Download PDF
Semin Respir Crit Care Med 2004; 25(6): 713-719
DOI: 10.1055/s-2004-860985
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Corticosteroid Therapy in Patients with Severe Sepsis and Septic Shock

Didier Keh1 , Serge Goodman2 , Charles L. Sprung2
  • 1Department of Anesthesiology and Intensive Care Medicine, Charité - Campus Virchow-Klinikum, Humboldt University, Berlin, Germany
  • 2Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Further Information

Publication History

Publication Date:
22 December 2004 (online)

    Permissions and Reprints

ABSTRACT

Corticosteroids have been considered for decades for the treatment of severe sepsis and septic shock, based on their pivotal role in the stress response and their hemodynamic and antiinflammatory effects. Whereas short-term therapy with high doses of corticosteroids (up to 42 g hydrocortisone equivalent for 1-2 days) has been ineffective or potentially harmful, prolonged therapy with lower doses (200-300 mg hydrocortisone for 5-7 days or longer) in septic shock has recently revealed beneficial effects in several randomized, controlled trials. Assuming relative adrenal insufficiency (RAI) and peripheral cortisol resistance, treatment with low-dose hydrocortisone improved shock reversal, reduced inflammation, and improved outcome. Shock reversal and reduction of mortality were more effective in patients with RAI, and most significant in patients with severe shock. Diagnosis of RAI with corticotropin tests in septic shock, however, is highly dependent on cut-off values and definition of RAI. Thus, it is not clear yet which patients benefit most from low-dose hydrocortisone and if treatment should be restricted to patients with RAI. In addition the role of fludrocortisone is uncertain. Nevertheless, based on current data, low-dose hydrocortisone therapy should definitely be considered in vasopressor-dependent septic shock. This review will address some critical points.

KEYWORDS

Septic shock - sepsis - corticosteroids - low-dose hydrocortisone - adrenal insufficiency

