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Gluco- and mineralocorticoid biological effects of a 7-day treatment with low doses of hydrocortisone and fludrocortisone in septic shock

Bruno Laviolle| Djillali Annane| Claire Fougerou| Eric Bellissant
Original
Volume 38, Issue 8 / August , 2012

Pages 1306 - 1314

Abstract

Purpose

The benefits of low-dose steroids in septic shock remain controversial. We investigated if these low doses were able to induce their expected hormonal effects by analyzing the biological modifications observed during the study, which first demonstrated the survival benefit of low-dose steroids.

Methods

This was a multicenter, placebo-controlled, randomized, double-blind study in which 299 septic shock patients received a 7-day treatment with a combination of hydrocortisone (50 mg intravenously four times daily) and fludrocortisone (50 μg orally once daily) or matching placebos. Gluco- and mineralocorticoid biological effects observed during the 7 days of treatment were compared between groups.

Results

Steroids significantly decreased eosinophil counts from day 2 to day 7. Steroids significantly increased plasma glucose from day 2 (compared with placebos: +0.8 mmol/l) to day 7 (+1.8 mmol/l) and cholesterol from day 3 (+0.54 mmol/l) to day 7 (+0.39 mmol/l). Steroids significantly increased plasma sodium from day 3 (+2 mmol/l) to day 7 (+5 mmol/l) and significantly decreased plasma potassium on day 7 (−0.2 mmol/l). Steroids significantly decreased urinary sodium/potassium ratio from day 2 (−47 %) to day 7 (−57 %) and sodium fractional excretion from day 3 (−25 %) to day 7 (−66 %). Steroids significantly increased urine output on day 4 and 5 and osmolar clearance from day 4 to day 7, and decreased free-water clearance from day 4 to day 7, this effect being significant on day 4 and 6.

Conclusions

In septic shock, low-dose steroids induced both gluco- and mineralocorticoid biological effects and seemed to improve renal function. Most of these effects appeared after 2–3 days of treatment and lasted at least until the end of treatment.

