Our study aimed to evaluate the effect of dexamethasone initiation time on critically ill COVID-19 patients' clinical outcomes. A total of 475 patients were included in the analysis; dexamethasone was initiated early within three days of ICU admission in the majority of the included 435 (91.5%) patients. After adjusting for age, need for MV within 24 hours of ICU admission, and study centers, we found that dexamethasone early initiation is associated with lower 30-day ICU mortality. Additionally, it was associated with shorter hospital LOS, ICU LOS, and MV duration among survived patients.
The clinical presentation of COVID-19 ranges in severity from asymptomatic mild disease to severe pneumonia, leading to acute respiratory distress syndrome (ARDS) and associated with a high mortality rate. 17,18. In critically ill COVID-19 patients, the clinical presentation of ARDS, massive vascular inflammation, disseminated intravascular coagulation, and shock is triggered frequently, with an ARDS occurrence rate of 17–41% of all cases 19,20. The dysregulated inflammatory immune response observed with COVID-19 is similar to multifactorial ARDS, where plenty of evidence has proven corticosteroids ability to down-regulate the inflammatory immune response and accelerate disease resolution 21,22,23. Although the World Health Organization (WHO) initially did not recommend using corticosteroids for COVID-19 treatment, as of September 02, 2020, the WHO recommended using systemic corticosteroids in critically ill patients with severe COVID-19 over no use 24. Furthermore, the surviving sepsis guideline recommends steroid administration in severe COVID19 cases with ADRS requiring MV and patients with refractory shock 25.
Our study found survival benefits with the early initiation of dexamethasone in critically ill COVID-19 patients. Several previous studies have mixed results regarding the benefits of corticosteroid use in COVID-19 patients. A recent systematic review and meta-analysis compared the effect of corticosteroids versus standard of care; the study suggested that corticosteroids were associated with a significant reduction in the mortality rates in COVID-19 patients 26. Furthermore, another meta-analysis by Sterne et al., that included data from seven randomized clinical trials aimed to evaluate the association between corticosteroids administration and 28-day all-cause mortality reported that corticosteroids associated with lower mortality rates compared with standard of care 27. However, none of these meta-analyses included studies that assessed the association between the corticosteroids, specifically dexamethasone initiation time and mortality benefits.
In our study, early dexamethasone initiation was associated with a significant reduction in 30 days ICU mortality (p-value = < 0.01). Our results are in line with the RECOVERY trial findings, which conclude that the use of dexamethasone was associated with lower 28-day mortality among patients who received respiratory support 10. However, the RECOVERY trial did not assess the effect of early dexamethasone initiation on the 30 days mortality 10. The definition of early versus late corticosteroids initiation is debatable in critically ill patients in general and, more specifically, in COVID-19 patients. We decided to choose three days cutoff margin for early vs. late initiation definition based on clinical judgment. It is well known that COVID19 related lung injury and its associated hyperinflammatory and overreacting immune response occur early in ARDS presentation. Typically, if critically ill patients fail other supportive measures, early corticosteroid initiation can mediate downregulation of systemic and pulmonary inflammation, restore homeostasis, and enhance disease resolution.
The present study found shorter hospital length of stay (LOS), ICU LOS, and MV duration in the early group compared to the late group of dexamethasone. In parallel to our findings, a recent prospective study by Monedero et al. compared outcomes between patients who received either early, delayed, or not received corticosteroids. They found that early corticosteroids use in critically ill COVID19 patients associated with shorter MV duration and less ICU LOS 28 This study results could be limited by the fact that they combined no steroids and late initiation in one group, and they included patients who received steroids earlier before ICU admission in the early group. In our study, the two groups have similar baseline characteristics with a defined cutoff margin of corticosteroid initiation time based on the ICU admission timeframe. Moreover, we only included patients who received dexamethasone to have a consistent comparison with the RECOVERY trial 10. Additionally, to further investigate if early dexamethasone initiation is different from just initiating dexamethasone at any given point.
In terms of ICU complications during ICU stay, our study found that early initiation of dexamethasone was associated with a lower incidence of acute kidney injury. That could be related to dexamethasone's prolonged and potent anti-inflammatory effect on downregulation of the inflammation and enhancing disease resolution. Our findings are consistent with Monedero et al. 28; they reported a lower rate of acute renal failure in the early group. Moreover, in our study, we assessed the complication of having respiratory failure required MV during ICU stay for patients who were not initially ventilated and found no difference between the groups. However, Monedero et al. 28 reported a lower rate of mechanical ventilation in the early steroids group.
We believe that our multicenter prospective cohort study is the first study that highlights the appropriate time of dexamethasone initiation and its effects on critically ill COVID19 patients' mortality and morbidity. It is prospective design allows to prospectively explore the association between the time of dexamethasone therapy initiation in COVID-19 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 and some residual confounding factors are still possible. Second, this study only focused on the ICU-related outcomes, but the safety outcomes and steroids-related side effects need to be addressed in further studies. Third, we cannot exclude missing data for some variables due to the observational design. Lastly, there was a dynamic change in the national and international COVID-19 management guidelines as more evidence continued to emerge, which affected the general practice.