Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis
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《英国医生杂志》
1 Critical Care Department, Université de Versailles Saint-Quentin en Yvelines, Assistance Publique-H?pitaux de Paris, H?pital Raymond Poincaré, Garches 92380, France, 2 Clinical Investigation Centre, INSERM 0203, Université de Rennes 1, Centre Hospitalier Universitaire, H?pital de Pontchaillou, Rennes 35033, France, 3 Critical Care Department, Université de Nancy 1, Centre Hospitalier Universitaire, H?pital Central, Nancy 54000, France, 4 Institut für Anaesthesiology, Klinikum der Universit?t München, Munich, 81366, Germany, 5 Intensive Care Unit, Charité-Campus Virchow Clinic, Berlin, 13353, Germany, 6 Division of Pulmonary and Critical Care Medicine, Maimonides Medical Centre, Brooklyn, New York, NY 11219, USA
Correspondence to: D Annane djillali.annane@rpc.ap-hop-paris.fr
Abstract
Each year severe sepsis occurs in about three people per 1000 population and accounts for 2% of hospital stays.1 About 3% of such patients will develop septic shock,2 which itself accounts for 10% of stays in intensive care units.3 Overall, hospital mortality is 30% for severe sepsis and 50-60% for septic shock.1-3
Researchers have explored the biological mechanisms of septic shock for potential interventions. Corticosteroids have been tested because of their interactions with immune responses.4 Indeed, these hormones affect inflammation through their effects on white blood cells, cytokines, and nitric oxide production. However, cytokines may suppress the cortisol response to the adrenocorticotropin hormone, causing poor adrenal activity,5 and body tissues may become resistant to corticosteroids.6 The prevalence of adrenal insufficiency in septic shock is about 50%. For these reasons, it has been anticipated that corticosteroids could be beneficial in septic shock.
Initial studies with corticosteroids in sepsis and septic shock used short courses of high doses. They did not show any evidence of benefit, as shown by two meta-analyses of the randomised trials published during the period 1966-93.7 8 However, these reviews did not exclude a benefit of longer durations of treatment ( 5 days) and lower doses ( 300 mg hydrocortisone or equivalent a day), as observed in more recent trials.9-14 We systematically reanalysed the effects of corticosteroids in severe sepsis and septic shock, considering all currently available data.
Methods
Description of studies
We identified 23 trials on corticosteroids in severe sepsis or septic shock.9-14 18-34 Of these, we excluded seven (table 1) 18 21 22 25 26 29 34 and included 16 trials (n = 2063) (table 2). For six trials (n = 524) we extracted data from both published and unpublished souces.9-12 14 28 For one trial, contact with authors did not provide any additional information.32 For the nine other trials the primary investigators could not be contacted.13 19 20 23 24 27 30 31 33 Tables 3 and 4 give details of the studies included.
Table 1 Characteristics of studies excluded from meta-analysis of corticosteroids for patients with severe sepsis or septic shock
Table 2 Characteristics of included randomised controlled trials
Table 3 Assessment of methodological quality of studies with Cronin et al's "methodologic quality form"*8
Table 4 Assessment of methodological quality of studies with method recommended by Cochrane Infectious Diseases Group
All cause mortality at 28 days
We extracted data for all cause mortality at 28 days from 15 trials (n = 2022) (fig 1). There were 351/1033 (34%) deaths in the treated group compared with 329/989 (33%) in the control group. There was significant heterogeneity in the results (2 = 33.09, P = 0.003). The relative risk of dying at 28 days was 0.92 (95% confidence interval 0.75 to 1.14, P = 0.46; random effects model).
Fig 1 Effects of corticosteroids on all cause mortality at 28 days in patients with severe sepsis and septic shock
The subgroup analysis on five trials (n = 465) with long courses of low dose corticosteroids no longer showed heterogeneity across the trials, and the all cause mortality at 28 days was lower (0.80, 0.67 to 0.95, P = 0.01). In contrast, the subgroup analysis on eight trials (n = 1115) with short courses of high dose corticosteroids did not show any difference (0.97, 0.72 to 1.31, P = 0.84; random effects model). Subgroup analyses based on high quality trials had a relative risk near 1.0 and failed to explain heterogeneity (data not shown).
