Articles That May Change Your Practice: Novel Strategies for Coronavirus Disease 2019 Respiratory Failure

      On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, with the worldwide spread of this virus representing a threat to global health. A minority of those infected with COVID-19 progress to pneumonia requiring hospitalization, with some progressing further to acute hypoxemic respiratory failure (AHRF). The pandemic has prompted the need for clarity on how to support the oxygenation and ventilation needs of those with AHRF caused by COVID-19. Evidence early in the pandemic suggested those who received invasive mechanical ventilatory support had higher mortality, prompting the search for possible alternatives or adjuncts to mitigate the risk of ventilator-induced lung injury.
      A prior “article” described the use of the prone position for those with severe ARDS as a proven adjunct to improve oxygenation and ventilation and reduce mortality. The rapidly evolving evidence in the management of the patient with AHRF caused by COVID-19 has prompted a number of authors to develop novel options in the management of this challenging patient population. What follows is a summary of recent studies that may be beneficial to those with COVID-19–related AHRF and can be adopted for use in the transport setting.
      Ferreyro BL, Angriman F, Munshi L, et al. Association of noninvasive oxygenation strategies with all-cause mortality in adults with acute hypoxemic respiratory failure: a systematic review and meta-analysis. JAMA. doi:10.1001/jama.2020.9524, accessed June 27, 2020.
      The authors of this network meta-analysis evaluated the association of noninvasive oxygenation strategies with outcomes in adults with AHRF. The authors conducted a systematic literature search through April 2020 to identify randomized controlled trials of adult patients with AHRF, comparing high-flow nasal cannula (HFNC), face mask noninvasive ventilation (NIV), helmet NIV, or standard oxygen therapy and evaluating 1 or both of the 2 outcomes of mortality or tracheal intubation. The concept of a “network meta-analysis” uses evidence from clinical trials that share common treatment methods to generate indirect evidence to rank order them.
      The authors included 25 studies and 3,804 adult patients with AHRF. They found that compared with standard oxygen therapy, the 3 other noninvasive ventilation methods were associated with a lower risk of tracheal intubation: face mask NIV (14 trials, 1,725 patients; relative risk [RR] = 0.26), helmet NIV (3 trials, 330 patients; RR = 0.26), and HFNC (5 trials, 1,479 patients; RR = 0.76). Both forms of NIV were also associated with a lower risk of death (face mask: RR = 0.83 and helmet: RR = 0.40). The authors concluded that in adult patients with AHRF, treatment with noninvasive oxygenation strategies compared with standard oxygen therapy was associated with a lower risk of death. They noted that further research is needed to better understand the relative benefits of each strategy studied.
      Although the findings suggest the potential benefits of NIV, the sensitivity analyses reveal subtleties in the authors’ findings. If patients with severe hypoxemia (PaO2:fraction of inspired oxygen ratios ≤ 200) in whom NIV is known to have benefits (eg, patients with chronic obstructive pulmonary disease and congestive heart failure) are excluded, there are no mortality benefits to face mask NIV compared with standard oxygen therapy. The same is not true in the association between helmet NIV and intubation or mortality, suggesting the interface by which NIV is applied may be a factor in how NIV may be beneficial in this those with AHRF. Nevertheless, the data suggest it may be reasonable to not commit some patients to invasive mechanical ventilation and its potential complications. A trial of HFNC may be considered for the patient who does not respond to positive end-expiratory pressure (PEEP) or the use of some form of NIV if the patient is PEEP responsive but has ongoing hypoxemia. What the authors’ findings demonstrate is that a single approach to COVID-19–related AHRF is inappropriate, with multiple options needed to manage the heterogeneity present in this diverse patient population.
      Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med. doi:10.1007/s00134-020-06033-2, accessed June 27, 2020.
      The Surviving Sepsis Campaign panel recommends that mechanically ventilated patients with COVID-19 should be managed similarly to other patients with acute respiratory failure. However, these authors found that ventilated patients with COVID-19 in Northern Italy did not meet the traditional ARDS definition, with many having severe hypoxemia associated with near normal respiratory system compliance. This is a feature rarely seen with severe ARDS.
      Based on their observations, the authors hypothesized that different COVID-19 patterns are found at presentation depending on 3 factors: 1) the severity of infection, the host response, the physiological reserve, and comorbidities; 2) the ventilatory responsiveness of the patient to hypoxemia; and 3) the time elapsed between the onset of disease and presentation to hospital. The interaction between these factors leads to 2 clinical phenotypes: 1) “type L,” with low elastance (high compliance), low ventilation-to-perfusion ratios, and low recruitability, and 2) “type H,” with high elastance (low compliance), high right-to-left shunt, and high recruitability. Given this hypothesis, the respiratory treatment to each type should be different.
