key: cord-0933433-wnvcggx4
authors: Grieco, Domenico Luca; Menga, Luca S.; Cesarano, Melania; Spadaro, Savino; Bitondo, Maria Maddalena; Berardi, Cecilia; Rosà, Tommaso; Bongiovanni, Filippo; Maggiore, Salvatore Maurizio; Antonelli, Massimo
title: Phenotypes of Patients with COVID-19 Who Have a Positive Clinical Response to Helmet Noninvasive Ventilation
date: 2017-11-17
journal: Am. j. respir. crit. care med
DOI: 10.1164/rccm.202105-1212le
sha: a688d4b212b5d9e506ca79f5df23858b7709daff
doc_id: 933433
cord_uid: wnvcggx4

nan

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 and moderate to severe respiratory failure (Pa O 2 /FI O 2 , 200 mm Hg and Pa CO 2 > 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 hoc analyses to establish whether any bedside available parameter before randomization (Pa O 2 2 3 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 Pa O 2 /(FI O 2 3 VAS dyspnea) , 30 before randomization. In these post hoc analyses, we report study outcomes in the two groups after classifying patients according to 1) whether they were normo-or hypocapnic; and 2) whether their Pa O 2 / (FI O 2 3 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 (Pa O 2 / FI O 2 < 200) were randomized to receive 48-hour continuous treatment with helmet noninvasive ventilation (positive endexpiratory pressure 10-12 cm H 2 O and pressure support 10-12 cm H 2 O) 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 hoc analyses, intergroup differences in study outcomes were analyzed in the subgroups of patients exhibiting 1) Pa CO 2 less than 35mm Hg or 35mm Hg or more; and 2) Pa O 2 / (FI O 2 3 VAS dyspnea) , 30 or >30 (median of the cohort). Pa O 2 /FI O 2 , Pa CO 2 , 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, Pa O 2 /(FI O 2 3 VAS dyspnea) was considered equal to

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 U test, 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, Pa O 2 /FI O 2 at 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 .

Pa CO 2 before treatment start. Among 109 analyzed patients, 59 patients had Pa CO 2 of less than 35 mm Hg and 50 had Pa CO 2 of 35 mm Hg or more.

In patients with Pa CO 2 of 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 243% (95% confidence interval [CI], 261% to 219%) 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 228% (95% CI, 247% to 26%) and an adjusted odds ratio of 0.15 (95% CI, 0.03 to 0.69; P = 0.015).

This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please contact Diane Gern (dgern@thoracic.org).

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. In patients with Pa CO 2 of 35 mm Hg or less, there were no significant differences between the helmet and the high-flow group for any analyzed outcome.

In patients with Pa O 2 /(FI O 2 3 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, 27% 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 Pa O 2 /(FI O 2 3 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 hoc analyses of the HENIVOT trial indicate that the beneficial effects of helmet noninvasive ventilation over highflow nasal oxygen in patients with COVID-19 with moderate to severe hypoxemia are magnified and limited to the subgroup of patients with Pa O 2 /(FI O 2 3 VAS dyspnea) , 30 and/or Pa CO 2 of less than 35mm Hg before treatment start.

Pa O 2 /FI O 2 and VAS dyspnea are markers of disease severity (5); hypocapnia may reflect dysregulation of brain homeostasis toward a lower level of Pa CO 2 , resulting in increased inspiratory effort, high VT, and tachypnea (6) 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. Table 1 .

Results from this post hoc analysis 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. Pa O 2 /(FI O 2 3 VAS dyspnea) and Pa CO 2 are 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 hoc nature 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 Pa O To the Editor:

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of inflammatory lung injury characterized by increased alveolar permeability, severe hypoxemia, and reduced lung compliance (1, 2) . The Pa O 2 /FI O 2 (P/F) ratio plays a key role in defining ARDS, although it may vary with FI O 2 and positive end-expiratory pressure (PEEP) (3, 4) . According to the Berlin definition of ARDS, the criteria for hypoxemia are a P/F ratio <300 mm Hg with a PEEP of >5 cm H 2 O (2). However, the rationale for choosing 300 mm Hg as the P/F cutoff remains obscure. In the absence of an available gold standard to determine the cutoff of P/F ratios for differentiating patients with and without ARDS, evaluating the construct validity of P/F ratios may provide new insights into this issue. Construct validity refers to a concept that cannot be directly observed, but its characteristics can be measured by other indicators (5) . In this study, we evaluated the construct validity of P/F ratios in defining ARDS to explore whether there was a threshold to identify hypoxemic events matching the characteristics of ARDS. We hypothesized that a poor respiratory outcome (death or ventilator dependence) and low respiratory compliance (,40 ml/cm H 2 O) due to widespread lung injury would be the key features of ARDS compared with non-ARDS respiratory failure (2) .

In this retrospective multi-ICU study, we identified adult patients who received invasive mechanical ventilation (MV) for .24 hours and had arterial blood gas analysis on the first day of MV from October 2014 to July 2020 at the National Taiwan University Hospital in Taiwan. Patient demographics, P/F ratios and ventilator settings on the first MV day, respiratory compliance, and outcomes at ICU discharge were collected. For measurement of respiratory compliance, patients were put on the volume control mode with constant flow.

Measurements of respiratory mechanics were only performed in patients who had been adequately sedated or had no spontaneous breathing. The static compliance of the total respiratory system was calculated by dividing the inflation volume by the difference between the end-inspiratory plateau pressure and the PEEP set by the ventilator. Stata software version 15 was used for statistical analysis. The need for written informed consent was waived by the Research Ethics Committee of the National Taiwan University Hospital (No. 202009066RINC) because this was a retrospective study and procedures were adopted to protect and anonymize personal patient information.

The primary analysis was to evaluate the relationship between P/F ratios and the composite outcome of death and MV dependence at ICU discharge using logistic regression. The secondary analysis evaluated the relationship between P/F ratios and ICU mortality using logistic regression, and the relationship between P/F ratios and static respiratory compliance using linear regression. Respiratory compliance was standardized to predicted body weight to account for the influence of body size on Table 1 . Characteristics of the Study Cohort (N = 4,060)

Value

Effect of helmet noninvasive ventilation vs high-flow nasal oxygen on days free of respiratory support in patients with COVID-19 and moderate to severe hypoxemic respiratory failure: the HENIVOT randomized clinical trial

Respiratory support during the COVID-19 pandemic: is it time to consider using a helmet?

An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy

Dyspnoea and respiratory muscle ultrasound to predict extubation failure

REVA Network (Research Network in Mechanical Ventilation) and the Groupe de Recherche en R eanimation Respiratoire en Onco-H ematologie (GrrrOH); List of contributors who included study patients: Angers University Hospital, Angers, France. Dyspnoea in patients receiving noninvasive ventilation for acute respiratory failure: prevalence, risk factors and prognostic impact: a prospective observational study

Respiratory drive in critically ill patients

Pa O 2 /FI O 2 ratio

Definition of abbreviations: APACHE = Acute Physiology and Chronic Health Evaluation

Supported by Ministry of Science and Technology, Taiwan grant 109-2314-B-002-179 and Taiwan Health Foundation

Author disclosures are available with the text of this letter at www.atsjournals.org.

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.