medigraphic.com

2026, Number 2

<< Back Next >>

Med Crit 2026; 40 (2)

Rational and evidence-based use of glucocorticoids and mineralocorticoids in patients with septic shock in the Intensive Care Unit

Pérez I, Paredes MC, Tórra OL, Sánchez A

Language: Spanish
References: 53
Page: 142-151
PDF size: 667.84 Kb.


ABSTRACT

Introduction: septic shock remains a leading cause of morbidity and mortality in intensive care units. Glucocorticoids have been shown to reduce vasopressor dependence without impacting mortality; however, their combined use with mineralocorticoids remains controversial with respect to this latter outcome. Recent studies have reopened the debate on the benefit of combining hydrocortisone and fludrocortisone. Objective: to critically analyze the historical and contemporary evidence on the use of steroids, particularly combination therapy with glucocorticoids and mineralocorticoids, in the management of septic shock. Material and methods: a narrative review of the literature was conducted from the 1930s to 2024, including controlled clinical trials, observational studies, meta-analyses, and international guidelines. Relevant clinical outcomes such as mortality, shock reversal, duration of vasopressor support, and metabolic complications were assessed. Results: trials conducted after 2000, such as APROCCHSS, demonstrated a significant reduction in mortality and faster reversal of shock with the combination of hydrocortisone and fludrocortisone. Evidence analyzing hydrocortisone-only therapy shows benefits in duration of shock but no benefits in mortality. Large-scale cohort studies and recent meta-analyses suggest an additional benefit of combination therapy, especially in more severely ill patients and older adults. However, population heterogeneity and a lack of head-to-head comparative trials limit the strength of current recommendations. Conclusions: steroids in septic shock show a consistent effect in reversing shock, and with the use of combination therapy, a possible reduction in mortality, although the certainty of the evidence is moderate. Meta-analyses have also shown a posterior probability of superiority with combination therapy for the mortality outcome. Cautious use of combination therapy is suggested based on the risk-benefit profile, prioritizing patients at higher risk and considering the need for studies that define sepsis subphenotypes that benefit most from it.


REFERENCES

  1. Perla D, Marmorston J. Suprarenal cortical hormone and saltin the treatment of pneumonia and other severe infections.Endocrinology. 1940;27(3):367-374.

  2. Selye H. The general adaptation syndrome and the diseases ofadaptation. J Allergy. 1946;17:231.

  3. Selye H. Thymus and adrenals in the response of the organismto injuries and intoxications. Br J Exp Pathol. 1936;17(3):234-248.

  4. Meduri GU. An historical review of glucocorticoid treatment insepsis. Disease pathophysiology and the design of treatmentinvestigation. Sepsis. 1999;3(1):21-38.

  5. Kass EH, Ingbar SH, Finland M. Effects of adrenocorticotropichormone in pneumonia: clinical, bacteriological and serologicalstudies. Ann Intern Med. 1950;33(5):1081-1098.

  6. Levitin H, Kendrick MI, Kass EH. Effect of route of administrationon protective action of corticosterone and cortisol againstendotoxin. Proc Soc Exp Med. 1956;93(2):306-309.

  7. Breen G. Corticosteroids in the acute infections. Lancet.1965;285(7377):158-160.

  8. Hahn EO, Houser HB, Rammelkamp CH, Denny FW,Wannamaker LW. Effect of cortisone on acute streptococcalinfections and post-streptococcal complications. J Clin Invest.1951;30(3):274-281.

  9. Weitzman S, Berger S. Clinical trial design in studies ofcorticosteroids for bacterial infections. Ann Intern Med.1974;81(1):36-42.

  10. Schumer W. Steroids in the treatment of clinical septic shock.Ann Surg. 1976;184(3):333-341.

  11. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, LongWM, et al. The effects of high-dose corticosteroids in patientswith septic shock: a prospective, controlled study. N Engl J Med.1984;311(18):1137-1143.

  12. Cronin L, Cook DJ, Carlet J, Heyland DK, King DBM, LansangMAD, et al. Corticosteroid treatment for sepsis: a criticalappraisal and meta-analysis of the literature. Crit Care Med.1995;23(8):1430-1439.

  13. Annane D, Sébille V, Charpentier C, Bollaert PE, FrancoisB, Korach JM, et al. Effect of treatment with low doses ofhydrocortisone and fludrocortisone on mortality in patients withseptic shock. JAMA. 2002;288(7):862-871.

  14. Sprung CL, Annane D, Keh D, Moreno R, Singer M, FreivogelK, et al. Hydrocortisone therapy for patients with septic shock. NEngl J Med. 2008;358(2):111-124.

