Phenotypes of Patients with COVID-19 Who Have a Positive Clinical Response to Helmet Noninvasive Ventilation

Abstract

To the Editor: Recently, we published the results of a randomized trial (HENIVOT) comparing helmet noninvasive ventilation followed by high-flow nasal oxygen versus high-flow nasal oxygen alone in patients with coronavirus disease (COVID-19) and moderate to severe respiratory failure (PaO2/FiO2 < 200 mm Hg and PaCO2 ⩾ 45 mm Hg). Results showed no significant intergroup difference in the primary outcome (28-day respiratory support-free days), but lower intubation rate and increased 28-day invasive ventilation-free days in the helmet group (1). The accompanying editorial addressed the relevant issue of personalizing treatments by identifying subphenotypes of patients who may best benefit from each technique (2). We performed post hocanalyses to establish whether any bedside available parameter before randomization (PaO2/FiO2, PaCO2, respiratory rate, visual analog scale [VAS] dyspnea, PaO2/[FiO2 × respiratory rate], SpO2/[FiO2 × respiratory rate] (3), PaO2/[FiO2 × VAS dyspnea]) could help identify subgroups of patients who could most benefit from the interventions of the trial. The parameters that were found to identify subgroups of patients with different response to treatments were presence of hypocapnia and PaO2/(FiO2 × VAS dyspnea) < 30 before randomization. In these post hocanalyses, we report study outcomes in the two groups after classifying patients according to 1) whether they were normo- or hypocapnic; and 2) whether their PaO2/(FiO2 × VAS dyspnea) was less than 30 or at 30 or more. A total of 109 patients admitted to four ICUs in Italy with COVID-19 and moderate to severe hypoxemic respiratory failure (PaO2/FiO2 ⩽ 200) were randomized to receive 48-hour continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure 10–12 cm H2O and pressure support 10–12 cm H2O) eventually followed by high-flow nasal oxygen, or high-flow nasal oxygen alone (flow, 60 L/min). Full details of study protocol are provided elsewhere (clinicaltrials.gov NCT04502576) (1). The study was approved by the ethics committee of all centers. In these post hocanalyses, intergroup differences in study outcomes were analyzed in the subgroups of patients exhibiting 1) PaCO2less than 35mm Hg or 35mm Hg or more; and 2) PaO2/(FiO2 × VAS dyspnea) < 30 or ⩾30 (median of the cohort). PaO2/FiO2, PaCO2, and VAS dyspnea were measured while patients were receiving Venturimask oxygen before randomization. VAS dyspnea was assessed by visual analog scale, ranging from 0 to 10, with 10 representing the worst symptom (4, 5). For patients with VAS dyspnea = 0, PaO2/(FiO2 × VAS dyspnea) was considered equal to PaO2/FiO2. The number of days free of respiratory support (high-flow nasal oxygen, noninvasive, and invasive ventilation) within 28 days after enrollment was the primary endpoint. The rate of endotracheal intubation within 28 days, the number of days free of invasive mechanical ventilation at Days 28 and 60, in-ICU and in-hospital mortality, mortality at Days 28 and 60, and ICU and hospital length of stay were secondary outcomes. Data are expressed as number of events (percentage) or median (interquartile range [IQR]). Ordinal quantitative variables were compared with the Mann-Whitney Utest, after the nonnormal distribution was determined with the Shapiro-Wilk test. Comparisons between groups regarding qualitative variables were performed with the Fisher’s exact or the chi-square test, as appropriate. Multivariate analyses adjusting for simplified acute physiology score II, sequential organ failure assessment, PaO2/FiO2at inclusion, and site of enrollment and time of randomization as random effects were conducted through linear or logistic regression models. Kaplan-Meier curves are displayed for results concerning intubation. All results with two-sided P ⩽ 0.05 are considered statistically significant. Statistical analysis was performed with IBM SPSS 26. Demographic study endpoints are displayed in Table 1. Kaplan-Meier tables are displayed in Figure 1. Characteristics at Inclusion and Study Outcomes, according to Study Group* Definition of abbreviations: CI = confidence interval; OR = odds ratio; SAPS II = Simplified Acute Physiology Score II; VAS = visual analog scale. There were no missing data among the two groups. For calculations, PaO2was expressed in