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Year : 2004  |  Volume : 8  |  Issue : 3  |  Page : 145-147

Return of corticosteroids for septic shock- new dose, new insights

Departments of Pulmonology, Critical Care and Sleep Medicine, Delhi Heart and Lung Institute, 3-mm 2, Panchkuin Road, New Delhi - 110055, India

Correspondence Address:
R K Mani
C-60, Niti Bagh, Khel Geon Marg, New Delhi - 110 049
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Mani R K. Return of corticosteroids for septic shock- new dose, new insights. Indian J Crit Care Med 2004;8:145-7

How to cite this URL:
Mani R K. Return of corticosteroids for septic shock- new dose, new insights. Indian J Crit Care Med [serial online] 2004 [cited 2019 Jan 16];8:145-7. Available from:

The use of corticosteroids for critical illness has been a contentious issue for decades. Physicians have intuitively felt that corticosteroid therapy may be beneficial and at the same time, felt apprehensive about its potential for adverse effects. Every physician would like to have a physiological basis for using a drug and to have its use validated through a well-designed study. Corticosteroids have been tested for several critical situations especially for sepsis and ARDS.[1],[2] The early trials showed disappointing results generating much skepticism.[1],[3] Until the late 80s Methylprednisolone "pulses" were used for 2-3 days in septic shock with non-beneficial outcome in terms of mortality reduction, while the incidence of infections were higher.[3] Meta analyses later reaffirmed this fact.[4],[5] Out went both "baby and bathwater" and the issue of corticosteroids in septic shock was buried for nearly a decade.

The corticosteroid issue was resurrected when it was realized that adrenal insufficiency exists frequently in critical illness. The current definition of "relative adrenal insufficiency" is rapid clinical and hemodynamic improvement in catecholamine-dependent patients after the administration of 200 to 300 mg hydrocortisone per day, which also seems the best available clue to its diagnosis until now. Although absolute adrenal insufficiency occurs only in a miniscule minority (1-3%), relative adrenal insufficiency (RAI) was found in up to 80%.[6] The estimates varied according to the threshold values used to diagnose hypocortisolemia and the dose of ACTH used for the stimulation test.[7] It became evident that in the majority of critically ill patients the body fails to mount an adequate stress response with respect to cortisol even with a preexisting normal adrenal function. The anti-inflammatory and hemodynamic effects of coticosteroids are getting better understood- it suppresses inflammation at several levels, suppresses nitric oxide synthase induction and up regulates vascular responsiveness to catecholamines. Studies also revealed how evidence of poor adrenal reserves was associated with a poor outcome among critically ill patients.[6]

In this issue of IJCCM, Chacko et al from CMC Vellore have studied the cortisol responsiveness of consecutive patients of septic shock by using the ACTH stimulation test with a dose of 1 mcg.[8] The study is timely and has implications for the treatment of patients of septic shock that carries a high mortality. Having excluded patients with preexisting adrenal insufficiency, the prevalence of RAI in this study was 81.6% out of 49 patients with matching characteristics such as age, APACHE score, pH and sodium levels for both "responders" and "non-responders" to ACTH stimulation. They rightly conclude that low-dose corticosteroids should be considered for patients in India, as RAI appears to occur in the majority of patients of septic shock.

The hypothesis that "stress" doses of corticosteroids might help in septic shock was tested initially in small studies[9],[10] and later, in a multi center randomized double blind, placebo-controlled study.[11] Annane et al[11] showed that early treatment (within hours) in 299 patients with sepsis, low dose hydrocortisone combined with fludrocortisone had beneficial effects. In those who had <9 mcg/dl increase in cortisol in response to stimulation (the "non responders") corticosteroids had a beneficial effect as compared to placebo in terms of longer days of survival and shorter days of dependence on vasopressor support. Notably they did not demonstrate an improvement in crude mortality nor did they show any benefit in "responders". In meta analyses of the trials conducted after 1997 as compared to those before 1989,[12],[13] there was a consistent improvement in overall mortality and shock reversal, whether they were responders or non-responders. The premise on which the earlier studies had administered high dose steroids was that immunosuppression could alter the course of septic shock. This could have led to the harmful effects by increased incidence of severe secondary infections.[13] In contrast, the later studies were based on correcting the relative insufficiency of cortisol and to attenuate rather than suppress inflammation. The modified approach led to a lower dose and a longer duration (5 days, then tapered over 5-7 days).[13],[14] Keh et al[15] in a recent crossover study have demonstrated that corticosteroids in low doses may only attenuate, not suppress inflammatory response thus giving credence to these conclusions.