REFERENCES

  • 1 Meduri G U. An historical review of glucocorticoid treatment in sepsis: disease pathophysiology and the design of treatment investigation.  Sepsis. 1999;  3 21-38
    CrossrefPubMedGoogle Scholar
  • 2 Lebel M H, Freij B J, Syrogiannopoulos G A et al.. Dexamethasone therapy for bacterial meningitis: results of two double-blind, placebo-controlled trials.  N Engl J Med. 1988;  319 964-971
    PubMedGoogle Scholar
  • 3 Odio C M, Faingezicht I, Paris M et al.. The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis.  N Engl J Med. 1991;  324 1525-1531
    PubMedGoogle Scholar
  • 4 de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis.  N Engl J Med. 2002;  347 1549-1556
    CrossrefPubMedGoogle Scholar
  • 5 Hoffman S L, Punjabi N H, Kumala S et al.. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone.  N Engl J Med. 1984;  310 82-88
    CrossrefPubMedGoogle Scholar
  • 6 Meduri G U, Chinn A J, Leeper K V et al.. Corticosteroid rescue treatment of progressive fibroproliferation in late ARDS: patterns of response and predictors of outcome.  Chest. 1994;  105 1516-1527
    PubMedGoogle Scholar
  • 7 Meduri G U, Headley A S, Golden E et al.. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial.  JAMA. 1998;  280 159-165
    CrossrefPubMedGoogle Scholar
  • 8 Montaner J S, Lawson L M, Levitt N, Belzberg A, Schechter M T, Ruedy J. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS).  Ann Intern Med. 1990;  113 14-20
    PubMedGoogle Scholar
  • 9 Gagnon S, Boota A M, Fischl M A, Baier H, Kirksey O W, La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial.  N Engl J Med. 1990;  323 1444-1450
    CrossrefPubMedGoogle Scholar
  • 10 Oelkers W. Adrenal insufficiency.  N Engl J Med. 1996;  335 1206-1212
    CrossrefPubMedGoogle Scholar
  • 11 Annane D, Briegel J, Sprung C L. Corticosteroid insufficiency in acutely ill patients.  N Engl J Med. 2003;  348 2157-2159
    CrossrefPubMedGoogle Scholar
  • 12 Brigham K L, Bowers R E, McKeen C R. Methylprednisolone prevention of increased lung vascular permeability following endotoxemia in sheep.  J Clin Invest. 1981;  67 1103-1110
    PubMedGoogle Scholar
  • 13 Hinshaw L B. Development of animal models for application to clinical trials in septic shock.  Prog Clin Biol Res. 1989;  308 835-846
    PubMedGoogle Scholar
  • 14 Hinshaw L B, Archer L T, Beller-Todd B K et al.. Survival of primates in LD100 septic shock following steroid/antibiotic therapy.  J Surg Res. 1980;  28 151-170
    CrossrefPubMedGoogle Scholar
  • 15 Hinshaw L B, Beller B K, Archer L T, Flournoy D J, White G L, Phillips R W. Recovery from lethal Escherichia coli shock in dogs.  Surg Gynecol Obstet. 1979;  149 545-553
    PubMedGoogle Scholar
  • 16 Hinshaw L B, Beller-Todd B K, Archer L T et al.. Effectiveness of steroid/antibiotic treatment in primates administered LD100 Escherichia coli. .  Ann Surg. 1981;  194 51-56
    PubMedGoogle Scholar
  • 17 Barnes P J. Anti-inflammatory mechanisms of glucocorticoids.  Biochem Soc Trans. 1995;  23 940-945
    PubMedGoogle Scholar
  • 18 Chrousos G P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.  N Engl J Med. 1995;  332 1351-1362
    CrossrefPubMedGoogle Scholar
  • 19 Sapolsky R M, Romero L M, Munck A U. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.  Endocr Rev. 2000;  21 55-89
    CrossrefPubMedGoogle Scholar
  • 20 Schumer W. Steroids in the treatment of clinical septic shock.  Ann Surg. 1976;  184 333-341
    CrossrefPubMedGoogle Scholar
  • 21 Sprung C L, Caralis P V, Marcial E H et al.. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study.  N Engl J Med. 1984;  311 1137-1143
    CrossrefPubMedGoogle Scholar
  • 22 Lefering R, Neugebauer E A. Steroid controversy in sepsis and septic shock: a meta-analysis.  Crit Care Med. 1995;  23 1294-1303
    CrossrefPubMedGoogle Scholar
  • 23 Cronin L, Cook D J, Carlet J et al.. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature.  Crit Care Med. 1995;  23 1430-1439
    CrossrefPubMedGoogle Scholar
  • 24 Slotman G J, Fisher Jr C J, Bone R C, Clemmer T P, Metz C A. Detrimental effects of high-dose methylprednisolone sodium succinate on serum concentrations of hepatic and renal function indicators in severe sepsis and septic shock. The Methylprednisolone Severe Sepsis Study Group.  Crit Care Med. 1993;  21 191-195
