articles. The final reference list was generated on the basis of relevance to the topics covered in this Viewpoint.

Capturing the multifactorial nature of ARDS-'two-hit' approach to model murine acute lung injury

Fifty years of research in ARDS. spontaneous breathing during mechanical ventilation. Risks, Mechanisms, and Management

Impact of respiratory rate and dead space in the current era of lung protective mechanical ventilation

Bench test evaluation of volume delivered by modern ICU ventilators during volume-controlled ventilation

The role of hypercapnia in acute respiratory failure

Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome

Stability of ARDS subphenotypes over time in two randomised controlled trials

Mechanical ventilation in COVID-19: interpreting the current epidemiology

Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis

Optimum end-expiratory airway pressure in patients with acute pulmonary failure

Depression of cardiac output is a mechanism of shunt reduction in the therapy of acute respiratory failure

Acute respiratory distress syndrome: the Berlin definition

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

Covid-19 in critically ill patients in the seattle region -case series

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy

Postmortem examination of patients with COVID-19

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

Guidelines on the management of acute respiratory distress syndrome

Formal guidelines: management of acute respiratory distress syndrome

Noninvasive ventilation of patients with acute respiratory distress syndrome. Insights from the LUNG SAFE study

Basing respiratory management of coronavirus on physiological principles

Inspiratory effort assessment by esophageal manometry early predicts noninvasive ventilation outcome in de novo respiratory failure: a pilot study

Driving pressure and survival in the acute respiratory distress syndrome

Setting positive end-expiratory pressure in acute respiratory distress syndrome

Prone positioning in severe acute respiratory distress syndrome

Use of prone positioning in nonintubated patients with COVID-19 and hypoxemic acute respiratory failure

Respiratory parameters in patients with COVID-19 after using noninvasive ventilation in the prone position outside the intensive care unit

Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study

Prone position for acute respiratory distress syndrome. A systematic review and meta-analysis

ECMO for ARDS: from salvage to standard of care?

Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study

Optimizing the trade-off between learning and doing in a pandemic

A call for rational intensive care in the era of COVID-19

Misinformation during the coronavirus disease 2019 Outbreak

Critical illness in patients with COVID-19: mounting an effective clinical and research response