Is COVID-19 ARDS? What about lung compliance?

COVID-19: Keeping the baby in the bath (Part 3)

All models are wrong, but some are useful”

George Box 1976

Another “paradigm shift” is the argument that acute respiratory distress syndrome (ARDS) is now newly broken, that COVID-19 is not ARDS, and that established ARDS therapies are inappropriate for COVID-19 patients or may cause harm.

ARDS is an acute syndrome of hypoxia (P/F ratio <300) and bilateral lung opacities on imaging not fully explained by a cardiogenic cause or fluid overload (ARDS Definition Task Force, 2012). ARDS is not a disease. ARDS has always been a heterogeneous mix of different diseases. It would be surprising if the pathogenesis and progression of ARDS did not vary, at least in the beginning, considering how different “direct” causes like bacterial pneumonia and “indirect” causes such as pancreatitis are. Whether ARDS represents a “final common pathway” of lung injury, iatrogenic insults (such as fluid overload or ventilator-induced lung injury (VILI)), or host responses, is debatable. Diffuse alveolar damage (DAD) is often regarded as the key pathological finding in ARDS, and is being seen in autopsies of COVID-19 patients (Barton et al, 2020; Tian et al, 2020). However, others argue that DAD is not a universal feature of COVID-19 pneumonia at autopsy (Magro et al, 2020). So does this mean that COVID-19 is not ARDS? We don’t think so, because even before the COVID-19 pandemic, less than 50% of all ARDS patients had DAD at autopsy (Thille et al, 2013). ARDS has always been a construct in the minds of clinicians and researchers. It exists not because it is perfect, but because it has utility. It has utility for clinicians as it gives us a frame of reference for categorising patients, providing appropriate therapies, and prognosticating. It has utility for research as it allows otherwise heterogeneous patient groups to be studied in adequately powered clinical trials and provides a touchstone for new concepts and discoveries. 

So, do COVID-19 patients have ARDS? They do if they meet the criteria of the Berlin definition (ARDS Definition Task Force, 2012). However, of interest, at least a subset of COVID-19 pneumonia patients have preserved lung compliance and present with “silent hypoxaemia”. An L-phenotype has been proposed by Gatinoni and colleagues in an interesting article that stimulates thought and suggests a framework for how to manage COVID-19 patients (Gattinoni et al, 2020). However, there are few patient data, and certainly no experimental evidence, to support this model and the proposed implications for patient management. Furthermore, some patients with “silent hypoxia” and good lung compliance improve their oxygenation with prone positioning (including when performed awake). This doesn’t quite fit the expected response of the L-phenotype in this model, which implies that L patients should be less prone-responsive. Other reports suggest that patients with COVID-19 respiratory failure exhibit similar gas exchange, respiratory system mechanics, and response to prone ventilation as prior large cohorts of patients with ARDS (Ziehr et al, 2020). It is plausible that, at least in the early stages, COVID-19 patients may have different ventilator requirements to other ARDS patients. However, until there is compelling scientific evidence, standard approaches to ventilation should apply.

Furthermore, the concept of different ARDS phenotypes is not new (Wilson & Calfee, 2020). Approaches to phenotyping include physiological (e.g. stratification by P/F ratio), clinical (e.g. baseline clinical characteristics, time course, and radiographic patterns) and biologic (e.g. inflammatory markers). Calfee and colleagues, using a combined clinical and biologic approach, have previously performed a number of secondary analyses of major ARDS randomised controlled trials that identify two distinct subphenotypes of ARDS, namely the hyperinflammatory and hypoinflammatory subphenotypes (Calfee et al, 2014). Their characteristics are shown in table 1. Furthermore these subphenotypes appear stable over the first 3 days of intensive care; in other words, patients do not switch phenotypes over this time period (Delucchi et al, 2018). While such analyses are primarily hypothesis-generating and require further research, they are based on substantially more robust data than any proposed COVID-19 phenotypes and demonstrate that ARDS has never been a homogeneous entity. It is critical to note, however, that the phenotypes rigorously derived by Calfee and colleagues are not the same as the proposed COVID-19 L/H phenotypes.

Table 1. Features of the hyperinflammatory and hypoinflammatory ARDS phenotypes described by Calfee and colleagues. Sources are identified in the table.

