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

Condition(s) targeted: Sepsis; Adrenal Insufficiency

Intervention: Fludrocortisone (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: CAMC Health System

Official(s) and/or principal investigator(s):
John A Bethea, Pharm.D., Principal Investigator, Affiliation: Charleston Area Medical Center (CAMC)

Overall contact:
John A Bethea, Pharm.D., Phone: 304-388-6260, Email: audis.bethea@camc.org

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.

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

Study design: Treatment, Randomized, Single Blind, Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: Twenty-eight day (all cause) mortality

Secondary outcome: Intensive care unit survival, duration of intensive care unit stay, duration of hospitalization, survival to hospital discharge, time to vasopressor withdrawal

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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.

John A Bethea, Pharm.D., Phone: 304-388-6260, Email: audis.bethea@camc.org

Charleston Area Medical Center, Charleston, West Virginia 25301, United States; Recruiting
John A Bethea, Pharm.D., Principal Investigator
Carol A Morreale, Pharm.D., Sub-Investigator
Rajeeve T Thachil, M.D., Sub-Investigator

Related publications:

Balk RA. Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations. Crit Care Clin. 2000 Apr;16(2):179-92. Review.

Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588-95. Review. No abstract available.

Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003 Mar;31(3):946-55. Review. No abstract available.

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. Review. No abstract available.

Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Reducing mortality in sepsis: new directions. Crit Care. 2002 Dec;6 Suppl 3:S1-18. Epub 2002 Dec 5. Review.

Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002 Jan 9;287(2):236-40. Review. No abstract available.

Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med. 1997 Oct 30;337(18):1285-92. Review. No abstract available.

Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002 Nov;122(5):1784-96. Review.

Annane D. Corticosteroids for septic shock. Crit Care Med. 2001 Jul;29(7 Suppl):S117-20. Review.

Williamson DR, Lapointe M. The hypothalamic-pituitary-adrenal axis and low-dose glucocorticoids in the treatment of septic shock. Pharmacotherapy. 2003 Apr;23(4):514-25. Review.

Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med. 2001 Jun;163(7):1520-3. Review. No abstract available.

Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 Feb 20;348(8):727-34. Review. No abstract available.

Starting date: September 2006
Ending date: September 2010
Last updated: April 13, 2007