Corticosteroid treatment and mortality in mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients: a multicentre cohort study

Abstract

Background: Some unanswered questions persist regarding the effectiveness of corticosteroids for severe coronavirus disease 2019 (COVID-19) patients. We aimed to assess the clinical effect of corticosteroids on intensive care unit (ICU) mortality among mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients.

Methods: This was a retrospective study of prospectively collected data conducted in 70 ICUs (68 Spanish, one Andorran, one Irish), including mechanically ventilated COVID-19-associated ARDS patients admitted between February 6 and September 20, 2020. Individuals who received corticosteroids for refractory shock were excluded. Patients exposed to corticosteroids at admission were matched with patients without corticosteroids through propensity score matching. Primary outcome was all-cause ICU mortality. Secondary outcomes were to compare in-hospital mortality, ventilator-free days at 28 days, respiratory superinfection and length of stay between patients with corticosteroids and those without corticosteroids. We performed survival analysis accounting for competing risks and subgroup sensitivity analysis.

Results: We included 1835 mechanically ventilated COVID-19-associated ARDS, of whom 1117 (60.9%) received corticosteroids. After propensity score matching, ICU mortality did not differ between patients treated with corticosteroids and untreated patients (33.8% vs. 30.9%; p = 0.28). In survival analysis, corticosteroid treatment at ICU admission was associated with short-term survival benefit (HR 0.53; 95% CI 0.39-0.72), although beyond the 17th day of admission, this effect switched and there was an increased ICU mortality (long-term HR 1.68; 95% CI 1.16-2.45). The sensitivity analysis reinforced the results. Subgroups of age < 60 years, severe ARDS and corticosteroids plus tocilizumab could have greatest benefit from corticosteroids as short-term decreased ICU mortality without long-term negative effects were observed. Larger length of stay was observed with corticosteroids among non-survivors both in the ICU and in hospital. There were no significant differences for the remaining secondary outcomes.

Conclusions: Our results suggest that corticosteroid treatment for mechanically ventilated COVID-19-associated ARDS had a biphasic time-dependent effect on ICU mortality. Specific subgroups showed clear effect on improving survival with corticosteroid use. Therefore, further research is required to identify treatment-responsive subgroups among the mechanically ventilated COVID-19-associated ARDS patients.

Keywords: COVID-19-associated acute respiratory distress syndrome; Corticosteroids; Intensive care unit; Invasive mechanical ventilation; Mortality.

Fig. 1

Study flowchart

Fig. 2

Forest plot of the cause-specific hazard model (time-dependent Cox regression) for ICU mortality. The time-dependent Cox regression included all the variables and those were adjusted as potential confounding factors. The interaction with time in this case was modelled using the step function to deal with non-proportional hazards of the covariate of interest (corticosteroid treatment). Through the step function, a partitioning of the time axis was made at day 17th, when the effect of the covariate changed over time. Consequently, the model allowed to estimate the effect of the treatment covariate before (corticosteroid treatment short-term) and after (corticosteroid treatment long-term) the 17th day of ICU admission. Notably, the regression model showed the protective effects of corticosteroids on survival up to day 17 of admission to the ICU, although these effects changed over time, as after the 17th day corticosteroid treatment at ICU admission was associated with higher mortality. Diagnosis GAP means the time (days) from disease onset to the confirmation of the diagnosis of SARS-CoV-2 infection; Hospital GAP (days) means the time from disease onset to hospital admission. ICU GAP (days) means the time from hospital to ICU admission. BMI body mass index, ACE angiotensin-converting enzyme, ARBs angiotensin receptor blockers, COPD chronic obstructive pulmonary disease, APACHE Acute Physiology And Chronic Health Evaluation, SOFA Sequential Organ Failure Assessment, LDH lactate dehydrogenase, WBC white blood cells count, CRP C-reactive protein, ARDS acute respiratory distress syndrome, FiO₂ fraction of inspired oxygen, Peep positive end-expiratory pressure, Vt tidal volume, pCO₂ partial pressure of carbon dioxide, RIFLE criteria Risk, Injury, Failure, Loss, End stage

Fig. 3

Survival analysis with the cause-specific hazard model and step function (time-dependent Cox regression) to investigate the association of corticosteroids and ICU mortality over time. The estimated survival curves showed the estimated effect of exposure of corticosteroids on ICU mortality over time. Survival curves cross each other implying time-dependency of corticosteroid exposure; hence step function approach was used to handle non-proportional hazards assumption by stratification of time on day 17 of follow-up when hazards changed the direction statistically significant. Then, the proportional hazards assumption was met for both periods. Models were adjusted for gender, age, body mass index, hospital GAP, ICU GAP, diagnosis GAP, shock, ACE inhibitors, ARBs, Comorbidity, asthma, COPD, chronic kidney disease, haematological disease, diabetes mellitus, neuromuscular disease, autoimmune disease, ischaemic heart disease, hypertension, immunosuppression, dyslipidaemia, hypothyroidism, APACHE II, SOFA, pulmonary infiltrates, lactate dehydrogenase, white blood cells count, creatinine, urea, C-reactive protein, procalcitonin, Lactate, d-dimer, antibiotics, oseltamivir, lopinavir plus ritonavir, remdesivir, interferon, hydroxychloroquine, Tocilizumab, bacterial co-infection, ARDS severity, fractional of inspired oxygen (FiO₂), positive end-expiratory pressure, tidal volume, partial pressure of carbon dioxide, pH, RIFLE criteria, myocardial dysfunction and corticosteroid treatment (short and long-term). ICU intensive care unit, ACE angiotensin-converting enzyme, ARBs angiotensin receptor blockers, COPD chronic obstructive pulmonary disease, APACHE Acute physiology and chronic health evaluation, SOFA sequential organ failure assessment, ARDS acute respiratory distress syndrome

Fig. 4

Subgroup sensitivity analysis. Propensity score matching was performed for each study subgroup as in the primary analysis to evaluate the estimated effect of corticosteroids on ICU mortality over time with cause-specific hazard model. Post hoc analysis was made for subgroups of duration of corticosteroid treatment and Tocilizumab. GAP corticosteroids mean the time (in days) since onset of symptoms to corticosteroid initiation. Models were adjusted for gender, age, body mass index, hospital GAP, ICU GAP, diagnosis GAP, shock, ACE inhibitors, ARBs, Comorbidity, asthma, COPD, chronic kidney disease, haematological disease, diabetes mellitus, neuromuscular disease, autoimmune disease, ischaemic heart disease, hypertension, immunosuppression, dyslipidaemia, hypothyroidism, APACHE II, SOFA, pulmonary infiltrates, lactate dehydrogenase, white blood cells count, creatinine, urea, C-reactive protein, procalcitonin, Lactate, d-dimer, antibiotics, oseltamivir, lopinavir plus ritonavir, remdesivir, interferon, hydroxychloroquine, Tocilizumab, bacterial co-infection, ARDS severity, fractional of inspired oxygen (FiO₂), positive end-expiratory pressure, tidal volume, partial pressure of carbon dioxide, pH, RIFLE criteria, myocardial dysfunction and corticosteroid treatment (short and long-term). ICU intensive care unit, ACE angiotensin-converting enzyme, ARBs angiotensin receptor blockers, COPD chronic obstructive pulmonary disease, APACHE acute physiology and chronic health evaluation, SOFA sequential organ failure assessment, ARDS acute respiratory distress syndrome, CRP C-reactive protein