  15. Annane D, Cariou A, Maxime V, Azoulay E, D’honneur G, TimsitJF, et al. Corticosteroid treatment and intensive insulin therapyfor septic shock in adults: a randomized controlled trial. JAMA.2010;303(4):341-348.

  16. Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S,et al. Effect of hydrocortisone on development of shock amongpatients with severe sepsis: the hypress randomized clinical trial.JAMA. 2016;316(17):1775-1785.

  17. Briegel J, Mohnle P, Keh D, Lindner JM, Vetter AC, BogatschH, et al. Corticotropin-stimulated steroid profiles to predict shockdevelopment and mortality in sepsis: from the HYPRESS study.Crit Care. 2022;26(1):343.

  18. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, BellomoR, et al. Adjunctive glucocorticoid therapy in patients with septicshock. N Engl J Med. 2018;378(9):797-808.

  19. Annane D, Renault A, Brun-Buisson C, Megarbane B, QuenotJP, Siami S, et al. Hydrocortisone plus fludrocortisone for adultswith septic shock. N Engl J Med. 2018;378(9):809-818.

  20. Bosch NA, Teja B, Law AC, Pang B, Jafarzadeh SR, Walkey AJ.Comparative effectiveness of fludrocortisone and hydrocortisonevs hydrocortisone alone among patients with septic shock. JAMAIntern Med. 2023;183(5):451-459.

  21. Yamamoto R, Nahara I, Toyosaki M, Fukuda T, Masuda Y,Fujishima S. Hydrocortisone with fludrocortisone for septicshock: a systematic review and meta-analysis. Acute Med Surg.2020;7(1):e563.

  22. Lai PC, Lai CH, Lai ECC, Huang YT. Do we need to administerfludrocortisone in addition to hydrocortisone in adult patientswith septic shock? An updated systematic review with bayesiannetwork meta-analysis of randomized controlled trials and anobservational study with target trial emulation. Crit Care Med.2024;52(4): e193-e202.

  23. Teja B, Berube M, Pereira TV, Law AC, Schanock C, Pang B, etal. Effectiveness of fludrocortisone plus hydrocortisone versushydrocortisone alone in septic shock: a systematic review andnetwork meta-analysis of randomized controlled trials. Am JRespir Crit Care Med. 2024;209(10):1219-1228.

  24. Evans L, Rhodes A, Alhazzani W, Antonelli M, CoopersmithCM, French C, et al. Surviving sepsis campaign: internationalguidelines for management of sepsis and septic shock 2021.Intensive Care Med. 2021;47(11):1181-1247.

  25. Tsolaki V, Siempos II. Monotherapy or combination therapy forseptic shock? A debate on steroids. Am J Respir Crit Care Med.2024;209(10):1179-1180.

  26. Shime N, Nakada Taka-Aki N, Yatabe T, Yamakawa K, AokiY, Inoue S, et al. The Japanese Clinical Practice guidelines formanagement of sepsis and septic shock 2024. Acute Med Surg.2025;12(1):e70037.

  27. Chaudhuri D, Nei AM, Rochwerg B, Balk RA, AsehnouneK, Cadena R, et al. 2024 focused update: guidelines onuse of corticosteroids in sepsis, acute respiratory distresssyndrome, and community-acquired pneumonia. Crit Care Med.2024;52(5):e219-e233.

  28. Pirracchio R, Annane D, Waschka AK, Lamontagne F, ArabiYM, Bollaert PE, et al. Patient-level meta-analysis of lowdosehydrocortisone in adults with septic shock. NEJM Evid.2023;2(6):EVIDoa2300034. doi: 10.1056/EVIDoa2300034.

  29. Fredrick FC, Meda AKR, Singh B, Jain R. Critical illnessrelatedcorticosteroid insufficiency: latest pathophysiology andmanagement guidelines. Acute Crit Care. 2024;39(3):331-340.

  30. Heming N, Sivanandamoorthy S, Meng P, Bounab R, AnnaneD. Immune effects of corticosteroids in sepsis. Front Immunol.2018;9:1736.

  31. Hannon R, Croxtall JD, Getting SJ, Roviezzo F, Yona S,Paul-Clark MJ, et al. Aberrant inflammation and resistanceto glucocorticoids in annexin 1−/− mouse. FASEB J.2003;17(2):253-255.

  32. Lasa M, Abraham SM, Boucheron C, Saklatvala J, Clark AR.Dexamethasone causes sustained expression of mitogenactivatedprotein kinase (MAPK) phosphatase 1 andphosphatase-mediated inhibition of MAPK p38. Mol Cell Biol.2002;22(22):7802-7811.

