Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone for the Treatment of Adrenal Insufficiency in Severe Sepsis - Full Text View

Sponsor:	CAMC Health System
Information provided by:	CAMC Health System
ClinicalTrials.gov Identifier:	NCT00368381

Purpose

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.

Condition	Intervention	Phase
Sepsis Adrenal Insufficiency	Drug: Fludrocortisone	Phase IV

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	A Blinded, Placebo Controlled Trial of Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone for the Treatment of Adrenal Insufficiency in Severe Sepsis

Resource links provided by NLM:

Genetics Home Reference related topics: X-linked adrenoleukodystrophy

MedlinePlus related topics: Sepsis

Drug Information available for: Hydrocortisone acetate Hydrocortisone Epinephrine bitartrate Epinephrine Proctofoam-HC Hydrocortisone hemisuccinate Hydrocortamate Hydrocortisone 21-sodium succinate Fludrocortisone Hydrocortisone cypionate Fludrocortisone 21-acetate Cortisol succinate Cortisol 21-phosphate

U.S. FDA Resources

Further study details as provided by CAMC Health System:

Primary Outcome Measures:

Twenty-eight day (all cause) mortality

Secondary Outcome Measures:

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

Estimated Enrollment:	788
Study Start Date:	September 2006
Estimated Study Completion Date:	September 2010

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00368381

Sponsors and Collaborators

CAMC Health System

Investigators

Principal Investigator:

John A Bethea, Pharm.D.

Charleston Area Medical Center (CAMC)

More Information

Publications:

Barber AE, Coyle SM, Fischer E, Smith C, van der Poll T, Shires GT, Lowry SF. Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings. Surgery. 1995 Aug;118(2):406-10; discussion 410-1.

van der Poll T, Barber AE, Coyle SM, Lowry SF. Hypercortisolemia increases plasma interleukin-10 concentrations during human endotoxemia--a clinical research center study. J Clin Endocrinol Metab. 1996 Oct;81(10):3604-6.

Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987 Sep 10;317(11):653-8.

Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984 Nov 1;311(18):1137-43.

Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med. 1995 Jul;23(7):1294-303.

Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995 Aug;23(8):1430-9.

Thomas JP, el-Shaboury AH. Aldosterone secretion in steroid-treated patients with adrenal suppression. Lancet. 1971 Mar 27;1(7700):623-5. No abstract available.

Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999 Apr;27(4):723-32.

Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998 Apr;26(4):645-50.

Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000 Feb 23;283(8):1038-45.

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71.

Rydvall A, Brandstrom AK, Banga R, Asplund K, Backlund U, Stegmayr BG. Plasma cortisol is often decreased in patients treated in an intensive care unit. Intensive Care Med. 2000 May;26(5):545-51.

Oelkers W. Adrenal insufficiency. N Engl J Med. 1996 Oct 17;335(16):1206-12. Review. No abstract available.

Zipser RD, Davenport MW, Martin KL, Tuck ML, Warner NE, Swinney RR, Davis CL, Horton R. Hyperreninemic hypoaldosteronism in the critically ill: a new entity. J Clin Endocrinol Metab. 1981 Oct;53(4):867-73.

Findling JW, Waters VO, Raff H. The dissociation of renin and aldosterone during critical illness. J Clin Endocrinol Metab. 1987 Mar;64(3):592-5.

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.

Responsible Party:	Charleston Area Medical Center Health System ( Audis Bethea, PharmD, BCPS )
Study ID Numbers:	06-05-1813
Study First Received:	August 23, 2006
Last Updated:	July 15, 2009
ClinicalTrials.gov Identifier:	NCT00368381 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by CAMC Health System:

sepsis
septicemia
sepsis syndrome
adrenal insufficiency

adrenal cortex hormones
hydrocortisone
fludrocortisone

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Systemic Inflammatory Response Syndrome
Adrenal Insufficiency
Hydrocortisone
Autoimmune Diseases
Immune System Diseases
Cortisol succinate
Adrenal Gland Diseases
Endocrine System Diseases

Infection
Pharmacologic Actions
Inflammation
Sepsis
Pathologic Processes
Therapeutic Uses
Addison Disease
Fludrocortisone
Hydrocortisone acetate

ClinicalTrials.gov processed this record on November 09, 2009