Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone for the Treatment of Adrenal Insufficiency in Severe Sepsis

Study Overview
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Brief Summary
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The purpose of this study is to determine if the combination of hydrocortisone plus fludrocortisone is more efficacious than hydrocortisone alone in treating adrenal insufficiency in severe sepsis.

Detailed Description
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Sepsis is a significant cause of morbidity and mortality in critically ill patients in the United States. As evidenced by its increasing prevalence and high mortality rates, sepsis is a complex and difficult syndrome to treat. Current therapeutic management of sepsis includes fluid resuscitation, vasopressor and inotropic support, maintenance of oxygen delivery, drotrecogin alpha, and steroid replacement therapy in patients who are found to have adrenal insufficiency. Studies in septic patients suggest that the administration of stress doses of hydrocortisone alone, or the combination of hydrocortisone plus fludrocortisone promotes an improvement in cardiovascular performance and a quicker resolution of shock symptoms. Current therapeutic guidelines for the treatment of severe sepsis recommend either hydrocortisone alone or combination therapy with hydrocortisone and fludrocortisone as therapeutic options for the treatment of adrenal dysfunction in severe sepsis. This study will help determine which regimen is more efficacious in this patient population.

Official Title
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A Blinded, Placebo Controlled Trial of Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone for the Treatment of Adrenal Insufficiency in Severe Sepsis

Conditions
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Sepsis, Adrenal Insufficiency

Intervention / Treatment
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* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and non-pregnant females > 18 years of age Patients admitted and/or pending admission to the intensive care unit Positive corticotropin stimulation test (Basal cortisol level of ≤ 34 μg/dL with Δ ≤ 9 μg/dL after administration of 250 mg of cosyntropin) Patient satisfies criteria for severe sepsis Infection - one or more of the following criteria Documented or Suspected - positive culture results (from blood, sputum, urine, etc.) Anti-Infective Therapy - patient is receiving antibiotic, antifungal, or other anti-infective therapy Pneumonia - documentation of pneumonia (x-ray, etc.) WBCs - WBCs found in normally sterile .uid (urine, CSF, etc.) Perforated Viscus - perforation of hollow organ (bowel) SIRS - two or more of the following Temperature > 38° or < 36° Heart rate > 90 bpm Respiratory rate above 20 breaths per minute WBC > 14,000/mm3 , < 4000/mm3, or >10% Bands Acute organ dysfunction - one or more of the following Cardiovascular - SBP < 90 mmHg or MAP < 70 mmHg despite 20 mL/kg of fluid resuscitation Respiratory - PaO2/FiO2 ratio < 250, PEEP > 7.5, or require mechanical ventilation Renal - low urine output (eg, <0.5 mL/kg/hr for 1 hour despite 20mL/kg of fluid resuscitation, increased creatinine (>50% increase from baseline) or require acute dialysis Hematologic - low platelet count (< 100,000/mm3) or PT/PTT > upper limit of normal Metabolic - low pH with high lactate (eg, pH < 7.30 and plasma lactate > upper limit of normal Hepatic - liver enzymes > 2x upper limit of normal CNS - altered consciousness or reduced Glasgow Coma Score Exclusion Criteria: Patients who respond to the short cosyntropin stimulation test(Δ > 9mg/dL) Pregnancy or breast-feeding mother Evidence of acute myocardial infarction, meningitis, pulmonary embolism AIDS (CD4 < 200 cells/mL) Contraindications for corticosteroids Formal indication for corticosteroids (specifically including patients with known adrenal insufficiency) Onset of shock > 24 hours Etomidate administration within the 6 hours preceding randomization Cardiac arrest prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydrocortision and fludrocortisone<br>Study is comparing hydrocortisone alone versus the combination of hydrocortisone and fludrocortisone in the treatment of adrenal insufficiency of septic patients. | Drug: Hydrocortisone<br>* Patients randomized to this arm will receive hydrocortisone for the treatment of adrenal insufficiency secondary to sepsis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality | All cause mortality during first 28-days after study randomization. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensive care unit survival, duration of intensive care unit stay, duration of hospitalization, survival to hospital discharge, time to vasopressor withdrawal | The various secondary endpoints are patient specific serrogate markers of improvement in clinical status. Time frame for these endpoints to occur is patient specific and can not be defined for the entire study population. | Unable to define | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septicemia, sepsis syndrome, adrenal insufficiency, adrenal cortex hormones, hydrocortisone, fludrocortisone