Our study identified a correlation between the administration of dexamethasone within 24 hours of oxygen supplementation (early dexamethasone) and a lower rate of HFNC or MV treatment in COVID-19 patients who required oxygen therapy or had a significant desaturation. In addition, the early dexamethasone group showed a significantly shorter total duration of oxygen supplementation and length of stay in hospital. Early dexamethasone treatment was significantly correlated with a lower rate of HFNC or MV treatment, even in multivariable logistic regression analysis and multivariable Cox regression analysis using three models. Although the early dexamethasone group required less HFNC or MV treatment, there was no difference in ECMO use or in-hospital mortality rates between the early and late dexamethasone groups. Therefore, early dexamethasone administration for hypoxemic COVID-19 patients may reduce the need for HFNC or MV treatment without increased mortality; thus, reducing the need for scarce medical resources in the COVID-19 pandemic .
Although we know that dexamethasone is associated with a lower mortality rate in COVID-19 patients undergoing oxygen therapy alone , information is needed about when dexamethasone treatment should be initiated to maximize the benefits. Considering the evidence to date, the administration of corticosteroids seems to be more effective for COVID-19 patients with active progression to ARDS than those with early-phase pneumonia. In the RECOVERY study, dexamethasone reduced more mortality in the invasive MV group (25.2%; rate ratio = 0.64 [95% CI = 0.51–0.81]), in which pneumonia was more advanced, than the oxygen-only group (37.5%; rate ratio = 0.82 [95% CI = 0.72–0.94]) . In the CoDEX study, dexamethasone benefited COVID-19 patients who used a MV after ARDS developed . A recently published meta-analysis showed that dexamethasone benefits a subgroup of patients with symptom onset > 7 days . The mechanism by which dexamethasone reduces the pulmonary and systematic inflammatory process may contribute to these results .
The invasive MV treatment group that received dexamethasone had a higher mortality rate than the oxygen-only group, which did not receive dexamethasone (29.3% vs. 26.2%) ; therefore, it is not advisable to withhold corticosteroids until HFNC or MV treatment begins. If dexamethasone can prevent the progression from requiring only oxygen supplementation to requiring a MV, it should have a substantial effect in reducing mortality. In RCTs that proved the efficacy of dexamethasone in ARDS, dexamethasone treatment was initiated in the early phase of ARDS (within 48 hours of onset) [3, 7]. This suggests that suppression of pathological inflammation by controlling macrophage activation and cytokine release in the early phase of ARDS may be important for a positive outcome .
In our study, the number of patients in the early and late dexamethasone treatment groups was almost the same, which reflects the controversy in clinical practice concerning the optimum time for dexamethasone administration. In the late dexamethasone group, it is likely that the physician did not expect the oxygen demand of the patient to increase; thus, dexamethasone would not have been be prescribed immediately. In fact, before studies on mortality reduction by dexamethasone were published, we had COVID-19 pneumonia cases where the oxygen demand gradually decreased without dexamethasone . However, there is still no good tool to predict whether COVID-19 pneumonia will worsen. Serious adverse events were no different between patients treated or not treated with dexamethasone, while the benefit of dexamethasone was significant only in the oxygen group [1, 2]. In our study, dexamethasone treatment within 24 hours of oxygen supplementation decreased the need for HFNC or MV interventions. The mean time from symptom onset to dexamethasone treatment was about 7.4 days. Therefore, when oxygen supplementation is needed, especially after 7 days of symptom onset, prompt administration of dexamethasone may be advantageous.
The present study has several limitations. First, this study was a retrospective observational study with a small number of patients. To control for confounding variables, we conducted multivariable analyses with three models. Second, the early dexamethasone group may have included more patients with less severe COVID-19 pneumonia, although there was no difference in SOFA scores and SAPS II between the early and late dexamethasone groups. The late dexamethasone group received dexamethasone only after progression of hypoxemia, whereas in the early group dexamethasone was administered as soon as hypoxemia occurred. Therefore, the patients with a milder disease, who improved without dexamethasone, may not have been included in the late dexamethasone group, but would have been included in the early dexamethasone group. Third, our study did not include very severe cases with rapid progression to ARDS. We excluded three patients who had severe hypoxemia at admission and needed HFNC treatment immediately, before dexamethasone was started. Although the anti-inflammatory effect of dexamethasone is likely to be most pronounced in ARDS patients with rapid progression, our results cannot be extrapolated to these patients. Fourth, the early and late dexamethasone groups had similar rates of remdesivir treatment; however, the timing of remdesivir administration was as late as that of dexamethasone in the late dexamethasone group.