It is not clear whether it is necessary to perform a stimulation test to identify the responders where low-dose corticosteroid therapy may be withdrawn.[14] It is not also clear what dose of ACTH should be used for stimulation- the standard 250 mcg or the low-dose 1 mcg.[7],[14] Chacko et al have used the 1 mcg dose to demonstrate relative adrenal insufficiency in patients with septic shock refractory to volume loading and dependent on vasopressors. While the current opinion favors the use of 250 mcg dose for stimulation[14] the justification for the use of the lower dose is the higher sensitivity and specificity of the results.[7] Another probably very important topic in interpreting cortisol levels, recently mentioned by Hamrahian et al.[16] is that most assays measure total (free plus protein-bound) cortisol. Because more than 90% of circulating cortisol is protein bound, changes in binding proteins can alter total cortisol levels without changes in free cortisol concentrations. Because free cortisol is responsible for the physiologic function of the hormone, measuring true free cortisol concentrations could be important in understanding the pathophysiology of the relative adrenal insufficiency syndrome. Indeed, it is possible that baseline cortisol value will be more sensitive in identifying RAI[7] and total serum cortisol as opposed to free cortisol values may be misleading in the presence of hypoproteinemia.[16] Nevertheless, this study from Vellore shows that RAI exists in Indian patients and therefore there is a basis to use low dose corticosteroids in septic shock in this part of the world as elsewhere.

Corticosteroids appear to have returned, but in a different package. As with its use in late ARDS, we have learnt to use lower doses and for longer time. Much need to be elucidated. We do not know whether it would be harmful to use corticosteroids in responders, whether fludrocotisone is needed, and whether corticosteroids need to be tapered or stopped abruptly once vasopressors are off. The ongoing CORTICUS study may have some answers. We hope that the new insights would help refine the use of the very beneficial and controversial corticosteroids.

  References Top

1.Meduri GU, Chinn AJ, Leeper KV, Wunderink RG, Tolley E, Winer-Muram HT, et al. Corticosteroid rescue treatment of progressive fibroproliferation in late ARDS: Patterns of response and predictors of outcome. Chest 1994;105:1516-27.  Back to cited text no. 1  [PUBMED]  
2.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.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Sprung CL, Caralis PV, Marcial EH, Pierce EH, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients of septic shock: A prospective, controlled study. N Engl J Med 1984;311:1137-43.  Back to cited text no. 3    
4.Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: A meta-analysis. Crit Care Med 1995;23:1294-303.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA. et al. Corticosteroid treatment for sepsis: A critical appraisal and metaanalysis of the literature. Crit Care Med 1995;23:1430-9.  Back to cited text no. 5    
6.Annane D, Sebille V, Troche 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.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003;31:141-5.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Chacko ST, John G, Thomas N, Nellickal AJ. Subclinical hypocortisolemia in patients with sepsis in a medical intensive care unit in India (the SHIPS study). Crit Care Med 2005;8:162-7.  Back to cited text no. 8    
9.Bollaert PE, Charpentier C, Levy B, Debouveric M, Audibert G, Larean A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645-50.  Back to cited text no. 9    
10.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.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.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.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock. Cochrane database Syst Rev BMJ 2004;329;480-4.  Back to cited text no. 12    
13.Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: The effect of steroids on survival and shock depends on the dose. Ann Intern Med 2004;141:47-56.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Keh D, Sprung CL. Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review. Crit Care Med 2004;32:s527-s533.  Back to cited text no. 14    
15.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;167:512-20.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629-38.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]

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