Interact CardioVasc Thorac Surg 2008;7:898-905. doi:10.1510/icvts.2008.185504
© 2008 European Association of Cardio-Thoracic Surgery
Best evidence topic - Cardiac general |
Is steroid therapy ever of benefit to patients in the intensive care unit going into septic shock
Lydia Richardsona,* and
Steven Hunterb
a Brighton and Sussex Medical School, Brighton, East Sussex, UK
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Received 4 June 2008;
accepted 3 July 2008
*Corresponding author. Tel.: +44 789 4559594; fax: +44 789 4559594.
E-mail address: l.e.richardson{at}bsms.ac.uk (L. Richardson).
 |
Abstract
|
|---|
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was, is steroid therapy ever of benefit to patients in the intensive care unit going into septic shock? Using the reported search 1505 papers were identified. Fourteen papers represented the best evidence on the subject. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments and weaknesses were tabulated. Recent guidelines from the Surviving Sepsis Campaign recommend using stress doses of corticosteroids for septic shock regardless of adrenal function. All patients undergoing cardiothoracic surgery are at risk of developing septic shock. The 14 papers demonstrated that 28-day mortality is unaffected by hydrocortisone, however, the time to shock reversal is significantly reduced. Steroids reduced inflammatory mediators (IL-6, IL-8 and CRP) and neutrophil activation whilst maintaining neutrophil phagocytic functions. Haemodynamically, they increased systemic vascular resistance (SVR) and mean arterial pressure (MAP) and reduced heart rate (HR) and glomerular permeability. We conclude that steroids have no effect on mortality but shorten time to shock reversal, therefore they have a limited capacity in septic shock patients. Their immunological and haemodynamic effects cannot be discounted and could benefit patients in severe septic shock with adrenal insufficiency.
Key Words: Steroid; Hydrocortisone; Septic shock; Intensive care unit; Mortality; Shock reversal
|
1. Introduction
|
|---|
A best evidence topic was constructed according to a structured protocol, described in the ICVTS [1].
|
2. Clinical scenario
|
|---|
A 67-year-old patient has returned to ICU following an aortic valve replacement. Four hours post-surgery he becomes febrile and tachycardic with an elevated white cell count. You recognise he is showing signs of sepsis and despite treatment, the patient deteriorates. You have recently attended a presentation from the Professor of Infectious Disease who suggested that a course of low dose steroids may be of benefit to some patients in septic shock, however, it is not part of empirical treatment. Would a course of steroids be of any benefit to this patient?
|
3. Three-part question
|
|---|
In patients who have undergone cardiothoracic surgery and are subsequently admitted into the [ICU], is [steroid therapy] ever of benefit in those going into [septic shock]?
|
4. Search strategy
|
|---|
Medline 1950 to February 2008 and Embase 1980 to February 2008 using OVID interface. [exp hydrocortisone/OR exp steroid/OR exp corticosteroid/OR exp methyleprednisolone/OR exp dexamethasone] AND [exp septic shock/OR exp sepsis/OR exp severe sepsis] AND [exp intensive care/OR exp intensive care unit/OR exp critical care]. Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials register was searched on 9th March 2008 using the search terms ‘hydrocortisone, steroid’ and ‘septic shock, sepsis’ and ‘intensive care’. The references of resulting papers were also reviewed.
|
5. Search outcome
|
|---|
Four hundred and fifty-nine abstracts were identified from Medline, 939 abstracts from Embase, 74 papers from the Cochrane database of systematic reviews and 33 from the Cochrane controlled trials register. From these studies, 14 represented the best evidence on the topic (Table 1). We included eight randomised controlled trials [2–9], two retrospective studies [10, 11], one systematic review [12] and three meta-analyses [13–15].
|
6. Comments
|
|---|
The Surviving Sepsis Campaign recommend using stress doses of corticosteroids regardless of adrenal function [16], however, the American College of Critical Care Medicine Task Force recommend that stress doses of corticosteroids should be limited to refractory septic shock or to patients with adrenal insufficiency [17]; those defined as non-responders to a corticotrophin stimulation [18].
Twenty-eight-day mortality was not significantly different in the treated and placebo group [5, 12] or between responders and non-responders to ACTH [5]. Annane et al. [7] found that treated responders have a higher 28-day mortality compared to placebo (61% vs. 53%) and that treated non-responders have a lower mortality rate compared to placebo (53% vs. 63%). de Jong et al. [11] suggest there is an inverse relationship between cortisol response to ACTH and disease severity, a theory supported by the finding of ICU- and one-year mortality rates being lowest in the treated non-responders [7] suggesting corticosteroids may be of benefit to those patients who have adrenal insufficiency.