mm Hg and FiO2as fraction of the unity (0.21–1). For nonnormal quantitative variables, comparison between groups was performed with Mann-Whitney test. Comparisons between groups for qualitative variables were performed with the chi-square test or the Fisher’s exact test, as appropriate in agreement with test’s assumptions. Mean differences and odds ratios are unadjusted. For adjusted results, seethe main text. Respiratory support: invasive or noninvasive mechanical ventilation, high-flow nasal cannula. * Values are displayed as median (interquartile range) if not otherwise specified. †The body mass index is the weight in kilograms divided by the square of the height in meters. ‡Dyspnea and discomfort were assessed through visual analog scales adapted for patients in the ICU ranging from 0 to 10. §One patient was discharged from hospital but died upon readmission. (A) Kaplan-Meier plots of the cumulative incidence of intubation from randomization to Day 28 in the subgroup of patients with PaCO2of less than 35 mm Hg (n = 59 patients) and 35 mm Hg or more (n = 50 patients) at study enrollment. The hazard ratio for endotracheal intubation in the helmet noninvasive ventilation group in patients with PaCO2of less than 35 mm Hg was 0.25 (95% CI, 0.11–0.57). The hazard ratio for endotracheal intubation in the helmet noninvasive ventilation group in patients with PaCO2of at least 35 mm Hg was 1.05 (95% CI, 0.44–2.53). (B) Kaplan-Meier plots of the cumulative incidence of intubation from randomization to Day 28 in the subgroup of patients with PaO2/(FiO2 × dyspnea) lower (n = 54 patients) and equal to or higher than (n = 55 patients) 30 at study enrollment. The hazard ratio for endotracheal intubation in the helmet noninvasive ventilation group in patients with PaO2/(FiO2 × VAS dyspnea) < 30 was 0.39 (95% CI, 0.19–0.82). The hazard ratio for endotracheal intubation in the helmet noninvasive ventilation group in patients with PaO2/(FiO2 × VAS dyspnea) ⩾ 30 was 0.63 (95% CI, 0.23–1.73). CI = confidence interval; VAS = visual analog scale. Among 109 analyzed patients, 59 patients had PaCO2of less than 35 mm Hg and 50 had PaCO2of 35 mm Hg or more. In patients with PaCO2of less than 35 mm Hg, the median (IQR) days free of respiratory support within 28 days after randomization were 21 (11–25) in the helmet group and 14 (0–21) in the high-flow group, a difference that was not significant before or after adjustment for covariates (P = 0.07). The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow group: 18% versus 61%, with an absolute risk reduction of −43% (95% confidence interval [CI], −61% to −19%) and an adjusted odds ratio of 0.10 (95% CI, 0.22 to 0.42; P = 0.002) (Figure 1C). In-ICU mortality was significantly lower in the helmet group than in the high-flow group: 11% versus 39%, with an absolute risk reduction of −28% (95% CI, −47% to −6%) and an adjusted odds ratio of 0.15 (95% CI, 0.03 to 0.69; P = 0.015). In patients with PaCO2of 35 mm Hg or less, there were no significant differences between the helmet and the high-flow group for any analyzed outcome. Among 109 analyzed patients, 55 patients had PaO2/(FiO2 × VAS dyspnea) ⩾ 30 and 54 had PaO2/(FiO2 × VAS dyspnea) ⩽ 30. In patients with PaO2/(FiO2 × VAS dyspnea] < 30, the median (IQR) days free of respiratory support within 28 days after randomization was 13 (0–24) in the helmet group and 1 (0–19) in the high-flow group, a difference that was not statistically significant (P = 0.29). At the adjusted analysis, the number of days free of respiratory support at 28 days was significantly higher in the helmet group, with an adjusted mean difference of 5 (95% CI, 0–10; P = 0.04). The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow group: 37% versus 70%, with an absolute risk reduction of 33% (95% CI, −7% to 54%) and an adjusted odds ratio of 0.11 (95% CI, 0.02 to 0.55; P = 0.008) (Figure 1B). In patients with PaO2/(FiO2 × VAS dyspnea) ⩾ 30, there were no significant differences between the helmet and the high-flow group for any analyzed outcome. The results of these post hocanalyses of the HENIVOT trial indicate that the beneficial effects of helmet noninvasive ventilation over high-flow nasal oxygen in patients with COVID-19 with moderate to severe hypoxemia are magnified and limited to the subgroup of patients with PaO2/(FiO2 × VAS dyspnea) < 30 and/or PaCO2of less than 35mm Hg before treatment