Association of Time-Varying Intensity of Ventilation With Mortality in Patients With COVID-19 ARDS: Secondary Analysis of the PRoVENT-COVID Study

Abstract

Background: High intensity of ventilation has an association with mortality in patients with acute respiratory failure. It is uncertain whether similar associations exist in patients with acute respiratory distress syndrome (ARDS) patients due to coronavirus disease 2019 (COVID-19). We investigated the association of exposure to different levels of driving pressure (ΔP) and mechanical power (MP) with mortality in these patients. Methods: PRoVENT-COVID is a national, retrospective observational study, performed at 22 ICUs in the Netherlands, including COVID-19 patients under invasive ventilation for ARDS. Dynamic ΔP and MP were calculated at fixed time points during the first 4 calendar days of ventilation. The primary endpoint was 28-day mortality. To assess the effects of time-varying exposure, Bayesian joint models adjusted for confounders were used. Results: Of 1,122 patients included in the PRoVENT-COVID study, 734 were eligible for this analysis. In the first 28 days, 29.2% of patients died. A significant increase in the hazard of death was found to be associated with each increment in ΔP (HR 1.04, 95% CrI 1.01-1.07) and in MP (HR 1.12, 95% CrI 1.01-1.36). In sensitivity analyses, cumulative exposure to higher levels of ΔP or MP resulted in increased risks for 28-day mortality. Conclusion: Cumulative exposure to higher intensities of ventilation in COVID-19 patients with ARDS have an association with increased risk of 28-day mortality. Limiting exposure to high ΔP or MP has the potential to improve survival in these patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04346342.

Keywords: acute respiratory distress syndrome; coronavirus disease 2019; driving pressure; mechanical power; mortality.

Conflict of interest statement

AS reports personal fees from Dräger, outside of the submitted work. MaS reports personal fees from Hamilton and Xenios/Novalung, outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Schuijt, van Meenen, Martin–Loeches, Mazzinari, Schultz, Paulus and Serpa Neto.

Figures

Figure 1

Driving pressure and mechanical power over the first four days of ventilation in the included patients. Top panels (A, B): mean daily values of ΔP and MP according to a maximum of four measurements in the day of start of ventilation and three measurements in the next days. Bottom panels (C, D): ΔP and MP per time point of assessment. Circles are means and error bars are 95% confidence intervals. Both variables were calculated using only measurements without spontaneous breathing activity. P values from a mixed-effect model with time as fixed effect (as continuous variable) and patients as random effect to account for repeated measurements.

Figure 2

Time-varying hazard ratio of driving pressure and mechanical power for 28-day mortality. (A), Time-varying ΔP, and (B) time-varying MP. Time-varying hazard ratio obtained from a Bayesian joint model estimating the association between ΔP and MP and 28-day mortality, including p-splines in an interaction term. The strength of the association decreased over time. All models were adjusted for age, gender, body mass index, PaO2 to FiO2 ratio, plasma creatinine, medical history of hypertension, heart failure, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, active hematological neoplasia and/or active solid tumor, use of angiotensin converting enzyme inhibitors, use of angiotensin II receptor blockers, use of a vasopressor or inotropes, fluid balance, arterial pH, mean arterial pressure, and heart rate. Natural cubic splines were used in both the fixed-effects and random-effects models to account for the nonlinearity of the longitudinal exposure profiles.

Figure 3

Association between intensity of exposure to higher driving pressure and mechanical power and 28-day mortality. (A, D): Association between percentage of measurements with ΔP > 15 cmH2O and MP > 17 J/min and 28-day mortality. Percentage calculated from a maximum of 13 measurements extracted every 8 h. (B, E): Association between cumulative dose of ΔP > 15 cmH2O and MP > 17 J/min and 28-day mortality. Cumulative dose calculated as area under the ΔP and MP time curve above the thresholds described above divided by the number of hours of exposure, as a measure of dose. Using this definition, 1 cmH2O or 1 J/min of dose describes that a patient's average ΔP or MP was 1 cmH2O or 1 J/min above the thresholds described for the duration of the exposure window, respectively. (C,F) Association between time-weighted average ΔP and MP and 28-day mortality. Time-weighted average calculated as the area under the ΔP and MP time curve divided by the number of hours of exposure. All models were adjusted for age, gender, body mass index, PaO2 to FiO2 ratio, plasma creatinine, medical history of hypertension, heart failure, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, active hematological neoplasia and/or active solid tumor, use of angiotensin converting enzyme inhibitors, use of angiotensin II receptor blockers, use of a vasopressor or inotropes, fluid balance, arterial pH, mean arterial pressure, and heart rate. Dashed lines and gray areas represent hazard ratio and 95% confidence interval for increasing values the variable analyzed as a continuous variable and centralized in the mean of each variable. ΔP is driving pressure and MP is mechanical power.