Time to shock reversal was significantly (P<0.001) shorter in the treated group; 3.3 vs. 5.8 days [5], (53 vs. 120 h) [4], (7 vs. 9 days) [7], (2 vs. 9 days) [8], (68% vs. 21% shock reversal) [9]. The systematic review [12] and one meta-analysis [13] reported shorter time to shock reversal, however, one group observed a longer time to shock reversal in the steroid group [10].
In four trials who measured IL-6 serum concentration [3, 4], IL-6 and IL-8 [6] and C-reactive protein [2], found these inflammatory mediators were lower in patients receiving hydrocortisone. Hydrocortisone reduced hydrogen peroxide release from neutrophils and reduced their expression of activation markers but maintained their phagocytic functions [3, 6].
Hydrocortisone significantly increased MAP and SVR [6, 8] from day 0 to 5, reduced HR [6] and lowered glomerular permeability [2], all of which would contribute to a shorter time to shock reversal.
The dosing regime of hydrocortisone varied amongst the RCTs, some administered a loading IV bolus ranging from 50 mg to 100 mg followed by an IV infusion [3, 4, 6, 8], the latter ranging from 200 mg [5, 7] to 240 mg [6] to 300 mg [2, 9] per day for a 5–8-day course. The meta-analysis by Minneci et al. [13] and the systematic review by Annane et al. [12] both found long courses of low dose hydrocortisone to be more beneficial in terms of shock reversal and mortality compared to a short course of high doses.
|
7. Clinical bottom line
|
|---|
The largest RCT [5] reveals that steroids have no effect on 28-day mortality of patients (responders and non-responders), however, this study is inadequately powered. Steroids appear to shorten the time to shock reversal which may be explained by the increase in SVR and MAP and reduction in inflammatory mediators, neutrophil activation, glomerular permeability and HR observed post-steroid treatment. Patients with greater disease severity as indicated by a minimal response to ACTH, may be those who significantly benefit from long course, low dose steroid treatment.
|
References
|
|---|
- Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interat CardioVasc Thorac Surg 2003;2:405–409.[CrossRef]
- Rinaldi S, Adembri C, Grechi S, Gaudio R. Low-dose hydrocortisone during severe sepsis: effects on microalbuminuria. Crit Care Med 2006;34:2334–2339.[CrossRef][Medline]
- Kaufman I, Briegel J, Schliephake F, Hoezel A, Chouker A, Hummel T, Schelling G, Thiel M. Stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependant neutrophil functions. Intensive Care Med 2008;34:334–349.
- Oppert M, Schindler R, Husung C, Offermann K, Graf KJ, Boenisch O, Barckow D, Frei U, Eckardt KU. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med 2005;33:2457–2464.[CrossRef][Medline]
- 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. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111–124.[Abstract/Free Full Text]
- Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of low dose hydrocortisone in septic shock. Am J Respir Crit Care Med 2003;167:512–520.[Abstract/Free Full Text]
- 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. Effects of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. J Am Med Assoc 2002;288:862–871.[Abstract/Free Full Text]
- Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomised, double-blind, single-centre study. Crit Care Med 1999;27:723–732.[CrossRef][Medline]
- Bollaert PE, 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.[CrossRef][Medline]
- Raurich JM, Llompart-Pou JA, Ibanez J, Frontera G, Perez O, Garcia L, Ayestaran JI. Low-dose steroid therapy does not affect hemodynamic response in septic shock patients. J Crit Care 2007;22:324–330.[CrossRef][Medline]
- de Jong MFC, Beishuizen A, Spijkstra JJ, Groeneveld J. Relative adrenal insufficiency as a predictor of disease severity, mortality, and beneficial effects of corticosteroid treatment in septic shock. Crit Care Med 2007;35:1896–1903.[CrossRef][Medline]
- Annane D, Bellissant E, Bollaert PR, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock. Cochrane Database of Syst Rev 2004, Issue 1.
- Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47–56.[Abstract/Free Full Text]
- Cronin L, Cook D, Carlet J, Heyland D, King D, Lansang MA, Fisher CJ. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23:1430–1439.[CrossRef][Medline]
- Lefering R, Neugebauer E. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med 1995;23:1294–1303.[CrossRef][Medline]
- Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker M, Ramsay G, Zimmerman JL, Vincent J-L, Levy M. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–873.[CrossRef][Medline]
- Annane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Curr Opin Crit Care 2005;11:449–453.[CrossRef][Medline]
- Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–734.[Free Full Text]
|
|
Top
Abstract
1. Introduction