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

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ClinicalTrials.gov Identifier: NCT00368381

Recruitment Status : Withdrawn (Study closed for PI failure to submit renewal paperwork)

First Posted : August 24, 2006

Last Update Posted : February 13, 2012

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Audis Bethea, Pharm.D., CAMC Health System

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Sepsis Adrenal Insufficiency	Drug: Hydrocortisone	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	0 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Blinded, Placebo Controlled Trial of Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone for the Treatment of Adrenal Insufficiency in Severe Sepsis
Study Start Date :	September 2006
Actual Primary Completion Date :	July 2009
Actual Study Completion Date :	September 2009

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Familial glucocorticoid deficiency

MedlinePlus related topics: Sepsis

Drug Information available for: Hydrocortisone acetate Hydrocortisone Epinephrine bitartrate Epinephrine Epinephrine hydrochloride Hydrocortisone sodium succinate Racepinephrine hydrochloride Racepinephrine Hydrocortisone cypionate Fludrocortisone acetate Hydrocortisone valerate Hydrocortisone probutate Proctofoam-HC

U.S. FDA Resources

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

All cause mortality [ Time Frame: 28 days ]
All cause mortality during first 28-days after study randomization.

Secondary Outcome Measures :

Intensive care unit survival, duration of intensive care unit stay, duration of hospitalization, survival to hospital discharge, time to vasopressor withdrawal [ Time Frame: Unable to define ]
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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00368381

Sponsors and Collaborators

CAMC Health System

Investigators

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Principal Investigator:	John A Bethea, Pharm.D.	Charleston Area Medical Center (CAMC)

More Information

Publications of Results:

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. doi: 10.1016/s0039-6060(05)80352-6.

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. doi: 10.1210/jcem.81.10.8855809.

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. doi: 10.1056/NEJM198709103171101.

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. doi: 10.1056/NEJM198411013111801.

Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med. 1995 Jul;23(7):1294-303. doi: 10.1097/00003246-199507000-00021.

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. doi: 10.1097/00003246-199508000-00019.

Thomas JP, el-Shaboury AH. Aldosterone secretion in steroid-treated patients with adrenal suppression. Lancet. 1971 Mar 27;1(7700):623-5. doi: 10.1016/s0140-6736(71)91554-6. 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. doi: 10.1097/00003246-199904000-00025.

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. doi: 10.1097/00003246-199804000-00010.

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. doi: 10.1001/jama.283.8.1038.

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaud 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. doi: 10.1001/jama.288.7.862. Erratum In: JAMA. 2008 Oct 8;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe].

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. doi: 10.1007/s001340051202.

Oelkers W. Adrenal insufficiency. N Engl J Med. 1996 Oct 17;335(16):1206-12. doi: 10.1056/NEJM199610173351607. 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. doi: 10.1210/jcem-53-4-867.

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. doi: 10.1210/jcem-64-3-592.

Other Publications:

Balk RA. Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations. Crit Care Clin. 2000 Apr;16(2):179-92. doi: 10.1016/s0749-0704(05)70106-8.

Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588-95. doi: 10.1056/NEJMra002709. No abstract available.

Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003 Mar;31(3):946-55. doi: 10.1097/01.CCM.0000057403.73299.A6. No abstract available.

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. doi: 10.1056/NEJMra021333. 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(Suppl 3):S1-18. doi: 10.1186/cc1860. Epub 2002 Dec 5.

Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002 Jan 9;287(2):236-40. doi: 10.1001/jama.287.2.236. 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. doi: 10.1056/NEJM199710303371807. 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. doi: 10.1378/chest.122.5.1784.

Annane D. Corticosteroids for septic shock. Crit Care Med. 2001 Jul;29(7 Suppl):S117-20. doi: 10.1097/00003246-200107001-00036.

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. doi: 10.1592/phco.23.4.514.32123.

Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med. 2001 Jun;163(7):1520-3. doi: 10.1164/ajrccm.163.7.2012022. No abstract available.

Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 Feb 20;348(8):727-34. doi: 10.1056/NEJMra020529. No abstract available.

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Responsible Party:	Audis Bethea, Pharm.D., Clinical Pharmacy Specialist, Trauma/Surgery, CAMC Health System
ClinicalTrials.gov Identifier:	NCT00368381
Other Study ID Numbers:	06-05-1813
First Posted:	August 24, 2006 Key Record Dates
Last Update Posted:	February 13, 2012
Last Verified:	February 2012

Keywords provided by Audis Bethea, Pharm.D., CAMC Health System:


sepsis septicemia sepsis syndrome adrenal insufficiency	adrenal cortex hormones hydrocortisone fludrocortisone

Additional relevant MeSH terms:

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Sepsis Toxemia Adrenal Insufficiency Infections Systemic Inflammatory Response Syndrome Inflammation	Pathologic Processes Adrenal Gland Diseases Endocrine System Diseases Hydrocortisone Anti-Inflammatory Agents

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