start. PaO2/FiO2and VAS dyspnea are markers of disease severity (5); hypocapnia may reflect dysregulation of brain homeostasis toward a lower level of PaCO2, resulting in increased inspiratory effort, high Vt, and tachypnea (6). Results from this post hocanalysis are consistent with data indicating that the physiologic benefit of helmet noninvasive ventilation over high-flow nasal oxygen is prominent among patients with more severe oxygenation impairment and intense inspiratory effort (7). These results may aid bedside patient phenotyping for clinical decision making and personalizing treatments. High-flow nasal oxygen is a simple, easy-to-use tool applied worldwide (8). Conversely, helmet noninvasive ventilation is a less diffuse technique (9) and requires a mechanical ventilator and personnel expertise, whose shortage in the context of the COVID-19 pandemic may limit the number of patients who may have access to this kind of support. PaO2/(FiO2 × VAS dyspnea) and PaCO2are bedside-available parameters that may help identify patients in whom helmet noninvasive ventilation as applied in the HENIVOT trial may improve clinical outcome (7, 10). Our study has limitations: The post hocnature of these analyses and the small sample make the results hypothesis generating, warranting further confirmatory investigations; the thresholds proposed should be taken cautiously; and VAS dyspnea is mainly used to compare dyspnea within a subject before and after a stimulus is applied, but it has been recently used to compare subjects undergoing noninvasive support (4, 5). We believe that its application in the present investigation is legitimate. In patients with COVID-19 and moderate to severe hypoxemic respiratory failure, these analyses suggest that high-flow oxygen is as effective as helmet noninvasive ventilation in patients who show PaO2/(FiO2 × VAS dyspnea) ⩾ 30 and/or PaCO2 of 35 mm Hg or more under conventional oxygen, whereas helmet noninvasive ventilation as applied in the HENIVOT trial may improve clinical outcome among subjects exhibiting PaO2/(FiO2 × VAS dyspnea) < 30 and/or PaCO2 of less than 35 mm Hg. Supported by the Italian Society of Anesthesia, Analgesia, and Intensive Care Medicine 2017 MSD award. The funder had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. D.L.G. and L.S.M. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The study was endorsed by the “Insufficienza respiratoria acuta e assistenza respiratoria-IRAAR” study group of the Italian Society of Anesthesia, Analgesia and Intensive Care Medicine. Author Contributions: D.L.G. and M.A. conceived the study. All authors contributed to data acquisition. L.S.M. conducted statistical analysis. D.L.G. interpreted the data and wrote the first draft of the manuscript. S.M.M. and M.A. critically revised the manuscript. M.A. organized the study as an overall supervisor. All authors reviewed the final draft of the manuscript and agreed on submitting it to the Journal. Originally Published in Press at DOI: 10.1164/rccm.202105-1212LEon November 17, 2017 Author disclosuresare available with the text of this letter. The authors thank all ICU doctors, residents, nurses, and personnel from the participating centers, whose sacrifice, efforts, devotion to patients, and passion have made possible this timely report. They also thank Dr. Cristina Cacciagrano and Dr. Emiliano Tizi for their contribution to study organization. Members of the COVID-ICU Gemelli Study Group:Jonathan Montomoli, Giulia Falò, Tommaso Tonetti, Salvatore L. Cutuli, Gabriele Pintaudi, Eloisa S. Tanzarella, Edoardo Piervincenzi, Antonio M. Dell’Anna, Luca Delle Cese, Simone Carelli, Maria Grazia Bocci, Luca Montini, Giuseppe Bello, Daniele Natalini, Gennaro De Pascale, Matteo Velardo, Carlo Alberto Volta, V. Marco Ranieri, Giorgio Conti, Riccardo Maviglia, Giovanna Mercurio, Paolo De Santis, Mariano Alberto Pennisi, Gian Marco Anzellotti, Flavia Torrini, Carlotta Rubino, Tony C. Morena, Veronica Gennenzi, Stefania Postorino, Joel Vargas, Nicoletta Filetici, Donatella Settanni, Miriana Durante, Laura Cascarano, Mariangela Di Muro, Roberta Scarascia, Martina Murdolo, Alessandro Mele, Serena Silva, Carmelina Zaccone, Francesca Pozzana, Alessio Maccaglia, Martina Savino, Antonella Potalivo, Francesca Ceccaroni, Angela Scavone, Gianmarco Lombardi, and Teresa Michi.

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