To assess the effect of low dose corticosteroids on outcomes in adults with septic shock.
We systematically reviewed randomised clinical trials (RCTs) comparing low-dose corticosteroids to placebo in adults with septic shock. Trial selection, data abstraction and risk of bias assessment were performed in duplicate. The primary outcome was short-term mortality. Secondary and tertiary outcomes included longer-term mortality, adverse events, quality of life, and duration of shock, mechanical ventilation and ICU stay.
There were 22 RCTs, including 7297 participants, providing data on short-term mortality. In two low risk of bias trials, the relative risk (RR) of short-term mortality with corticosteroid versus placebo was 0.98 [95% confidence interval (CI) 0.89–1.08, p = 0.71]. Sensitivity analysis including all trials was similar (RR 0.96; 95% CI 0.91–1.02, p = 0.21) as was analysis of longer-term mortality (RR 0.96; 95% CI 0.90–1.02, p = 0.18). In low risk of bias trials, the risk of experiencing any adverse event was higher with corticosteroids; however, there was substantial heterogeneity (RR 1.66; 95% CI 1.03–2.70, p = 0.04, I2 = 78%). No trials reported quality of life outcomes. Duration of shock [mean difference (MD) −1.52 days; 95% CI −1.71 to −1.32, p < 0.0001], duration of mechanical ventilation (MD −1.38 days; 95% CI −1.96 to −0.80, p < 0.0001), and ICU stay (MD −0.75 days; 95% CI −1.34 to −0.17, p = 0.01) were shorter with corticosteroids versus placebo.
In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced.
PROSPERO registration no. CRD42017084037.
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Annane D (2005) Glucocorticoids in the treatment of severe sepsis and septic shock. Curr Opin Crit Care 11:449–453
Chrousos GP (1995) The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. New Engl J Med 332:1351–1362
Wagner HN Jr, Bennett IL Jr, Lasagna L, Cluff LE, Rosenthal MB, Mirick GS (1956) The Effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 98:197–215
Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr (1995) Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 23:1430–1439
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K (1999) Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 27:723–732
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A (1998) Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 26:645–650
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 (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. J Am Med Assoc 288:862–871
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J (2008) Hydrocortisone therapy for patients with septic shock. New Engl J Med 358:111–124
Annane D, Cariou A, Maxime V, Azoulay E, D’Honneur G, Timsit JF, Cohen Y, Wolf M, Fartoukh M, Adrie C, Santre C, Bollaert PE, Mathonet A, Amathieu R, Tabah A, Clec’h C, Mayaud J, Lejeune J, Chevret S (2010) Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. J Am Med Assoc 303:341–348
Moran JL, Graham PL, Rockliff S, Bersten AD (2010) Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a bayesian meta-analytic perspective. Crit Care 14:R134
Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. New Engl J Med 378:809–818
Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J (2018) Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 378(9):797–808
Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR (2005) Optimal search strategies for retrieving scientifically strong studies of treatment from medline: analytical survey. BMJ 330:1179
Wilczynski NL, McKibbon KA, Walter SD, Garg AX, Haynes RB (2013) Medline clinical queries are robust when searching in recent publishing years. J Am Med Inform Assoc 20:363–368
Wong SS, Wilczynski NL, Haynes RB (2006) Developing optimal search strategies for detecting clinically sound treatment studies in embase. J Med Libr Assoc 94:41–47
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC (2011) The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928
Wetterslev J, Thorlund K, Brok J, Gluud C (2009) Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol 9:86
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
Harbord RM, Egger M, Sterne JA (2006) A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 25:3443–3457
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101
Villar J, Mackey ME, Carroli G, Donner A (2001) Meta-analyses in systematic reviews of randomized controlled trials in perinatal medicine: comparison of fixed and random effects models. Stat Med 20:3635–3647
Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C (2014) Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol 14:120
Wetterslev J, Jakobsen JC, Gluud C (2017) Trial sequential analysis in systematic reviews with meta-analysis. BMC Med Res Methodol 17:39
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer T, Varonen H, Vist GE, Williams JW Jr, Zaza S (2004) Grading quality of evidence and strength of recommendations. BMJ 328:1490
