ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients With Septic Shock

Primary Objective To evaluate the impact of intravenous hydrocortisone versus placebo on all cause mortality at 90 days in critically ill patients with septic shock. The hypothesis is that hydrocortisone, compared to placebo, reduces 90-day all-cause mortality in patients admitted to an ICU with septic shock. 'Shock' is defined as the need for vasopressors or inotropes to maintain a systolic blood pressure > 90 millimetres of mercury (mmHg), or mean arterial blood pressure > 60mmHg or a mean arterial pressure (MAP) target set by the treating clinician for maintaining perfusion. 'Septic shock' is shock that is secondary to sepsis

Secondary Objectives To assess the impact of intravenous hydrocortisone versus placebo on the recovery from, and the complications of, septic shock and the development of treatment related adverse reactions.

Study Design This study is a multi centre, randomised, blinded, placebo controlled trial comparing intravenous hydrocortisone with placebo in critically ill patients with septic shock.

Randomisation will be achieved via a secure interactive web based system using permuted block minimisation. Randomisation will be stratified by participating site and by operative or non-operative admission to the ICU.

The primary endpoint for this trial will be death from all causes at 90 days.

Pre defined sub groups will include the following categories:

• Operative (admitted to ICU from operating theatre or recovery room) versus non-operative admission.
• Dose of adrenaline or noradrenaline at randomisation - ≤ 15 mcg / minute versus > 15 mcg / minute.

3,800 patients will be enrolled in this study at approximately 50 - 60 study sites. Eligible patients will be randomised to receive either intravenous hydrocortisone 200mg or placebo per day for 7 days.

For all patients, data will be collected at baseline and then daily whilst the patient is in the ICU. Patients will be followed up to day 14, regardless of where the patient resides in the hospital, to monitor the development of bacteraemia. Additional follow up will occur at 90 days and at 6 months post randomisation.

Inclusion criteria

• Aged 18 years or older
• Documented site of infection, or strong suspicion of infection, with 2 of the 4 clinical signs of inflammation:

• Core temperature > 38°C or < 35°C
• Heart rate > 90 beats per minute
• White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils
• Respiratory rate > 20 breaths per minute, or PaCO2 < 32 mmHg, or mechanical ventilation.
• Being treated with mechanical ventilation at the time of randomisation
• Being treated with vasopressors or inotropes to maintain a systolic blood pressure > 90mmHg, or mean arterial blood pressure > 60mmHg, or a MAP target set by the treating clinician for maintaining perfusion
• Administration of vasopressors or inotropes for = 4 hours and present at time of randomisation.

Exclusion criteria

• Met all inclusion criteria more than 24 hours ago
• Clinician expects to prescribe systemic corticosteroids for an indication other than septic shock (not including nebulised or inhaled corticosteroid)
• Patients treated with etomidate
• Patients receiving treatment with Amphotericin B for systemic fungal infections at time of randomisation
• Patients with documented cerebral malaria at the time of randomisation
• Patients with documented strongyloides infection at the time of randomisation
• Death is deemed inevitable or imminent during this admission and either the attending physician, patient or surrogate legal decision maker is not committed to active treatment
• Death from underlying disease is likely within 90 days
• Patient has been previously enrolled in the ADRENAL study.