Mortality in intensive care unit
We extracted data for mortality in intensive care units from four trials (n = 425), all of which investigated the effects of long courses of low dose corticosteroids (fig 2). There were 108/216 (50%) deaths in the intensive care unit in the treated group compared with 127/209 (61%) in the control group (0.83, 0.70 to 0.97, P = 0.02).
Fig 2 Effects of corticosteroids on mortality in intensive care unit in patients with severe sepsis and septic shock
Mortality in hospital
We extracted data for hospital mortality from 13 trials (n = 1418) (fig 3). There were 279/730 (38%) hospital deaths in the treated group compared with 271/688 (39%) in the control group. There was significant heterogeneity in the results (2 = 27.68, P = 0.006). The relative risk of dying in hospital was 0.89 (0.71 to 1.11, P = 0.30; random effects model).
Fig 3 Effects of corticosteroids on mortality in hospital in patients with severe sepsis and septic shock
The subgroup analysis on five trials (n = 465) with long courses of low dose corticosteroids no longer showed heterogeneity across the trials and showed reduced mortality in hospital (0.83, 0.71 to 0.97, P = 0.02). In contrast, the subgroup analysis on six trials (n = 511) with short courses of high dose corticosteroids did not show any difference in hospital mortality (0.89, 0.57 to 1.37, P = 0.59; random effects model). Subgroup analyses based on high quality trials had a relative risk near 1.0 and failed to explain heterogeneity (data not shown).
Shock reversal at day 7
We extracted data for shock reversal at day 7 from six trials (n = 728) (fig 4). There were 218/389 (56%) shock reversals at day 7 in the treated group compared with 154/339 (45%) in the control group (1.43, 1.01 to 2.01, P = 0.04; random effects model). There was significant heterogeneity in the results (2 = 20.38, P = 0.001).
Fig 4 Effects of corticosteroids on shock reversal in patients with severe sepsis and septic shock
The subgroup analysis on four trials (n = 425) with long courses of low dose corticosteroids no longer showed heterogeneity across the trials, and showed increased rate of shock reversals at 7 days (108/216 (50%) v 65/209 (31%); 1.60, 1.27 to 2.03, P < 0.0001).
Shock reversal at day 28
We extracted data for shock reversal at day 28 from four trials (n = 425) (fig 4). There were 117/216 (54%) shock reversals at day 28 in the treated group compared with 90/209 (43%) in the control group (1.26, 1.04 to 1.52, P = 0.02).
Adverse events
There was no evidence that corticosteroids increased the risk of gastroduodenal bleeding (10 trials, n = 1321; 1.16, 0.82 to 1.65, P = 0.40), superinfections (12 trials, n = 1705; 0.93, 0.73 to 1.18, P = 0.54), or hyperglycaemia (6 trials, n = 608; 1.22, 0.84 to 1.78, P = 0.30) (fig 5). Only one trial reported the definition for hyperglycaemia,32 the others reporting only the number of patients with hyperglycaemia. Another trial reported a significant rise in serum sodium concentration (> 155 mmol/l) in 6/20 (30%) patients in the treated group and in 1/20 (5%) patients in the placebo group.10
Fig 5 Adverse effects of corticosteroids in patients with severe sepsis and septic shock
Discussion
Angus D, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29: 1303-10.
Rangel-Frausto MS, Pittet D, Hwang T, Woolson RF, Wenzel RP. The dynamics of disease progression in sepsis: Markov modeling describing the natural history and the likely impact of effective antisepsis agents. Clin Infec Dis 1998;27: 185-90.
Annane D, Aegerter P, Jars-Guincestre MC, Guidet B. Current epidemiology of septic shock: the CUB-Réa Network. Am J Resp Crit Care Med 2003;168: 165-72.
Annane D, Cavaillon JM. Corticosteroids in sepsis: from bench to bedside? Shock 2003;20: 197-207.
Annane D, Sébille V, Troché G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotrophin. JAMA 2000;283: 1038-45.
Meduri GU, Chrousos GP. Duration of glucocorticoid treatment and outcome in sepsis: is the right drug used the wrong way? Chest 1998;114: 355-60.
Lefering R, Neugebauer EAM. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med 1995;23: 1294-303.
Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23: 1430-9.
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;26: 645-50.
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27: 723-32.
Chawla K, Kupfer Y, Tessler S. Hydrocortisone reverses refractory septic shock. Crit Care Med 1999;27: A33.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288: 862-71.
