In this retrospective cohort study based on a large critical care database MIMIC-III (v1.4), we found that systemic corticosteroid treatment did not decrease 30-day mortality or shorten hospital length of stay in critically ill patients with AECOPD in ICU.
Biologically, glucocorticoids can relieve airways inflammation and in return reduce the airways resistance to improve the dyspnea and the work of breathing . The use of systemic glucocorticoids has been recommended during COPD exacerbations by GOLD 2021 (https://goldcopd.org/2021-gold-reports/). One strong available evidence is a cochrane meta-analysis which summarized the efficacy of systemic corticosteroid therapy on the outcomes of AECOPD . The results of this review showed beneficial effects of systemic corticosteroid treatment on treatment failure, relapse by one month and shortening length of stay in AECOPD hospital inpatients not requiring assisted ventilation outside ICU. Meanwhile, 30-day mortality was not reduced by treatment with systemic corticosteroid compared with placebo. However, it is important to realize that treatments developed outside the ICU may not prove effective in the ICU and even if such approaches provide benefit for critically ill patients, the risk-benefit calculus may be different .
There have been two researches conducted double-blind, multicenter, placebo-controlled randomized trials comparing corticosteroids with placebo to document the value of these agents in the treatment of severe AECOPDs requiring ventilatory support in ICU. However, the results of these two studies are contradictory. Alia et al.  reported a significant reduction in the median duration of mechanical ventilation (3 days vs 4 days; p = 0.04), a trend toward a shorter median length of ICU stay (6 days vs 7 days; p = 0.09), and significant reduction in the rate of NIV failure (0% vs 37%; p = 0.04) associated with corticosteroid treatment. Abroug et al.  observed similar median mechanical ventilation duration (6 days vs 6 days; p = 0.87), similar intensive care unit length of stay (9 days vs 8 days; p = 0.88) and no statistical difference NIV failure rate (15.7% vs 12.7%; p = 0.59) between the steroid-treated and control group. The different results may be explained by the different routes of corticosteroid steroid used in the studies and the severity of AECOPD (more severe respiratory acidosis and hypercapnia in the latter). Combining these two studies, the review by Walters et al.  drew the conclusion that there was no difference in length of ICU stay and the duration of assisted ventilation for corticosteroid treatment compared with the control for AECOPD patients requiring assisted ventilation in the ICU setting.
Short-term administration of systemic glucocorticoids may cause secondary infections, hyperglycemia, and a range of mood and behavioral changes . Adverse effects of the long-term therapy include osteoporosis, hypertension, myopathy, and adrenal insufficiency [19–22]. Increased risk of hyperglycemia requiring treatment following systemic glucocorticoid usage was both reported by Alia et al.  and Abroug et al. . The risk–benefit balance of systemic steroids is negative from the results of the study by Abroug et al. . In this study, we observed no statistically significant difference in 30-day mortality and in-hospital mortality between systemic corticosteroid group and the control group (Table 3 and Fig. 2). In addition, patients received systemic corticosteroid treatment had a greater chance of being hospitalized for more than eight days from the multivariate logistic regression (Table 3 and Fig. 2). The result was similar after PSM (Table 6). Taken the side effects into consideration, we recommend that the systematic administration of corticosteroids in severe COPD exacerbation in ICU needs to be cautious.
Some randomized studies showed that therapy with oral prednisolone is equally effective to intravenous administration of glucocorticoids [23, 24]. A pharmacoepidemiological cohort study conducted at 414 US hospitals involving almost 80,000 AECOPD patients to a non–intensive care setting demonstrated that the risk of treatment failure (in-hospital mortality, initiation of mechanical ventilation, or readmission for AECOPD within 30 days of discharge) among patients treated with low doses of oral steroids was not worse than for those treated with high dose intravenous therapy . However, the study regarding the route of steroid administration with AECOPDs in ICU has not been carried out. In this cohort study, oral administration presented similar efficacy with intravenous and the combined administration, with no difference in 30-day mortality and hospital LOS (> 8days). Besides, patients receiving intravenous steroids had higher risk of death within 30 days or in hospital, as well as a greater probability to stay in hospital for more than 8 days compared to the combined administration. Real-world information reminds us that studies with regard to steroids treatment should not be limited to the comparison of oral and intravenous administration, the co-administration method should also be included.