Keywords

References

  1. Annane D, Bellissant E, Sebille V, Lesieur O, Mathieu B, Raphael JC, Gajdos P (1998) Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br J Clin Pharmacol 46:589–597
    • View reference on PubMed
    • View reference on publisher's website
  2. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E (2000) A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283:1038–1045
    • View reference on PubMed
    • View reference on publisher's website
  3. Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63–78
    • View reference on PubMed
    • View reference on publisher's website
  4. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M (2008) Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36:1937–1949
    • View reference on PubMed
    • View reference on publisher's website
  5. 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. JAMA 288:862–871
    • View reference on PubMed
    • View reference on publisher's website
  6. Beale R, Janes JM, Brunkhorst FM, Dobb G, Levy MM, Martin GS, Ramsay G, Silva E, Sprung CL, Vallet B, Vincent JL, Costigan TM, Leishman AG, Williams MD, Reinhart K (2010) Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry. Crit Care 14:R102
    • View reference on PubMed
    • View reference on publisher's website
  7. 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. N Engl J Med 358:111–124
    • View reference on PubMed
    • View reference on publisher's website
  8. 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. JAMA 303:341–348
    • View reference on PubMed
    • View reference on publisher's website
  9. Marik PE (2011) Glucocorticoids in sepsis: dissecting facts from fiction. Crit Care 15:158
    • View reference on PubMed
    • View reference on publisher's website
  10. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y (2004) Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 329:480
    • View reference on PubMed
    • View reference on publisher's website
  11. Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, Keh D, Kupfer Y, Oppert M, Meduri GU (2009) Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 301:2362–2375
    • View reference on PubMed
    • View reference on publisher's website
  12. Cooper MS, Stewart PM (2003) Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348:727–734
    • View reference on PubMed
    • View reference on publisher's website
  13. Reilly PM, Wilkins KB, Fuh KC, Haglund U, Bulkley GB (2001) The mesenteric hemodynamic response to circulatory shock: an overview. Shock 15:329–343
    • View reference on PubMed
    • View reference on publisher's website
  14. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL (2008) Surviving sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 34:17–60
  15. Marik PE (2009) Critical illness-related corticosteroid insufficiency. Chest 135:181–193
    • View reference on PubMed
    • View reference on publisher's website
  16. Annane D, Outin H, Fisch C, Bellissant E (2004) The effect of waiving consent on enrollment in a sepsis trial. Intensive Care Med 30:321–324
  17. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41
    • View reference on PubMed
    • View reference on publisher's website
  18. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the european society of intensive care medicine. Intensive Care Med 22:707–710
  19. Oelkers W, Diederich S, Bahr V (1992) Diagnosis and therapy surveillance in Addison’s disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. J Clin Endocrinol Metab 75:259–264
    • View reference on PubMed
    • View reference on publisher's website
  20. Arlt W, Allolio B (2003) Adrenal insufficiency. Lancet 361:1881–1893
    • View reference on PubMed
    • View reference on publisher's website
  21. Laviolle B, Le Maguet P, Verdier MC, Massart C, Donal E, Laine F, Lavenu A, Pape D, Bellissant E (2010) Biological and hemodynamic effects of low doses of fludrocortisone and hydrocortisone, alone or in combination, in healthy volunteers with hypoaldosteronism. Clin Pharmacol Ther 88:183–190
    • View reference on PubMed
    • View reference on publisher's website
  22. Prigent H, Maxime V, Annane D (2004) Science review: mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids. Crit Care 8:243–252
    • View reference on PubMed
    • View reference on publisher's website
  23. Venkatesh B, Cohen J, Hickman I, Nisbet J, Thomas P, Ward G, Hall J, Prins J (2007) Evidence of altered cortisol metabolism in critically ill patients: a prospective study. Intensive Care Med 33:1746–1753
  24. 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
    • View reference on PubMed
    • View reference on publisher's website
  25. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359–1367
    • View reference on PubMed
    • View reference on publisher's website
  26. Memis D, Gursoy O, Tasdogan M, Sut N, Kurt I, Ture M, Karamanlioglu B (2007) High C-reactive protein and low cholesterol levels are prognostic markers of survival in severe sepsis. J Clin Anesth 19:186–191
    • View reference on PubMed
    • View reference on publisher's website
  27. Druilhe A, Letuve S, Pretolani M (2003) Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis 8:481–495
    • View reference on PubMed
    • View reference on publisher's website
  28. Annane D, Sebille V, Bellissant E (2006) Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 34:22–30
    • View reference on PubMed
    • View reference on publisher's website
  29. Beishuizen A, Vermes I, Hylkema BS, Haanen C (1999) Relative eosinophilia and functional adrenal insufficiency in critically ill patients. Lancet 353:1675–1676
    • View reference on PubMed
    • View reference on publisher's website
  30. Russell JA, Walley KR, Gordon AC, Cooper DJ, Hebert PC, Singer J, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ (2009) Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med 37:811–818
    • View reference on PubMed
    • View reference on publisher's website
  31. Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3rd (2001) Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 29:487–493
    • View reference on PubMed
    • View reference on publisher's website
  32. Desjars P, Pinaud M, Bugnon D, Tasseau F (1989) Norepinephrine therapy has no deleterious renal effects in human septic shock. Crit Care Med 17:426–429
    • View reference on PubMed
    • View reference on publisher's website
  33. Mitaka C, Hirata Y, Masaki Y, Takei T, Yokoyama K, Imai T (2000) S-Methylisothiourea sulfate improves renal, but not hepatic dysfunction in canine endotoxic shock model. Intensive Care Med 26:117–124
  34. Quintanilla AP, Delgado-Butron C, Zeballos J (1976) Renal hemodynamics and water excretion in Addison’s disease. Metabolism 25:419–425
    • View reference on PubMed
    • View reference on publisher's website
  35. Baptista JP, Udy AA, Sousa E, Pimentel J, Wang L, Roberts JA, Lipman J (2011) A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care 15:R139
    • View reference on PubMed
    • View reference on publisher's website

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