Yildiz O, Doganay M, Aygen B, Guven M, Keleutimur F, Tutuu A. Physiologic-dose steroid therapy in sepsis. Crit Care 2002;6: 251-9.
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, et al. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Resp Crit Care Med 2003;167: 512-0.
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20: 864-74.
Clarke M, Oxman A, eds. Cochrane reviewers' handbook 4.2.0 . In: The Cochrane Library. Issue 3. Chichester: John Wiley, 2003.
Juni P, Altman DG, Egger M. Systematic reviews in healthcare: assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Hahn EO, Houser HB, Rammelkamp CH Jr, Denny FW, Wannamaker LW. Effect of cortisone on acute streptococcal infections and poststreptococcal complications. J Clin Invest 1951;30: 274-81.
Wagner HN, Bennett IL, Lasagna L, Cluff LE, Rosenthal MB, Mirick GS. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1955;98: 197-215.
Cooperative Study Group. The effectiveness of hydrocortisone in the management of severe infections. JAMA 1963;183: 462-5.
Rogers J. Large doses of steroids in septicaemic shock. Br J Urol 1970;42: 742.
Thompson WL, Gurley HT, Lutz BA, Jackson DL, Kvols LK, Morris IA. Inefficacy of glucocorticoids in shock (double-blind study). Clin Res 1976;24: 258A.
Klastersky J, Cappel R, Debusscher L. Effectiveness of betamethasone in management of severe infections. A double-blind study. N Engl J Med 1971;284: 1248-50.
Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976;184: 333-41.
McKee JI, Finlay WE. Cortisol replacement in severely stressed patients. Lancet 1983;1: 484.
Hughes GS Jr. Naloxone and methylprednisolone sodium succinate enhance sympathomedullary discharge in patients with septic shock. Life Sci 1984;35: 2319-26.
Lucas C, Ledgerwood A. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Arch Surg 1984;119: 537-41.
Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984;311: 1137-43.
Weigelt JA, Norcross JF, Borman KR, Snyder WH 3rd. Early steroid therapy for respiratory failure. Arch Surg 1985;120: 536-40.
Bone RG, Fisher CJ, 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;317: 653-8.
Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987;317: 659-65.
Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Resp Dis 1988;138: 62-8.
Slusher T, Gbadero D, Howard C, Lewison L, Giroir B, Toro L, et al. Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Ped Infect Dis J 1996;15: 579-83.
Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280: 159-65.
Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337: 582-3.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348: 727-34.
Annane D, Bellissant E, Bollaert P, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Syst Rev 2004;(1): CD002243.(Djillali Annane, professo)
Correspondence to: D Annane djillali.annane@rpc.ap-hop-paris.fr
Abstract
Each year severe sepsis occurs in about three people per 1000 population and accounts for 2% of hospital stays.1 About 3% of such patients will develop septic shock,2 which itself accounts for 10% of stays in intensive care units.3 Overall, hospital mortality is 30% for severe sepsis and 50-60% for septic shock.1-3
Researchers have explored the biological mechanisms of septic shock for potential interventions. Corticosteroids have been tested because of their interactions with immune responses.4 Indeed, these hormones affect inflammation through their effects on white blood cells, cytokines, and nitric oxide production. However, cytokines may suppress the cortisol response to the adrenocorticotropin hormone, causing poor adrenal activity,5 and body tissues may become resistant to corticosteroids.6 The prevalence of adrenal insufficiency in septic shock is about 50%. For these reasons, it has been anticipated that corticosteroids could be beneficial in septic shock.
Initial studies with corticosteroids in sepsis and septic shock used short courses of high doses. They did not show any evidence of benefit, as shown by two meta-analyses of the randomised trials published during the period 1966-93.7 8 However, these reviews did not exclude a benefit of longer durations of treatment ( 5 days) and lower doses ( 300 mg hydrocortisone or equivalent a day), as observed in more recent trials.9-14 We systematically reanalysed the effects of corticosteroids in severe sepsis and septic shock, considering all currently available data.
Methods
Description of studies
We identified 23 trials on corticosteroids in severe sepsis or septic shock.9-14 18-34 Of these, we excluded seven (table 1) 18 21 22 25 26 29 34 and included 16 trials (n = 2063) (table 2). For six trials (n = 524) we extracted data from both published and unpublished souces.9-12 14 28 For one trial, contact with authors did not provide any additional information.32 For the nine other trials the primary investigators could not be contacted.13 19 20 23 24 27 30 31 33 Tables 3 and 4 give details of the studies included.
