Implications of Early Respiratory Support Strategies on Disease Progression in Critical COVID-19

A Matched Subanalysis of the Prospective RISC-19-ICU Cohort

Pedro D. Wendel Garcia; Hernán Aguirre-Bermeo; Philipp K. Buehler; Mario Alfaro-Farias; Bernd Yuen; Sascha David; Thomas Tschoellitsch; Tobias Wengenmayer; Anita Korsos; Alberto Fogagnolo; Gian-Reto Kleger; Maddalena A. Wu; Riccardo Colombo; Fabrizio Turrini; Antonella Potalivo; Emanuele Rezoagli; Raquel Rodríguez-Garcia; Pedro Castro; Arantxa Lander-Azcona; Maria C. Martín-Delgado; Herminia Lozano-Gómez; Rolf Ensner; Marc P. Michot; Nadine Gehring; Peter Schott; Martin Siegemund; Lukas Merki; Jan Wiegand; Marie M. Jeitziner; Marcus Laube; Petra Salomon; Frank Hillgaertner; Alexander Dullenkopf; Hatem Ksouri; Sara Cereghetti; Serge Grazioli; Christian Bürkle; Julien Marrel; Isabelle Fleisch; Marie-Helene Perez; Anja Baltussen Weber; Samuele Ceruti; Katharina Marquardt; Tobias Hübner; Hermann Redecker; Michael Studhalter; Michael Stephan; Daniela Selz; Urs Pietsch; Anette Ristic; Antje Heise; Friederike Meyer zu Bentrup; Marilene Franchitti Laurent; Patricia Fodor; Tomislav Gaspert; Christoph Haberthuer; Elif Colak; Dorothea M. Heuberger; Thierry Fumeaux; Jonathan Montomoli; Philippe Guerci; Reto A. Schuepbach; Matthias P. Hilty; Ferran Roche-Campoon


Crit Care. 2021;25(175) 

In This Article


In this subpopulation of a prospective, critically ill COVID-19 cohort during the first peak of the pandemic, 70% of patients were intubated and mechanically ventilated on the day of admission to the ICU. Use of SOT, HFNC and NIV was limited to 10% of the patients, respectively. The incidence of intubation and IMV in patients initially supported with HFNC and NIV was 12–15% lower than in patients with SOT. Compared to the other respiratory support strategies, NIV was associated with higher ICU mortality rates. A prognostic score considering age, respiratory rate and diabetes mellitus at ICU admission performed moderately in identifying HFNC and NIV patients with increased mortalities after delayed intubation and may help to discern patients who are at lower risk for increased ICU mortality during a HFNC or NIV trial.

International guidelines in place at the onset of the pandemic recommended early IMV for critically ill COVID-19 patients; HFNC and NIV were not recommended, mainly due to safety concerns related to the production of aerosols, which could jeopardize the health of hospital staff.[23] Notwithstanding those recommendations, the proportion of patients ventilated with noninvasive respiratory support strategies in this study was comparable to that described in the setting of the LUNGSAFE study, in which 15% of patients received noninvasive respiratory support.[24] Numerous COVID-19 cohort studies conducted in Europe and the United States have described similar proportions of noninvasive support measures.[7,18,25,26,27]

Although contradictory results have been reported regarding the value of HFNC to avoid intubation,[20,28] this technique has been shown to reduce mortality rates in cases of acute hypoxemic failure,[20] thus finding its place in international respiratory support recommendations.[29] In critically ill COVID-19 patients, other studies have shown—consistent with the data presented in our study—lower intubation and IMV rates, but without any reduction in ICU mortality.[30] The initially postulated risk of virus aerosolisation can probably be minimized by using conventional type I surgical masks over the nasal cannula.[31] By contrast, NIV remains controversial in the treatment of ARDS, a debate that is evident in the absence of unambiguous recommendations in clinical guidelines.[32] Although the use of NIV has been correlated with a reduced need for IMV and lower mortality rates in mild ARDS,[33] the available evidence in severer expressions of ARDS indicates higher mortality rates.[20,24,34] In ARDS of viral etiology especially, the use of NIV is associated with high failure rates (up to 85%).[35]

Patients may—in an attempt to maintain homeostasis—initiate a vicious cycle through vigorous breathing efforts, exacerbating their lungs pathology by means of extremely elevated transpulmonary forces, leading to excessive stress and increased pulmonary inflammation.[36,37] In our study, this patient-induced biotrauma might be one of the factors explaining the pronounced CRP dynamics in the noninvasively supported groups as opposed to those receiving early IMV.[38] Consequently, the prolonged use of noninvasive ventilation, delaying intubation in patients who ultimate fail and thus require IMV, has been associated with higher mortality rates in ARDS,[39–43] as well as in critically ill COVID-19 patients.[44–46] The excess mortality observed in patients treated with NIV in this study might thus be explained by the longer period of harmful spontaneous breathing in patients failing NIV therapy, exacerbated by an increased respiratory rate and disproportionate tidal volumes induced by NIV therapy.[24,47]

If faced with a choice, physicians will intuitively prioritize avoidance of intubation and IMV, provided that this strategy does not imply any increase in mortality risk. Thus, the data presented in this study suggests that the best strategy appears to be an initial closely monitored HFNC trial with thorough assessment of clinical improvement, followed by proactive intubation and IMV in patients with a high risk of failure and mortality. The use of prognostic scores, such as the one exemplified in this study, may support clinical decision making to differentiate between patients who are treatable with noninvasive respiratory support strategies from those likely to have a worse outcome if intubation is delayed.[48,49] To which degree static scores or dynamic scores taking advantage of the temporal assessment of patients, such as the ROX score, may improve ICU outcome nevertheless remains to be assessed.[18,49]

The present study has several limitations. First, the lack of randomization between respiratory support groups and it being a retrospective analysis, lead to many possible outcome modifying biases, such as the inability to assess the influence of human and material resources on treatment outcomes. Nonetheless, the lack of randomization was minimized through the application of propensity score matching to numerous variables at ICU admission, thus ensuring the comparability of the study groups in terms of the most objectively assessable patient characteristics. Second, the lack of a universal respiratory support protocol implies a high level of center- and clinician-related variability and prevents a mechanistic reasoning behind the described effects. On the other hand, the observational nature of this study potentially reflects the clinicians' expertise more than a protocolized, randomized four-arm study, thereby reducing bias caused by variations in clinical experience or disfavour of a specific type of respiratory support strategy. Consequently the present study offers a representative view of the respiratory support strategies employed during the first peak of the pandemic. Third, some of the crude mortality trends observed in this study lacked statistical significance. However, given the moderate numbers of patients in each ventilation strategy, the large number of centers, the lack of a centralized protocol, and the statistical significance in the adjusted analyses, the observed signals provide a certain robustness for clinical decision-making and the development of hypotheses for future confirmatory, controlled studies. Fourth, the available registry data did not allow to determine the time on IMV for all patients, thus preventing an analysis of ventilator-free time. Fifth, the data underlying the prognostic score analysis were assessed on a daily basis, thus diminishing the prognostic capacity for scores, which require higher temporal resolution. Finally, the here proposed prognostic score has not been validated in other NIV and HFNC populations, thus caution is advised when employing it in a clinical framework; external validation is warranted.