Dequin P, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(13):1298-1306.
To identify the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 infection and acute respiratory failure.
As of Oct. 6, 2020, more than 30 million people worldwide have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a little more than 1 million people have died of coronavirus disease 2019 (COVID-19). The majority of people with COVID-19 experience mild symptoms however a significant proportion have severe symptoms, such as dyspnea, respiratory rate >30/min, blood oxygen saturation <93%, and/or lung infiltrates >50% within 24-48 hours. There is a higher rate of complication among those with preexisting medical conditions such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer.1
Although there is still much to learn regarding the exact pathophysiology of COVID-19, the resulting lung injury is thought to be from both direct cytotoxicity of the virus and an exaggerated immune response. Therefore, immunomodulatory drugs such as corticosteroids, are being investigated as a potential treatment to control the excessive inflammation.2 In a retrospective study of COVID-19 patients in Wuhan, China, better outcomes were associated with methylprednisolone administration in patients with acute respiratory distress syndrome.3
Despite the encouraging results of certain studies, some critics believe that immunosuppression can hamper viral clearance, potentially leading to increased mortality. The goal of this study, that was embedded within the ongoing CAPE COVID trial, was to evaluate the effectiveness of hydrocortisone for the treatment of ICU patients with COVID-19-associated acute respiratory failure.
The CAPE COVID Trial. This study was designed to assess the superiority of low-dose hydrocortisone compared with placebo in reducing mortality of day 28 in ICU patients with community-acquired pneumonia.
Multicenter, randomized, double-blind, and sequential trial
One of four severe criteria had to be present:
- Need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of 5cm H2O or more
- A ratio of PaO2 to fraction of inspired oxygen (FIO2) less than 300 on high-flow oxygen therapy with an FIO2 value of at least 50%
- For patients receiving oxygen through a reservoir mask, a PaO2:FIO2 ratio less than 300, estimated using pre specified charts
- A Pulmonary Severity Index greater than 130
- Septic Shock
- Do-not-intubate orders
For a total of 14 days, patients received a continuous intravenous infusion of hydrocortisone at an initial dose of 200 mg/d until day 7, and then decreased to 100 mg/d for 4 days, and 50mg/d for 3 days. Patients whose respiratory and general status had sufficiently improved by day 4, a short treatment regimen was used - 200 mg/d for 4 days, and then 100mg/d for 2 days, followed by 50 mg/d for 2 days, totaling 8 days.
Treatment failure, which was defined as death or persistent dependence of mechanical ventilation or high-flow oxygen therapy, on day 21.
- The need for tracheal intubation (excluding those intubated at inclusion)
- The use of prone position (the number of sessions)
- The use of extracorporeal membrane (ECMO) or inhaled nitric oxide (with the number of days the treatment was used)
- The PaO2:FIO2 ratio recorded daily from day 1 to day 7 and then on days 14 and 21
- The proportion of patients with and the number of episodes of nosocomial infections during the ICU stay
The study took place between March 7 and June 1, 2020 enrolling 149 patients, of whom 76 were randomized to the hydrocortisone group and 73 to the placebo group. The mean age was 63.1 (51.5-70.8) and 69.8% were men.
- On Day 21, treatment failure occurred in 32 of 76 patients in the hydrocortisone group (42.1%) vs. 37 of 73 (50.7%) in the placebo group.
- Difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29
- Sixteen patients in each group did not require intubation at baseline, of those, 8 (50%) in the hydrocortisone group and 12 (75%) in the placebo group later required intubation.
- There was no significant difference between the hydrocortisone and placebo groups for rates of prone positioning. 36/76 (47.4%) in the hydrocortisone group vs. 39/73 (53.4%) in the placebo group; hazard ratio, 0.85 (95% CI, 0.55 to 1.32); P = .47. The median number of sessions per patient was 2.0 for both groups.
- The number of patients requiring ECMO or inhaled nitric oxide was too low to allow for statistical testing.
- The evolution of PaO2:FIO2 during the first 7 days and on days 14 and 21 did not significantly differ between the two groups (P = .37).
- On day 28, there were 28 of 75 patients (37.3%) in the hydrocortisone group vs. 30 of 73 patients (41.3%) in the placebo group, with at least 1 episode of nosocomial infection. There were a total of 90 infections; 40 in the hydrocortisone group vs. 50 in the placebo group.
Overall, there was no significant reduction in the rate of treatment failure on day 21 with the use of hydrocortisone, compared to placebo. In addition, none of the prespecified secondary outcomes showed a significant difference.
This study was a multicenter and randomized trial composed of patients with baseline characteristics that could be extrapolated to the general population. The researchers carefully examined the data by conducting interim analyses every 50 patients and using statistical models that were suitable for making valid conclusions.
The early termination of this study was a major limitation. This occurred after the release of the dexamethasone trial, which showed that dexamethasone may reduce mortality on day 28 in mechanically ventilated patients. A 6 mg dose of dexamethasone is equivalent to approximately 160 mg of hydrocortisone, very close to the 200 mg of hydrocortisone used as the initial dose in this study. Second, this study did not record data relevant to COVID-19, such as the prevalence of cardiovascular and kidney disease. Third, the criteria for making a diagnosis of a nosocomial infection was not established. However, the double-blind nature of the trial suggests that comparing the rate of secondary infections between the two groups is a valid approach.
The inflammatory sequelae caused by SARS-CoV-2 have made corticosteroids a therapeutic option. Recent studies such as the CoDEX and RECOVERY trials, show potential benefit and relative reduction in short-term mortality with the use of dexamethasone. This clinical trial shows that low-dose hydrocortisone may not improve outcomes in critically ill COVID patients.
While the treatment for SARS-CoV-2 continues to evolve, the emergency department (ED) still remains a primary place for early medical intervention. The findings from this study can help guide our management for individuals with suspected COVID infection and in respiratory distress. There is growing evidence to support that initiating steroids with higher potency, relative to hydrocortisone, can positively alter the disease course of a critically ill patient.
- Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):1-11.
- Dequin P, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(13):1298-1306.
- Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China. 2020;323(13):1239-1242.