Table 1 Characteristics of studies excluded from meta-analysis of corticosteroids for patients with severe sepsis or septic shock
Table 2 Characteristics of included randomised controlled trials
Table 3 Assessment of methodological quality of studies with Cronin et al's "methodologic quality form"*8
Table 4 Assessment of methodological quality of studies with method recommended by Cochrane Infectious Diseases Group
All cause mortality at 28 days
We extracted data for all cause mortality at 28 days from 15 trials (n = 2022) (fig 1). There were 351/1033 (34%) deaths in the treated group compared with 329/989 (33%) in the control group. There was significant heterogeneity in the results (2 = 33.09, P = 0.003). The relative risk of dying at 28 days was 0.92 (95% confidence interval 0.75 to 1.14, P = 0.46; random effects model).
Fig 1 Effects of corticosteroids on all cause mortality at 28 days in patients with severe sepsis and septic shock
The subgroup analysis on five trials (n = 465) with long courses of low dose corticosteroids no longer showed heterogeneity across the trials, and the all cause mortality at 28 days was lower (0.80, 0.67 to 0.95, P = 0.01). In contrast, the subgroup analysis on eight trials (n = 1115) with short courses of high dose corticosteroids did not show any difference (0.97, 0.72 to 1.31, P = 0.84; random effects model). Subgroup analyses based on high quality trials had a relative risk near 1.0 and failed to explain heterogeneity (data not shown).
Mortality in intensive care unit
We extracted data for mortality in intensive care units from four trials (n = 425), all of which investigated the effects of long courses of low dose corticosteroids (fig 2). There were 108/216 (50%) deaths in the intensive care unit in the treated group compared with 127/209 (61%) in the control group (0.83, 0.70 to 0.97, P = 0.02).
Fig 2 Effects of corticosteroids on mortality in intensive care unit in patients with severe sepsis and septic shock
Mortality in hospital
We extracted data for hospital mortality from 13 trials (n = 1418) (fig 3). There were 279/730 (38%) hospital deaths in the treated group compared with 271/688 (39%) in the control group. There was significant heterogeneity in the results (2 = 27.68, P = 0.006). The relative risk of dying in hospital was 0.89 (0.71 to 1.11, P = 0.30; random effects model).
Fig 3 Effects of corticosteroids on mortality in hospital in patients with severe sepsis and septic shock
The subgroup analysis on five trials (n = 465) with long courses of low dose corticosteroids no longer showed heterogeneity across the trials and showed reduced mortality in hospital (0.83, 0.71 to 0.97, P = 0.02). In contrast, the subgroup analysis on six trials (n = 511) with short courses of high dose corticosteroids did not show any difference in hospital mortality (0.89, 0.57 to 1.37, P = 0.59; random effects model). Subgroup analyses based on high quality trials had a relative risk near 1.0 and failed to explain heterogeneity (data not shown).
Shock reversal at day 7
We extracted data for shock reversal at day 7 from six trials (n = 728) (fig 4). There were 218/389 (56%) shock reversals at day 7 in the treated group compared with 154/339 (45%) in the control group (1.43, 1.01 to 2.01, P = 0.04; random effects model). There was significant heterogeneity in the results (2 = 20.38, P = 0.001).
Fig 4 Effects of corticosteroids on shock reversal in patients with severe sepsis and septic shock
The subgroup analysis on four trials (n = 425) with long courses of low dose corticosteroids no longer showed heterogeneity across the trials, and showed increased rate of shock reversals at 7 days (108/216 (50%) v 65/209 (31%); 1.60, 1.27 to 2.03, P < 0.0001).
Shock reversal at day 28
We extracted data for shock reversal at day 28 from four trials (n = 425) (fig 4). There were 117/216 (54%) shock reversals at day 28 in the treated group compared with 90/209 (43%) in the control group (1.26, 1.04 to 1.52, P = 0.02).