      The type L patient typically responds well to simple maneuvers to increased inspired oxygen, reversing hypoxemia. The authors propose options such as HFNC, continuous positive airway pressure, or NIV. Success is noted with decreased work of breathing or inspiratory effort. However, evidence of increased work of breathing or inspiratory effort should prompt intubation to prevent lung injury. Once intubated, the type L patient can be ventilated with tidal volumes greater than 6 mL/kg thanks to high compliance without the risk of ventilator-induced lung injury. Excessive PEEP (> 8-10 cm H2O) should be avoided given the fact that lung recruitability is low. Type H patients should be treated as severe ARDS, with higher PEEP, prone positioning, and consideration of extracorporeal support.
      The authors based their types on the observation of clinical cases and consensus among colleagues; yet, their hypothesis is plausible. COVID-19 infection does not manifest itself with the same pathophysiological pattern in each patient, and there is currently no clear explanation for why some patients respond to traditional therapies used for patients with ARDS-like AHRF, whereas other patients do not respond to these same therapies. Recognition of these differences may be key in selecting the appropriate ventilation strategies given the diversity within the COVID-19 patient population.
      Henry BM, Lippi G. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): pooled analysis of early reports. J Crit Care. 2020;58:27-28.
      Severe COVID-19 infection can induce ARDS, leading to AHRF where extracorporeal membrane oxygenation (ECMO) may be considered as a rescue therapy. ECMO has been used in other viral diseases leading to AHRF, but little is known about its impact with COVID-19. The authors analyzed the early COVID-19 epidemiologic studies to evaluate the impact of ECMO on mortality.
      Data on the number of patients with ARDS and treated with ECMO and the mortality rate for each were determined. The obtained data were pooled using a random effects model, with estimation of the odds ratio and its 95% confidence interval for mortality in patients with or without ECMO support. Four studies, with 562 COVID-19 patients, were included in the pooled analysis. Of these, 234 (41.6%) patients developed ARDS, and 17 (7.2%) underwent ECMO. The mortality rate was 70.9% in patients receiving conventional therapy and 94.1% in patients undergoing ECMO. The pooled odds of mortality in ECMO versus conventional therapy was not significantly different (odds ratio = 2.00; 95% confidence interval, 0.49-8.16).
      Based on their results, the authors suggest that ECMO is neither harmful nor beneficial in COVID-19 patients progressing to ARDS. However, patients receiving ECMO are likely to be more critically ill, and the sample size of ECMO patients was limited and considerably small. The authors of this limited summary of existing data encourage others to recruit their patients into clinical trials or clinical registries so that more informative data can be obtained.
      Although ECMO may serve as an effective short-term rescue therapy in patients with severe acute respiratory distress syndrome and refractory hypoxemia, there is no conclusive evidence that ECMO is responsible for better clinical outcomes in patients who received ECMO than in patients who did not receive ECMO. This finding is in keeping with the National Institutes of Health's latest recommendation regarding ECMO in COVID-19.

      COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 treatment guidelines. Bethesda, MD: National Institutes of Health. Available at: Accessed June 27, 2020.

      COVID-19 is a novel viral disease with a variable and incompletely described clinical course. There are no proven effective specific treatment strategies, and the safety and efficacy of some care strategies remain unclear. In addition, the risk-benefit balance for current therapies is unclear. Those who develop severe infections and require critical care have a high mortality. Although traditional therapies for AHRF include mechanical ventilation, there exists heterogeneity in the disease that should prompt careful attention to how ventilation can be fine-tuned to the patient's pattern of disease. There also exist novel approaches that may prevent the need for invasive ventilation or the need for highly invasive, aggressive therapies (such as ECMO) when traditional approaches fail. What remains is the need for better evidence to help guide management of the critically ill COVID-19 patient.


      1. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 treatment guidelines. Bethesda, MD: National Institutes of Health. Available at: Accessed June 27, 2020.


      Russell D. MacDonald, MD, MPH, FCFP, FRCPC, is the medical director at Ornge Transport Medicine; medical director at Toronto Paramedic Services; a professor in the Faculty of Medicine at the University of Toronto; and an attending staff member at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. He can be reached at [email protected]