Early antibiotic therapy is associated with a lower probability of successful liberation from mechanical ventilation in patients with severe acute exacerbation of chronic obstructive pulmonary disease

Abstract

Background: While antibiotic therapy is advocated to improve outcomes in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) whenever mechanical ventilation is required, the evidence relies on small studies carried out before the era of widespread antibiotic resistance. Furthermore, the impact of systematic antibiotic therapy on successful weaning from mechanical ventilation was never investigated accounting for the competitive risk of death. The aim of the study was to assess whether early antibiotic therapy (eABT) increases successful mechanical ventilation weaning probability as compared to no eABT, in patients with AECOPD without pneumoniae, using multivariate competitive risk regression.

Methods: Retrospective analysis of patients admitted in 2 intensive care units (ICU) from 2012 to 2020 for AECOPD without pneumonia and requiring mechanical ventilation. eABT was defined as any anti-bacterial chemotherapy introduced during the first 24 h after ICU admission. The primary outcomes were the adjusted subdistribution hazard ratio (SHR) of the probability of being successfully weaned from mechanical ventilation (i.e. non-invasive and invasive ventilation) according to eABT status and accounting for the competitive risk of death.

Results: Three hundred and ninety-one patients were included, of whom 66% received eABT. eABT was associated with a lower probability of successful liberation from mechanical ventilation when accounting for the competing risk of death in multivariate analyses (SHR 0.71 [95% confidence interval, 0.57-0.89], p < 0.01), after adjustment with covariates of disease severity. This association was present in all subgroups except in patients under invasive mechanical ventilation on ICU day-1, in patients with ICU day-1 worst PaCO₂ > 74 torr (median value) and in patients with a documented bacterial bronchitis at ICU admission. Ventilator-free days at day 28, ICU-free days at day 28 and invasive mechanical ventilation-free days at day 28, were significantly lower in the eABT group, while there was no significant difference in mortality at day 28 between patients who received eABT and those who did not.

Conclusions: eABT was independently associated with a lower probability of being successfully weaned from mechanical ventilation, suggesting that the clinician decision to overrule systematic administration of eABT was not associated with a detectable harm in AECOPD ICU patients without pneumonia.

Keywords: Acute exacerbation; COPD; Chronic obstructive pulmonary disease; Mechanical ventilation; Ventilation weaning.

Fig. 1

Patients screening. Screening lasted from July 2012 to January 2020. eABT was defined as the first line of antibiotic therapy introduced during the first 24 h after ICU admission. eABT early antibiotic therapy, ICU intensive care unit

Fig. 2

Cumulative incidence of successful weaning from mechanical ventilation and death according to eABT. eABT was the first line of antibiotic therapy introduced during the first 24 h of ICU admission. Continuous lines are cumulative incidence function curves of the probability of being successfully weaned from mechanical ventilation modelled with univariate Fine and Gray regression accounting for the competitive risk of death, with eABT as the independent variable. Broken lines are cumulative incidence function curves of the probability of dying in the ICU. Shaded areas are 95% confidence intervals. eABT early antibiotic therapy, SHR subdistribution hazard ratio, CI95% 95% confidence interval, ICU intensive care unit

Fig. 3

Forest plot of the adjusted SHR computed with multivariate computing risk regression of the probability of being successfully weaned from mechanical ventilation. eABT was defined as the first line of antibiotic therapy introduced during the first 24 h of ICU admission. COPD frequent exacerbator status was defined as at least two acute exacerbations of COPD with hospital admission within one year. Respiratory sample at AECOPD onset was defined as bacterial respiratory sample performed between 48 h before ICU admission and the end of ICU day-1. Univariate Fine and Gray analysis was first performed on each variable of interest (Additional file 1: Table S1). Then, the following variables were selected for inclusion in the multivariate model because of their assumed relevance: eABT status, centre, age, truncated SAPS2 (leaving out age, Glasgow Coma Scale, PaO2/FiO2 and temperature components to avoid collinearity with the other variables), home NIV or home oxygen status, COPD frequent exacerbator status, ICU day-1 cardiovascular and renal SOFA subscore (to avoid multicollinearity with SAPS2), ICU day-1 highest body temperature, ICU day-1 worst Glasgow, ICU day-1 worst PaCO2, ICU day-1 worst PaO2/FiO2 (PaO2/FiO2 was entered as a categorical variable because it was reported as a SAPS2 value when data were collected), invasive mechanical ventilation on ICU-day-1, respiratory sample at AECOPD onset, and cardiogenic pulmonary oedema on ICU day-1. Interactions were systematically checked for. We did not report any significant interaction between eABT and other variables included in our model. Then, we reduced our model by deleting all variables with multivariate p-value > 0.1. SHR lower than 1 indicates a lower probability of being successfully weaned from mechanical ventilation, accounting for the competing risk of death. SHR subdistribution hazard ratio; CI95% 95% confidence interval, NIV non-invasive ventilation, PaCO2 CO2 arterial partial pressure; PaO2/FiO2 ratio of O2 arterial partial pressure on fraction of inspired O2, SAPS2 simplified acute physiology score 2, SOFA Sequential Organ Failure Assessment, eABT early antibiotic therapy, COPD chronic obstructive pulmonary disease, ICU intensive care unit

Fig. 4

Sensitivity analysis of the SHR of eABT in subgroups of patients assessed by modelling the probability of being successfully weaned from mechanical ventilation using multivariate competing risk regression. eABT was the first line of antibiotic therapy introduced during the first 24 h of ICU admission. Documented bacterial bronchitis was defined as bacterial documentation on respiratory sample performed between 48 h before ICU admission and the end of ICU day-1. Seventy-four Torr was the median value of ICU Day-1 worst PaCO2. SHR less than 1 indicates a lower probability of being successfully weaned from mechanical ventilation, accounting for the competing risk of death. SHR subdistribution hazard ratio, CI95% 95% confidence interval, eABT early antibiotic therapy, COPD chronic obstructive pulmonary disease, NIV non-invasive ventilation, ICU intensive care unit