  33. Vandewalle J, Libert C. Glucocorticoids in sepsis: to be or not tobe. Front Immunol. 2020;11:1318.

  34. LATAM Elsevier Health. Firestein y Kelley. Tratado deReumatología. Disponible en: https://tienda.elsevierhealth.com/firestein-y-kelley-tratado-de-reumatologia-9788413822631.html

  35. Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA,Beishuizen A, et al. Correction to: Guidelines for the diagnosisand management of critical illness-related corticosteroidinsufficiency (CIRCI) in critically ill patients (Part I): Societyof Critical Care Medicine (SCCM) and European Society ofIntensive Care Medicine (ESICM) 2017. Intensive Care Med.2018;44(3):401-402.

  36. Burry L, Little A, Hallett D, Mehta S. Detection of critical illness–related corticosteroid insufficiency using 1 μg adrenocorticotropichormone test. Shock. 2013;39(2):144-148.

  37. Van den Berghe G, Téblick A, Langouche L, Gunst J.The hypothalamus-pituitary-adrenal axis in sepsis- andhyperinflammation-induced critical illness: gaps in currentknowledge and future translational research directions.EBioMedicine. 2022;84:104284.

  38. Goodman LS, Gilman A. Goodman & Gilman: las basesfarmacológicas de la terapéutica. México: McGraw-Hill; 2003.

  39. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokineticsand pharmacodynamics of systemically administeredglucocorticoids. Clin Pharmacokinet. 2005;44(1):61-98.

  40. Ramsahoye BH, Davies SV, El-Gaylani N, Sandeman D, ScanlonMF. The mineralocorticoid effects of high dose hydrocortisone.BMJ. 1995;310(6980):656-657.

  41. Nethathe GD, Lipman J, Anderson R, Fuller PJ, Feldman C.Glucocorticoids with or without fludrocortisone in septic shock: anarrative review from a biochemical and molecular perspective.Br J Anaesth. 2024;132(1):53-65.

  42. Vinson GP. The mislabelling of deoxycorticosterone: makingsense of corticosteroid structure and function. J Endocrinol.2011;211(1):3-16.

  43. Walsham J, Hammond N, Blumenthal A, Cohen J, Myburgh J,Finfer S, et al. Fludrocortisone dose–response relationship inseptic shock: a randomised phase II trial. Intensive Care Med.2024;50(12):2050-2060.

  44. Fadel F, André-Grégoire G, Gravez B, Bauvois B, BouchetS, Sierra-Ramos C, et al. Aldosterone and vascularmineralocorticoid receptors in murine endotoxic and humanseptic shock. Crit Care Med. 2017;45(9):e954-e962.

  45. Cheng X, Fu Z, Liu Y, Zheng X, Hu T. Association of mortalitywith fludrocortisone addition to hydrocortisone treatment amongseptic shock patients: a propensity score matching analysis.Front Med. 2023;10:1190758.

  46. Gómez-Sánchez E, Gómez-Sánchez CE. The multifacetedmineralocorticoid receptor. Compr Physiol. 2014;4(3):965-994.

  47. Zennaro MC, Le Menuet D, Lombès M. Characterization of thehuman mineralocorticoid receptor gene 5’-regulatory region:evidence for differential hormonal regulation of two alternativepromoters via nonclassical mechanisms. Mol Endocrinol.1996;10(12):1549-1560.

  48. Modulation of transalveolar fluid absorption by endogenousaldosterone in adult rats. Exp Lung Res. 2001;27(2):143-155.

  49. Matthay MA, Dahabreh IJ, Thompson BT. Should we addfludrocortisone to hydrocortisone for treatment of septic shock?JAMA Intern Med. 2023;183(5):460-461.

  50. Aiba M, Fujibayashi M. Alteration of subcapsular adrenocorticalzonation in humans with aging: the progenitor zone predominatesover the previously well-developed zona glomerulosa after 40years of age. J Histochem Cytochem. 2011;59(5):557-564.

  51. Ranzani O, Annane D, Singer M. Fludrocortisone withhydrocortisone in sepsis: new evidence in an ongoing debate.Intensive Care Med. 2024;50(12):2138-2140.

  52. Hamitouche N, Comets E, Ribot M, Alvarez JC, Bellissant E,Laviolle B. Population pharmacokinetic-pharmacodynamic modelof oral fludrocortisone and intravenous hydrocortisone in healthyvolunteers. AAPS J. 2017;19(3):727-735.

  53. Teja B, Bosch NA, Walkey AJ. How we escalate vasopressorand corticosteroid therapy in patients with septic shock. Chest.2023;163(3):567-574.




2020     |     www.medigraphic.com