Eosinophil levels may be a helpful marker to predict outcomes in AECOPD and to direct corticosteroid therapy during exacerbations [26–29]. Singh et al.  assessed the prevalence of eosinophilic inflammation in COPD subjects and found that 37% of the COPD subjects had blood eosinophil counts persistently ≥ 2%. However, the prevalence of eosinophilic inflammation in COPD subjects requiring ICU admission has not been well defined. In this cohort study, only 17.57% of the subjects with a COPD exacerbation requiring ICU had a peripheral blood initial eosinophil concentration greater than 2% and the median of initial blood eosinophil concentrations was 0.4% which was lower than other researches [31–33] aimed at AECOPD. A previous study drew the receiver operating characteristic (ROC) curve for the prediction of in-hospital mortality by eosinophil concentrations in hospital admissions diagnosed with AECOPD in MIMIC-III v1.4 database . The area under the ROC curve for initial eosinophil concentration was 0.608 and the discriminatory eosinophil thresholds were 0.35% (sensitivity = 0.59, specificity = 0.61) for in-hospital mortality . Thus, the cut-off value 0.35% was also used to distinguish subgroups.
Lower-eosinophilic patients were found to experienced poorer clinical outcomes in a prospective, multicenter, observational cohort study . In addition, a retrospective observational cohort study showed that COPD exacerbations with acute respiratory failure requiring ICU admission had a shorter median length of ICU stay and lower mortality with a peripheral eosinophil level > 2% . Similar results appeared in our research. As shown in Supplementary Table 1, increased blood eosinophil level was associated with decreased 30-day mortality in our study (OR = 0.688, 95% CI: 0.688–0.946, p = 0.008).
Targeting corticosteroid therapy in a subgroup of exacerbations dependent on the peripheral eosinophil count may be helpful to reduce inappropriate use of systemic corticosteroids . Recent studies suggested that glucocorticoids may be more efficacious to treat acute COPD exacerbations in patients with higher levels of blood eosinophils ( ≥ 2%) [26–29]. However, things seem to be different in ICU. Little evidence was found that systemic corticosteroids provided benefit in patients with a blood eosinophil initial concentration < 2% in our study Table 4. What’s more, in the subgroup with a blood eosinophil initial concentration ≥ 2%, patients treated with systemic corticosteroids had a significantly increased in-hospital mortality compared with non-GC group (OR = 6.645, 95% CI: 1.537–28.723, p = 0.011). When the cut-off value set to 0.35%, the effect of eosinophil level on the efficacy of glucocorticoids on the mortality of severe AECOPD patients was more apparent. As shown in Table 4, there was no difference regarding 30-day mortality and in-hospital mortality in the steroid-treated and control groups in the subgroup of patients with initial eosinophil concentration < 0.35%. Critically, in the subgroup of patients with initial eosinophil concentration ≥ 0.35%, corticosteroid treatment resulted in worse outcomes compared with non-GC group. The adjusted odds ratio of 30-day mortality and in-hospital mortality for glucocorticoid therapy were 1.691 (95% CI: 1.002–2.855, p = 0.049) and 2.247 (95% CI: 1.218–4.147, p = 0.010) respectively.
Therefore, recommendation of systemic corticosteroid treatment is not supported in critically severe AECOPD with a high blood eosinophil initial concentration in ICU by these results until a more precise evidence emerges. More researches are needed to explore the cut-off value for eosinophils and the reasons for the conflicting results between ICU patients and non-ICU patients.
Although this study was relatively considerable sample size, it has several limitations. First, our research is a database-based retrospective single-center study. The inherent bias could not be avoided. Outcomes in this study only included 30-day mortality, in-hospital mortality and hospital LOS (> 8days), which were not as flexible as randomized controlled trials. Second, systemic steroids use in the 30 days prior to hospital admission was unknown. This may cause some bias in the results though it is closer to the real world. Third, only blood eosinophil concentrations were considered in this study because the numeric value of the blood eosinophil counts was hugely lacked in the MIMIC-III database. The subgroup analysis will be more complete if blood eosinophil counts were considered together.