effects of AGE on ventilation and outcomeS in COVID–19 ARDS

Writing committee

L. Hol, P. van Oosten, S.H.L.H. Nijbroek, Anissa M Tsonas, Michela Botta, A. Serpa Neto, F. Paulus, M.J. Schultz for the PRoVENT–COVID Collaborative group

STATISTICAL ANALYSIS PLAN, May 20, 2020

Inclusion criteria

Included in the PRoVENT–COVID study.

Exclusion criteria

Age not available.

Groups

We will create 4 age categories, based on quartiles.

Study aims

To compare ventilation management in the 4 age groups; to compare complications in the 4 age groups; and to compare outcomes in the 4 age groups.

Study hypotheses

Ventilation management is not different between the 4 age groups; complications are different between the 4 age groups; and outcomes are different between the 4 age groups.

Endpoints

The primary endpoint is a combination of key ventilator settings and ventilation parameters during the first 4 calendar days of invasive ventilation, including tidal volume, PEEP, respiratory system compliance, and driving pressure. Secondary ventilator management endpoints are the use of adjunctive treatments for refractory hypoxemia, including the use of alveolar recruitment maneuvers and prone positioning, and adjunctive strategies including the use of neuromuscular blocking agents and extracorporeal membrane oxygenation. Complication outcomes are venous thromboembolism, acute kidney injury, and the use of renal replacement therapy. Clinical endpoints are mortality at day 28, at ICU and hospital discharge, and at day 90, and the number of ventilator free days and alive at day 28 (VFD–28).

Power calculation

No statistical power calculation was conducted before the study, and sample size was based on available data.

Statistical analysis

Continuous variables are presented as medians (first quartile–third quartile) and categorical variables as numbers and percentages. The age groups are compared using Kruskal–Wallis test or ANOVA for continuous variables and Fisher exact tests for categorical variables. Differences in ventilatory variables between the age groups are visualized in cumulative distribution plots and box plots at the start of ventilation and at day 1, 2, and 3.

The effect of age categories on clinical outcomes will be reported in Kaplan–Meier curves and compared with Log-rank tests. Further comparison between the groups is made with (shared-frailty) cox proportional models with center as frailty. The proportional hazard assumption is assessed through Schoenfeld residuals. To assess the impact of age categories on 28-day mortality, variables are included in a multivariable model based on clinical relevance and when a p < 0.20 is found in an univariable assessment.

One sensitivity analysis is performed. The impact of age categories on 28-day mortality will be re-assessed within the mild, moderate, and severe categories of ARDS according to the Berlin definition.