Aboab J, Polito A, Orlikowski D, Sharshar T, Castel M, Annane D (2008) Hydrocortisone effects on cardiovascular variability in septic shock: a spectral analysis approach. Crit Care Med 36:1481–1486
Arabi YM, Aljumah A, Dabbagh O, Tamim HM, Rishu AH, Al-Abdulkareem A, Al Knawy B, Hajeer AH, Tamimi W, Cherfan A (2010) Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial. Can Med Assoc J 182:1971–1977
Chawla K, Kupfer Y, Tessler S (1999) Hydrocortisone reverses refractory septic shock. Crit Care Med 27:A33
Cicarelli DD, Vieira JE, Bensenor FE (2007) Early dexamethasone treatment for septic shock patients: a prospective randomized clinical trial. Sao Paulo Med J 125:237–241
Cooperative Study Group (1963) The effectiveness of hydrocortisone in the management of severe infections: a double-blind study. JAMA 183:462–465
Deng QM, Shang D, Wan XY (2011) Effects of low-dose glucocorticoid on renal function and prognosis in patients with sepsis. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 23:183–184
Gordon AC, Mason AJ, Perkins GD, Stotz M, Terblanche M, Ashby D, Brett SJ (2014) The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial. Crit Care Med 42:1325–1333
Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ (2016) Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the vanish randomized clinical trial. JAMA 316:509–518
Hu B, Li JG, Liang H, Zhou Q, Yu Z, Li L, Luo Y, Liu C, Gan Q (2009) The effect of low-dose hydrocortisone on requirement of norepinephrine and lactate clearance in patients with refractory septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 21:529–531
Kurugundla N, Irugulapati L, Kilari D, Amchentsev A, Devakonda A, George L, Raoof S (2008) Effect of steroids in septic shock patients without relative adrenal insufficiency. International conference A, American Thoracic Society 116
Lv QQ, Gu XH, Chen QH, Yu JQ, Zheng RQ (2017) Early initiation of low-dose hydrocortisone treatment for septic shock in adults: a randomized clinical trial. Am J Emerg Med 35(12):1810–1814
Meduri GU, Golden E, Umberger R (2009) Prospective double-blind randomized clinical trial on the effects of low-dose hydrocortisone infusion in patients with severe sepsis [abstract]. Chest 136:45S
Mirea L, Ungureanu R, Pavelescu D, Grintescu IC, Dumitrache C, Grintescu I, Mirea D (2014) Continuous administration of corticosteroids in septic shock can reduce risk of hypernatremia. Crit Care 18:S86
Oppert M, Schindler R, Husung C, Offermann K, Graf KJ, Boenisch O, Barckow D, Frei U, Eckardt KU (2005) Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med 33:2457–2464
Tandan S, Guleria R, Gupta N (2005) Low dose steroids and adrenocortical insufficiency in septic shock: a double-blind randomised controlled trial from India. Am J Respir Crit Care Med 171:A43
Tongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, Meduri GU (2016) Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care 20:329
Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J, Gabarrus A, Sellares J, Restrepo MI, Anzueto A, Niederman MS, Agusti C (2015) Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 313:677–686
Rinaldi L, Ferrari E, Marietta M, Donno L, Trevisan D, Codeluppi M, Busani S, Girardis M (2013) Effectiveness of sepsis bundle application in cirrhotic patients with septic shock: a single-center experience. J Crit Care 28:152–157
Venkatesh B, Finfer S, Myburgh J, Cohen J, Billot L (2018) Long-term outcomes of the ADRENAL trial. N Engl J Med 378(18):1744–1745
Resche-Rigon M, Azoulay E, Chevret S (2006) Evaluating mortality in intensive care units: contribution of competing risks analyses. Crit Care 10:R5
Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y (2015) Corticosteroids for treating sepsis. Cochrane Database Syst Rev: Cd002243
Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU (2005) Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 171:242–248
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H (2003) Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 167:512–520
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1987) A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. New Engl J Med 317:653–658
We would like to thank Agnes Wroblewski from the Douglas Piper Medical Library at RNSH for her assistance in obtaining elusive manuscripts included in this review. We are indebted to Dr Arne Andreasen, and Dr Soo Wan Kim for providing translations. We are deeply appreciative of Professors Annane, Arabi, Bollaert, Briegel, Gordon, Meduri, Sprung, and Torres, and Drs Cicarelli, Mirea, Rinaldi, Tongyoo, Gabarus-Barri for supplying additional details and clarifications regarding their studies.
This study received no funding.
Conflicts of interest
Professors Venkatesh, Finfer, Myburgh, Perner and Associate Professor Cohen were all members of the management committee of the ADRENAL study. The other authors have no conflicts of interest to declare.
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Rygård, S.L., Butler, E., Granholm, A. et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 44, 1003–1016 (2018). https://doi.org/10.1007/s00134-018-5197-6