Our study aimed to assess the time of dexamethasone initiation on the clinical outcomes of critically ill patients with COVID-19. A total of 487 patients were included in the analysis; dexamethasone was initiated early in most of the included patients (76.4%). This study included patients before releasing RECOVERY Collaborative group study results about dexamethasone use.(13) During that time, some clinicians were hesitant to start dexamethasone early in all patients due to conflicting evidence about steroids. After propensity score matching using the SOFA score, MV status within 24 hours of ICU admission, proning position status, and tocilizumab use within 24 hours of ICU admission, we found that dexamethasone early initiation was associated with lower respiratory failure that required MV support. Additionally, early initiation was associated with shorter hospital LOS among the survived patients.
In critically ill patients with COVID-19, the dysregulated inflammatory immune response observed can be counteracted by the use of CS to down-regulate the inflammatory immune response and accelerate disease resolution.(24, 25) Although the World Health Organization (WHO) initially did not recommend using CS for COVID-19 treatment, as of September 02, 2020, the WHO and the National Institute of Health (NIH) recommended using systemic CS in critically ill patients with severe COVID-19. (26, 27) Moreover, the use of dexamethasone is recommended by the surviving sepsis guideline for patients with severe COVID-19 requiring MV and patients with refractory shock. (28) However, none of these guidelines recommend the appropriate time for CS initation in patients with COVID-19.
In our study, early dexamethasone initiation was associated with a significant reduction in respiratory failure that required MV support among non-MV patients. Besides the mortality benefits that were observed with dexamethasone use, limited studies investigated the impact of late CS initiation on respiratory failure that required MV. Even though the NIH guideline recommends using CS in severely ill COVID-19 patients who require MV, our study found that early initiation of dexamethasone was associated with a lower odds of respiratory failure that required MV in non-MV patients (13, 26). That could be related to dexamethasone's prolonged and potent effect, which can mediate downregulation of systemic and pulmonary inflammation, restore homeostasis, and enhance disease resolution. In parallel to our findings, Monedero et al. reported a lower MV rate in the early steroids group(16) However, in that study, the cutoff of early initiation of CS was at 48 hours from ICU admission while including patients who were started on CS before ICU admission and including patients who received other CS types such as: methylprednisolone.(16)
Our results showed higher 30-day mortality and in-hospital mortality in the late initiation group; yet, were not statistically significant. Previous studies have found mortality benefits when comparing CS use to standard of care alone (13,14,29). In the RECOVERY trial the use of dexamethasone compared to standard of care was associated with lower 28-day mortality among patients hospitalized with COVID19 who received invasive mechanical ventilation or oxygen but not those who didn’t need respiratory support.(13) Suggesting that the benefit of dexamethasone in patients with COVID-19 is noticeable receiving dexamethasone more than seven days post-symptoms onset.(13)
Additionally, two meta-analyses and systemic reviews reported a significant reduction in the mortality rates in patients with COVID-19 receiving CS compared to standard care only. (14, 29) However, none of these studies assessed the respiratory failure requiring MV, mortality benefit, length of stay (LOS), nor MV duration in the patient who received early dexamethasone to patients who did not. On the other hand, an observational retrospective study including 615 patients with COVID-19 found that starting CS at > 72 hours from admission associated with significant mortality reduction (HR 0.56, 95% CI 0.38–0.82; p = 0.003) compared to earlier initiation of CS (within 24 hours). (30) It is noteworthy that most of the study patients received methylprednisolone (87%).(30).
We believe that our multicenter non-interventional cohort study is one of the first studies to highlight the appropriate time of dexamethasone initiation and its effects on the clinical outcomes of critically ill patients with COVID-19. It is prospective component allows to prospectively explore the association between the time of dexamethasone therapy initiation in COVID19 patients with ICU mortality. Additionally, it had a predefined cutoff margin of early vs. late initiation time, and it assessed several important clinical outcomes in the final analysis. Nevertheless, we also determined some limitations to our study. First, the observational nature of the study design limits the exclusion of missing data of some variables. Second, despite propensity score matching, some residual confounding factors are still possible. Lastly, there was a dynamic change in the national and international COVID-19 management guidelines as more evidence emerged, affecting the general practice.