Adverse events
There was no evidence that corticosteroids increased the risk of gastroduodenal bleeding (10 trials, n = 1321; 1.16, 0.82 to 1.65, P = 0.40), superinfections (12 trials, n = 1705; 0.93, 0.73 to 1.18, P = 0.54), or hyperglycaemia (6 trials, n = 608; 1.22, 0.84 to 1.78, P = 0.30) (fig 5). Only one trial reported the definition for hyperglycaemia,32 the others reporting only the number of patients with hyperglycaemia. Another trial reported a significant rise in serum sodium concentration (> 155 mmol/l) in 6/20 (30%) patients in the treated group and in 1/20 (5%) patients in the placebo group.10
Fig 5 Adverse effects of corticosteroids in patients with severe sepsis and septic shock
Discussion
Angus D, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29: 1303-10.
Rangel-Frausto MS, Pittet D, Hwang T, Woolson RF, Wenzel RP. The dynamics of disease progression in sepsis: Markov modeling describing the natural history and the likely impact of effective antisepsis agents. Clin Infec Dis 1998;27: 185-90.
Annane D, Aegerter P, Jars-Guincestre MC, Guidet B. Current epidemiology of septic shock: the CUB-Réa Network. Am J Resp Crit Care Med 2003;168: 165-72.
Annane D, Cavaillon JM. Corticosteroids in sepsis: from bench to bedside? Shock 2003;20: 197-207.
Annane D, Sébille V, Troché G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotrophin. JAMA 2000;283: 1038-45.
Meduri GU, Chrousos GP. Duration of glucocorticoid treatment and outcome in sepsis: is the right drug used the wrong way? Chest 1998;114: 355-60.
Lefering R, Neugebauer EAM. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med 1995;23: 1294-303.
Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23: 1430-9.
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;26: 645-50.
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27: 723-32.
Chawla K, Kupfer Y, Tessler S. Hydrocortisone reverses refractory septic shock. Crit Care Med 1999;27: A33.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288: 862-71.
Yildiz O, Doganay M, Aygen B, Guven M, Keleutimur F, Tutuu A. Physiologic-dose steroid therapy in sepsis. Crit Care 2002;6: 251-9.
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, et al. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Resp Crit Care Med 2003;167: 512-0.
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20: 864-74.
Clarke M, Oxman A, eds. Cochrane reviewers' handbook 4.2.0 . In: The Cochrane Library. Issue 3. Chichester: John Wiley, 2003.
Juni P, Altman DG, Egger M. Systematic reviews in healthcare: assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Hahn EO, Houser HB, Rammelkamp CH Jr, Denny FW, Wannamaker LW. Effect of cortisone on acute streptococcal infections and poststreptococcal complications. J Clin Invest 1951;30: 274-81.
Wagner HN, Bennett IL, Lasagna L, Cluff LE, Rosenthal MB, Mirick GS. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1955;98: 197-215.
Cooperative Study Group. The effectiveness of hydrocortisone in the management of severe infections. JAMA 1963;183: 462-5.
Rogers J. Large doses of steroids in septicaemic shock. Br J Urol 1970;42: 742.
Thompson WL, Gurley HT, Lutz BA, Jackson DL, Kvols LK, Morris IA. Inefficacy of glucocorticoids in shock (double-blind study). Clin Res 1976;24: 258A.
Klastersky J, Cappel R, Debusscher L. Effectiveness of betamethasone in management of severe infections. A double-blind study. N Engl J Med 1971;284: 1248-50.
Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976;184: 333-41.
McKee JI, Finlay WE. Cortisol replacement in severely stressed patients. Lancet 1983;1: 484.
Hughes GS Jr. Naloxone and methylprednisolone sodium succinate enhance sympathomedullary discharge in patients with septic shock. Life Sci 1984;35: 2319-26.
Lucas C, Ledgerwood A. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Arch Surg 1984;119: 537-41.
Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984;311: 1137-43.
Weigelt JA, Norcross JF, Borman KR, Snyder WH 3rd. Early steroid therapy for respiratory failure. Arch Surg 1985;120: 536-40.
Bone RG, Fisher CJ, 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;317: 653-8.
Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987;317: 659-65.
Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Resp Dis 1988;138: 62-8.
Slusher T, Gbadero D, Howard C, Lewison L, Giroir B, Toro L, et al. Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Ped Infect Dis J 1996;15: 579-83.
Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280: 159-65.
Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337: 582-3.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348: 727-34.
Annane D, Bellissant E, Bollaert P, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Syst Rev 2004;(1): CD002243.(Djillali Annane, professo)