Evaluation of the role of hydrocortisone either alone or combined with fludrocortisone in the outcome of septic shock in adults

This study was conducted at the intensive care unit (ICU) of Ain Shams University Hospitals. It was a prospective single blinded (only the patient was blinded) randomized controlled clinical study. After approval of the ethical committee of the institution, trial registration (ClinicalTrial.gov, NCT04492280), and obtaining a written informed consent from all patients or their legal guardians, the study was conducted between September 2018 and September 2020 on 66 patients subdivided randomly via computer closed envelopes method into 3 equal groups, 22 patients for each group: group C (control group), group H (hydrocortisone), and group HF (hydrocortisone and fludrocortisone).

Group C

These patients received standard therapy for sepsis which include the following: Measure lactate level, obtain blood cultures prior to administration of antibiotics, administer broad spectrum antibiotics, administer 30 mL/kg crystalloid for hypotension or lactate 4 mmol/L, apply vasopressors: norepinephrine as the first-choice vasopressor (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥ 65 mmHg, source control: specific anatomic diagnosis of infection requiring emergent source control, mechanical ventilation if indicated, e.g., Glasgow coma score < 8, stress ulcer prophylaxis: either proton pump inhibitors or histamine-2 receptor antagonists, nutritional support with early parenteral nutrition whenever possible, venous thromboembolism prophylaxis pharmacologic prophylaxis (unfractionated heparin or low-molecular-weight heparin), and blood sugar control: upper blood glucose level ≤ 180 mg/dL, glucose values will be monitored every 1 to 2 h until glucose values and insulin infusion rates are stable, then every 4 h thereafter in patients receiving insulin infusions.

Group H

These patients received standard therapy for sepsis plus hydrocortisone (Solucortef®, E.I.P.I.co. under license of Pfizer) at dose 50 mg every 6 h by intravenous route.

Group HF

These patients received standard therapy for sepsis plus hydrocortisone (Solucortef®) at dose of 50 mg every 6 h by intravenous route and fludrocortisone (Cortilon®, Amoun) 50 μg once daily by nasogastric tube for 1 week.

Patients included in this study were between 18 and 80 years old, both sexes who were suffering from septic shock and had any of the following criteria: clinical evidence of infection within the previous 72 h of ICU admission or Sepsis-Related Organ Failure Assessment (SOFA) score of 3 or 4 (on a scale of 0 to 4 for each of six organ systems) for at least 2 organs and at least 6 h or vasopressors therapy (norepinephrine, epinephrine, or any other vasopressors at a dose of ≥0.25 μg/kg/min) for at least 6 h to maintain a systolic blood pressure of at least 90 mmHg or mean blood pressure of at least 65 mmHg. The reasons for exclusion included refusal of patient or legal guardian to consent to participate in the study, pregnancy, lactation, and gastrointestinal bleeding.

The study end points were either improvement of the patient in the form of maintaining MAP ≥65 mmHg without vasopressors or death of patient. The primary outcome is the mortality rate due to septic shock. The secondary outcomes were the following: first, the time of weaning from vasopressors (in days). The number of days each patient required to cease the usage of vasopressors in their treatment regimen. Then, the mean number of days in each group was calculated to detect the statistical significance. Second, the SOFA score was calculated and recorded for each patient in every group on admission (baseline) and on a daily basis. Then, the mean value for each group everyday was calculated to check for statistically significant difference between the three groups. Third the duration of ICU stays due to septic shock as a cause (in days). The number of days each patient would spend in the ICU until they leave (either due to discharge or death). Then the mean number of days spent in each group was calculated to detect for the statistical significance between the three different groups. Fourth the complications of steroids: any complication that appeared on any of the patients was recorded and the total of each complication was calculated to give the percentage of the presence of this complication in each group to measure the effect of steroid therapy.

Statistical analysis was performed using the Statistical Package for Social Sciences (IBM SPSS Statistics) for Windows, version 20 (IBM© Corp., Armonk, NY, USA). For quantitative data, the Shapiro-Wilk test for normality was performed. Normally distributed data were summarized as mean and standard deviation (SD). The studied groups were compared using ANOVA and post-hoc paired t test when the results were significant. Qualitative data were summarized as frequencies and percentages, and associations were tested using the chi-square test. A p value < 0.05 was considered significant.

Sample size determination based on 0.05 power 0.8, Using G*power program, setting alpha error at 5% and power at 80% assuming an effect size of 0.4 per the combination of hydrocortisone and fludrocortisone on the outcome of septic shock patients, the needed sample will be 66 patients subdivided into 3 equal groups, 22 patients for each group. Random allocation sequence was generated using Random.org to assist in locating the patients in one of the three groups with reducing the chance of bias. The technique employed in this study was the simple random technique where the sequence was generated an opaque envelope containing folded papers having the number of the patients. The only side who blinding was applied to was the patient.

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