CharacteristicHyper-
inflammatory
phenotype
Hypo-
inflammatory
phenotype
Source
Plasma concentrations
of inflammatory biomarkers
HigherLower1
Vasopressor useHigherLower
Serum bicarbonateLowerHigher
Sepsis prevalenceHigherLower
MortalityHigherLower
Beneficial PEEP settingsHigherLower
Beneficial fluid strategyMore liberalMore conservative2
Beneficial response to statinsMore likelyLess likely3

Sources 1: Calfee et al, 2014 (ARMA & ALVEOLI trials); 2: Famous et al, 2017 (FACTT trial); 3: Calfee et al, 2018 (HARP2 trial)

Now, let us return to our understanding of ARDS and consider lung compliance. It is a misconception that ARDS means poor lung compliance. Lung compliance is not part of the 2012 Berlin definition of ARDS (ARDS Definition Task Force, 2012) as it was not found to be helpful, and wasn’t part of the 1994 AECC definition either (Bernard et al, 1994). In the original 1967 description of ARDS by Ashbaugh and colleagues, the 12 patients studied did have poor lung compliance, all being less than 20 mL/cmH20 (Ashbaugh et al, 1967). However, this is a very small sample of patients and in the major ARDS trials that inform the standard management of ARDS, ARDS patients typically have lung compliances that vary across a wide spectrum. For instance, analysis of data from the landmark ARDSNet ARMA trial (ARDSNet, 2000) shows that a quarter of the ARDS patients randomised to 6 mL/kg PBW tidal volumes had plateau pressures in the 10 to 20 cmH20 range, consistent with high lung compliance (Hager et al, 2005) (see Figure 1). Concerningly, this study also found no clear “cut off” suggesting a safe plateau pressure. Instead, the higher the plateau pressure measured, the higher mortality, which has implications for allowing high tidal volumes in ARDS/ COVID-19 patients.

On the other hand, one of the explanations for the mortality benefit of protective lung ventilation in the ARDSNet ARMA trial  (ARDSNet, 2000) is the phenomenon of practice misalignment, which occurs when randomization disrupts the normal relationship between clinically important characteristics and therapy titration (Deans et al, 2010). This re-analysis showed that in patients with more compliant lungs (compliance > 0.6 mL/cm H2O/kg PBW), decreasing tidal volume increased mortality compared to increasing tidal volume (37% vs. 21%), despite the overall study finding of a mortality benefit from low tidal volumes (Deans et al, 2010). Our conclusion is that higher tidal volumes in ARDS patients with high lung compliance are probably not (very) harmful. The problem is that lung compliance can change (e.g. through progression of disease) and then harm is likely from high tidal volumes and ventilator induced lung injury (VILI), or even – though controversial – patient self-inflicted lung injury (P-SILI). At the same time, there is no trivial way to prevent P-SILI if it exists; all strategies involve changes in sedation and prolonged neuromuscular blockade that themselves have risks.

Another group of patients with higher lung compliance are mechanically ventilated patients that do not have ARDS. Protective ventilation with lower tidal volumes has been associated with better clinical outcomes for patients without ARDS in systematic reviews (Serpa Neto et al, 2012). More recently though, the PREVENT trial found no benefit of 6 mL/kg PBW tidal volumes compared with 9 mL/kg PBW tidal volumes in critically ill non-ARDS patients, although there was no signal of harm either (Writing Group for the PReVENT Investigators et al, 2018). 

Once again, this brings us back to the need for highly trained, experienced, clinicians involved in bedside care. Care should be standardised where possible, but always optimised to the patient actually in the bed. We think the ARDSNet protective lung ventilation approach (ARDSNET, 2000) is a useful starting point for the management of any mechanically ventilated ARDS patient, including patients with COVID-19, especially when expert clinicians are not available to optimise ventilation further. It is unlikely to harm patients, and is more likely to provide benefit. However, when patients are “straying from the path” – and if they are critically ill, they almost always will – they need experts to monitor plateau pressures, static compliance, driving pressures, positive end expiratory pressure (PEEP), hemodynamic responses, sedation scores, and so on, to optimise the interventions being provided.

Mortality difference by quartile of Day 1 Pplat for patients in the ARDSNet ARMA trial

Figure 1. Mortality difference by quartile of Day 1 Pplat for patients in the ARDSNet ARMA trial (Hager et al, 2005). The range of Pplat levels in cmH20 and the number of patients (n) is detailed in each bar of the graph. ARR = absolute risk reduction; CI = confidence interval. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718413/

Next, we will discuss COVID-19: “To PEEP, or not to PEEP”?


Further reading

Please refer to these pages from the LITFL Critical Care Compendium for overviews of the key concepts discussed in this blogpost:

COVID-19: Keeping the baby in the bath series

  1. COVID-19: Keeping the baby in the bath (Introduction)
  2. “Silent hypoxaemia” and COVID-19 intubation
  3. Is COVID-19 ARDS? What about lung compliance?
  4. COVID-19: “To PEEP, or not to PEEP”?
  5. MacGyverism and “hacking COVID-19”
  6. Novel drug therapies and COVID-19 clinical trials
  7. Overcoming uncertainty in the Age of COVID-19

References

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

Critical care physician and health services researcher bringing the tools of social science and outcomes research to improve the care of patients with critical illnesses. I practice as an intensivist at the University of Michigan’s and the Ann Arbor VA's Critical Care Medicine units, where we work to bring the latest science and the best of clinical practice to patients  | iwashyna-lab  | @iwashyna |

Intensivist in Wellington, New Zealand. Started out in ED, but now feels physically ill whenever he steps foot on the front line. Clinical researcher, kite-surfer  | @DogICUma |

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