Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone for the Treatment of Adrenal Insufficiency in Severe Sepsis
NCT ID: NCT00368381
Last Updated: 2012-02-13
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
WITHDRAWN
Clinical Phase
PHASE4
Study Classification
INTERVENTIONAL
Study Start Date
2006-09-30
Study Completion Date
2009-09-30
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.
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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.
Conditions
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Sepsis
Adrenal Insufficiency
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Hydrocortision and fludrocortisone
Study is comparing hydrocortisone alone versus the combination of hydrocortisone and fludrocortisone in the treatment of adrenal insufficiency of septic patients.
Group Type
ACTIVE_COMPARATOR
Hydrocortisone
Intervention Type
DRUG
Patients randomized to this arm will receive hydrocortisone for the treatment of adrenal insufficiency secondary to sepsis.
Interventions
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Hydrocortisone
Patients randomized to this arm will receive hydrocortisone for the treatment of adrenal insufficiency secondary to sepsis.
Intervention Type
DRUG
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
* 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.
* 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.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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CAMC Health System
OTHER
Sponsor Role
lead
Responsible Party
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Audis Bethea, Pharm.D.
Clinical Pharmacy Specialist, Trauma/Surgery
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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John A Bethea, Pharm.D.
Role: PRINCIPAL_INVESTIGATOR
Charleston Area Medical Center (CAMC)
References
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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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
Annane D. Corticosteroids for septic shock. Crit Care Med. 2001 Jul;29(7 Suppl):S117-20. doi: 10.1097/00003246-200107001-00036.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
Oelkers W. Adrenal insufficiency. N Engl J Med. 1996 Oct 17;335(16):1206-12. doi: 10.1056/NEJM199610173351607. No abstract available.
Reference Type
RESULT
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.
Reference Type
RESULT
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.
Reference Type
RESULT
Other Identifiers
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06-05-1813
Identifier Type: -
Identifier Source: org_study_id
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