    PubMedGoogle Scholar
  • 25 Cooper M S, Stewart P M. Corticosteroid insufficiency in acutely ill patients.  N Engl J Med. 2003;  348 727-734
    CrossrefPubMedGoogle Scholar
  • 26 Marik P E, Zaloga G P. Adrenal insufficiency during septic shock.  Crit Care Med. 2003;  31 141-145
    CrossrefPubMedGoogle Scholar
  • 27 Annane D, Cavaillon J M. Corticosteroids in sepsis: from bench to bedside?.  Shock. 2003;  20 197-207
    PubMedGoogle Scholar
  • 28 Beishuizen A, Thijs L G, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma.  Intensive Care Med. 2001;  27 1584-1591
    CrossrefPubMedGoogle Scholar
  • 29 Meduri G U, Tolley E A, Chrousos G P, Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids.  Am J Respir Crit Care Med. 2002;  165 983-991
    PubMedGoogle Scholar
  • 30 Molijn G J, Spek J J, van Uffelen J C et al.. Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock.  J Clin Endocrinol Metab. 1995;  80 1799-1803
    CrossrefPubMedGoogle Scholar
  • 31 Matot I, Sprung C L. Corticosteroids in septic shock: resurrection of the last rites?.  Crit Care Med. 1998;  26 627-629
    CrossrefPubMedGoogle Scholar
  • 32 Bouachour G, Tirot P, Gouello J P, Mathieu E, Vincent J F, Alquier P. Adrenocortical function during septic shock.  Intensive Care Med. 1995;  21 57-62
    CrossrefPubMedGoogle Scholar
  • 33 Marik P E, Zaloga G P. Adrenal insufficiency in the critically ill: a new look at an old problem.  Chest. 2002;  122 1784-1796
    CrossrefPubMedGoogle Scholar
  • 34 Annane D, Sebille V, Troche G, Raphael J C, Gajdos P, Bellissant E. A three-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin.  JAMA. 2000;  283 1038-1045
    CrossrefPubMedGoogle Scholar
  • 35 Rothwell P M, Udwadia Z F, Lawler P G. Cortisol response to corticotropin and survival in septic shock.  Lancet. 1991;  337 582-583
    CrossrefPubMedGoogle Scholar
  • 36 Moran J L, Chapman M J, OqFathartaigh M S, Peisach A R, Pannall P R, Leppard P. Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock.  Intensive Care Med. 1994;  20 489-495
    CrossrefPubMedGoogle Scholar
  • 37 Bollaert P E, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone.  Crit Care Med. 1998;  26 645-650
    CrossrefPubMedGoogle Scholar
  • 38 Oppert M, Reinicke A, Gräf K J, Barckow D, Frei U, Eckardt K U. Plasma cortisol levels before and during “low-dose” hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock.  Intensive Care Med. 2000;  26 1747-1755
    CrossrefPubMedGoogle Scholar
  • 39 Perla D, Marmorston J. Suprarenal cortical hormone and salt in the treatment of pneumonia and other severe infections.  Endocrinology. 1940;  27 367-374
    PubMedGoogle Scholar
  • 40 Walker B R, Williams B C. Corticosteroids and vascular tone: mapping the messenger maze. Clin Sci (London); 1992 82: 597-605
    Google Scholar
  • 41 Ullian M E. The role of corticosteriods in the regulation of vascular tone.  Cardiovasc Res. 1999;  41 55-64
    CrossrefPubMedGoogle Scholar
  • 42 Radomski M W, Palmer R M, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells.  Proc Natl Acad Sci U S A. 1990;  87 10043-10047
    CrossrefPubMedGoogle Scholar
  • 43 Keh D, Boehnke T, Weber-Carstens S et al.. 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. 2003;  167 512-520
    CrossrefPubMedGoogle Scholar
  • 44 Heller A R, Heller S C, Borkenstein A, Stehr S N, Koch T. Modulation of host defense by hydrocortisone in stress doses during endotoxemia.  Intensive Care Med. 2003;  29 1456-1463
    CrossrefPubMedGoogle Scholar
  • 45 Lösel R M, Feuring M, Falkenstein E, Wehling M. Nongenomic effects of aldosterone: cellular aspects and clinical implications.  Steroids. 2002;  67 493-498
    CrossrefPubMedGoogle Scholar
  • 46 Wehling M, Spes C H, Win N et al.. Rapid cardiovascular action of aldosterone in man.  J Clin Endocrinol Metab. 1998;  83 3517-3522
    CrossrefPubMedGoogle Scholar
  • 47 Briegel J, Kellermann W, Forst H et al.. Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. The Phospholipase A2 Study Group.  Clin Investig. 1994;  72 782-787
    PubMedGoogle Scholar
  • 48 Annane D, Sebille V, Charpentier C et al.. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.  JAMA. 2002;  288 862-871
    CrossrefPubMedGoogle Scholar
