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


Baseline and Matching

Between March 13 and September 6, 2020, 1421 patients were included into the RISC-19-ICU registry. Of these 877 met the inclusion criteria at ICU admission (Figure 1). During the first 24 hours of ICU stay, 618 (70%) patients had been intubated and were receiving mechanical ventilation; of the remaining 259 patients, 85 (10%) were being treated with SOT, 87 (10%) with HFNC and 87 (10%) with NIV. Compared to the other three groups, patients under IMV presented higher severity scores, including increased need for vasoactive medication (Additional file 1: e-Table 1).

Figure 1.

Study flowchart

To allow for an unbiased assessment of respiratory strategies, a comparable population of IMV patients was extracted by propensity score matching against the other three groups based on 22 clinical, severity and laboratory parameters at admission (Additional file 1: e-Figure 1). After the matching process, 351 patients (85 SOT, 87 HFNC, 87 NIV and 92 IMV) were included in the final analysis. Matching quality was considered excellent, as reflected by an SMD ≤ 0.1 for all matching variables, excepting SAPS II (SMD = 0.13), bilirubin (SMD = 0.12), and mean arterial pressure (SMD = 0.11), in which the mean distributional difference between groups was nonetheless negligibly small (Additional file 1: e-Figure 1).

Characteristics of the Overall Population

After the matching process, the baseline characteristics across all four groups at ICU admission were similar (Table 1, Additional file 1: e-Table 2). Patients were treated at 49 different ICUs, all of which followed different ventilation approaches. Until IMV was required or the patient could be weaned, no obvious crossovers between ventilation therapies seem to have been present (Additional file 1: e-Table 3). Further, there was no obvious temporal relationship between the period of the pandemic during which patients were admitted to the ICU and the use of a specific respiratory support strategy or mortality rate (Additional file 1: e-Figure 2 and e-Figure 3).

Of the patients who were not intubated and invasively ventilated on ICU admission, 55% required intubation and IMV between the first and second day of their ICU stay. A smaller proportion of patients (p = 0.025) in the HFNC (52%) and NIV (49%) groups progressed toward delayed IMV, compared to those in the SOT group (64%) (Figure 2a).

Figure 2.

Kaplan–Meier curves for the a incidence of intubation and b intensive care unit mortality stratified by respiratory support strategy at intensive care unit admission. Forest plots reporting crude and multivariable adjusted (*italic) hazard ratios with 95% confidence intervals are displayed below the Kaplan–Meier curves for each respiratory support strategy. p values for between groups survival curve difference were calculated by means of the log-rank test

Overall, the ICU mortality rate was higher (p = 0.016) in patients initially ventilated with NIV than in the other groups (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%) (Figure 2b). In patients who did not progress toward intubation, the ICU mortality rates were as follows: 10% in the SOT, 7% in the HFNC, and 36% in the NIV group (Additional file 1: e-Table 4). The amount of therapy withdrawals was similar between groups (p = 0.408).

Characteristics of Patients Progressing Toward Intubation and Invasive Mechanical Ventilation

The median duration of the in-hospital stay until intubation was longer (p<0.001) in the NIV group (4 [IQR, 3–7] days) compared to the other three groups (SOT: 3 [1–5] days, HFNC: 3 [2–6] days, IMV: 1 [0–3] days) (Table 2). At the day of intubation, patients progressing toward mechanical ventilation had an overall median partial pressure of arterial oxygen to inspired fraction of oxygen (P/F) ratio of 137 [95–179] mmHg, with no variations between groups (p = 0.256) (Table 2). In all groups the initial ventilator settings and static compliance were similar. The use of corticosteroids and prone positioning were also comparable between groups. Patients under early IMV experienced less pronounced C-reactive protein (CRP) dynamics, with a lower proportional peak increase and a larger proportional decrease over the initial 7 days of ICU stay compared to patients in the noninvasive respiratory support groups (p = 0.02) (Additional file 1: e-Figure 4; Additional file 1: e-Table 5). Patients who received initial NIV therapy had a greater need for vasopressors during the ICU stay (p = 0.029).

ICU mortality in patients requiring IMV was 28% (65) with a median length of stay of 16 [9–26] days. Patients initially treated with NIV who progressed toward IMV presented a trend (p = 0.073) toward higher ICU mortality (37%) as opposed to patients in the other groups (SOT: 21%, HFNC: 31%) when compared to the early IMV group (25%) (Figure 3a). Patients who were initially treated with HFNC and NIV, and later required IMV, had longer (p = 0.018) ICU lengths of stay than patients under initial SOT when compared to early IMV (Figure 3b).

Figure 3.

Kaplan–Meier curves for a intensive care unit mortality and b intensive care unit length of stay stratified by respiratory support strategy at intensive care unit admission (only intubated patients). Forest plots reporting crude and multivariable adjusted (*italic) hazard ratios with 95% confidence intervals are displayed below the Kaplan–Meier curves for each respiratory support strategy. p values for between groups survival curve difference were calculated by means of the log-rank test

After multivariable adjustment for covariates, NIV was independently associated with a higher overall ICU mortality (adjusted HR 2.67, 95% CI [1.14–6.25]) as well as with an increased ICU mortality rate (adjusted HR 2.96, 95% CI [1.07–8.23]) and a prolonged length of ICU stay (adjusted HR 0.57, 95% CI [0.33–0.97]) in patients failing NIV and requiring delayed IMV, as opposed to the other respiratory support strategies (Figures 2b, 3a, b; Additional file 1: e-Figures 5–8).

Predictors of Mortality in Patients Initially Treated With HFNC or NIV Patients With Delayed Intubation and Invasive Mechanical Ventilation

To identify the HFNC and NIV patients with the worst ICU outcomes after progression to intubation and IMV, an iterative, multivariable GLM analysis was performed. The model identified age, respiratory rate and diagnosis of diabetes mellitus as independent prognostic factors of mortality (Additional file 1: e-Table 6; Additional file 1: e-Figure 9A). A prognostic score, based on the previously described model, presented a moderate prognostic ability (area under the receiver operating curve: 0.75, 95% CI [0.63–0.85]) for ICU mortality in these patients. This prognostic score was superior to all other tested prognostic scores at ICU admission (Additional file 1: e-Figure 9B; Additional file 1: e-Table 9). The Kaplan–Meier estimator presented in Additional file 1: e-Figure 9C shows the excellent (p<0.0001) dichotomizing capacity of a prognostic score of 134 points (Positive Likelihood Ratio for Mortality: 2.4) to identify patients with a higher risk of ICU mortality.