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

Sepsis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00368381
• Other study ID #: 06-05-1813
• Status: Withdrawn
• Phase: Phase 4
• First received: August 23, 2006
• Last updated: February 10, 2012
• Start date: September 2006
• Est. completion date: September 2009

Study information

• Verified date: February 2012
• Source: CAMC Health System
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 ? = 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(? > 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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adrenal Insufficiency
• Sepsis
• Toxemia

Intervention

Drug:
• Hydrocortisone
Patients randomized to this arm will receive hydrocortisone for the treatment of adrenal insufficiency secondary to sepsis.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
CAMC Health System

References & Publications (27)

Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with sept — View Citation

Annane D, Sébille V, Troché G, Raphaël 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. — View Citation

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

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

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 — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 Feb 20;348(8):727-34. Review. — View Citation

Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002 Jan 9;287(2):236-40. Review. — View Citation

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. — View Citation

Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003 Mar;31(3):946-55. Review. — View Citation

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. — View Citation

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. Review. — View Citation

Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med. 1997 Oct 30;337(18):1285-92. Review. — View Citation

Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588-95. Review. — View Citation

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

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. — View Citation

Oelkers W. Adrenal insufficiency. N Engl J Med. 1996 Oct 17;335(16):1206-12. Review. — View Citation

Rydvall A, Brändström AK, Banga R, Asplund K, Bäcklund 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. — View Citation

Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med. 2001 Jun;163(7):1520-3. Review. — View Citation

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. — View Citation

Thomas JP, el-Shaboury AH. Aldosterone secretion in steroid-treated patients with adrenal suppression. Lancet. 1971 Mar 27;1(7700):623-5. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All cause mortality	All cause mortality during first 28-days after study randomization.	28 days	No
Secondary	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	No