  • 49 Chawla K, Kupfer Y, Goldman I, Tessler S. Hydrocortisone reverses refractory septic shock [abstract].  Crit Care Med. 1999;  27 A33
    PubMedGoogle Scholar
  • 50 Yildiz O, Doganay M, Aygen B, Guven M, Keleutimur F, Tutuu A. Physiological-dose steroid therapy in sepsis.  Crit Care. 2002;  6 251-259
    CrossrefPubMedGoogle Scholar
  • 51 Briegel J, Forst H, Haller M et al.. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study.  Crit Care Med. 1999;  27 723-732
    CrossrefPubMedGoogle Scholar
  • 52 Huettemann E, Bernhardt A, Schelenz C, Reinhart K. Low dose hydrocortisone does not influence myocardial function in patients with septic shock [abstract].  Intensive Care Med. 2003;  29 S154
    PubMedGoogle Scholar
  • 53 Annane D, Bellissant E, Sebille V et al.. Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve.  Br J Clin Pharmacol. 1998;  46 589-597
    CrossrefPubMedGoogle Scholar
  • 54 Meduri G U, Kanangat S, Bronze M et al.. Effects of methylprednisolone on intracellular bacterial growth.  Clin Diagn Lab Immunol. 2001;  8 1156-1163
    CrossrefPubMedGoogle Scholar
  • 55 Galon J, Franchimont D, Hiroi N et al.. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells.  FASEB J. 2002;  16 61-71
    CrossrefPubMedGoogle Scholar
  • 56 Schelling G, Briegel J, Roozendaal B, Stoll C, Rothenhausler H B, Kapfhammer H P. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors.  Biol Psychiatry. 2001;  50 978-985
    CrossrefPubMedGoogle Scholar
  • 57 Rubenfeld G D. When survival is not the same as mortality.  Critical Care Alert. 2003;  10 113-115
    PubMedGoogle Scholar
  • 58 Annane D, Bellissant E, Bollaert P E, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock.  Cochrane Database Syst Rev. 2004;  (1):CD002243
    PubMedGoogle Scholar
  • 59 Van Den Berghe G, Wouters P, Weekers F et al.. Intensive insulin therapy in the critically ill patients.  N Engl J Med. 2001;  345 1359-1367
    CrossrefPubMedGoogle Scholar
  • 60 De Jonghe B, Sharshar T, Lefaucheur J P et al.. Paresis acquired in the intensive care unit: a prospective multicenter study.  JAMA. 2002;  288 2859-2867
    CrossrefPubMedGoogle Scholar
  • 61 Herridge M S, Cheung A M, Tansey C M et al.. One-year outcomes in survivors of the acute respiratory distress syndrome.  N Engl J Med. 2003;  348 683-693
    CrossrefPubMedGoogle Scholar
  • 62 Tunn S, Pappert G, Willnow P, Krieg M. Multicentre evaluation of an enzyme-immunoassay for cortisol determination.  J Clin Chem Clin Biochem. 1990;  28 929-935
    PubMedGoogle Scholar
  • 63 Miller A H, Pariante C M, Pearce B D. Effects of cytokines on glucocorticoid receptor expression and function: glucocorticoid resistance and relevance to depression.  Adv Exp Med Biol. 1999;  461 107-116
    PubMedGoogle Scholar
  • 64 Dökmetas H S, Colak R, Kelestimur F, Selcuklu A, Unluhizarci K, Bayram F. A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery.  J Clin Endocrinol Metab. 2000;  85 3713-3719
    CrossrefPubMedGoogle Scholar
  • 65 Zarkovic M, Ciric J, Stojanovic M et al.. Optimizing the diagnostic criteria for standard (250-microg) and low dose (1-microg) adrenocorticotropin tests in the assessment of adrenal function.  J Clin Endocrinol Metab. 1999;  84 3170-3173
    CrossrefPubMedGoogle Scholar
  • 66 Siraux V, De Backer D, Melot C et al.. High vers. low dose ACTH stimulation tests to assess adrenal function in patients with septic shock [abstract].  Intensive Care Med. 2002;  28 S75
    PubMedGoogle Scholar
  • 67 Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease.  J Clin Endocrinol Metab. 1998;  83 1558-1562
    CrossrefPubMedGoogle Scholar
  • 68 Siraux V, De Backer D, Yalavatti G S et al.. Methologic aspects of low and standard dose ACTH stimulation tests in patients with septic shock [abstract].  Intensive Care Med. 2002;  28 S75
    PubMedGoogle Scholar
  • 69 Rolih C A, Ober K P. The endocrine response to critical illness.  Med Clin North Am. 1995;  79 211-224
    PubMedGoogle Scholar
  • 70 Arlt W, Allolio B. Adrenal insufficiency.  Lancet. 2003;  361 1881-1893
    CrossrefPubMedGoogle Scholar

Didier KehM.D. 

Department of Anesthesiology and Intensive Care Medicine, Charité-Campus Virchow-Klinikum, Humboldt University

Augustenburger Platz 1, D-13353 Berlin, Germany

Email: didier.keh@charite.de

      >