Corticosteroids in Septic Shock

Corticosteroids in Septic Shock

A week after an elective colectomy, a 70yr old man developed septic shock and multiorgan failure secondary to anastomotic breakdown. He was managed according to surviving sepsis guidelines with source control, early antibiotics, fluids and noradrenaline. The patient remained hypotensive and refractory to noradrenaline therapy, and had vasopressin and low dose hydrocortisone infusion commenced.

What is the evidence for the use of corticosteroids in septic shock?

Tahir Ali

Septic shock is characterised by severe systemic inflammatory response resulting in (multi)organ failure and eventually death if untreated.(1) During health there is a careful balance between pro-inflammatory (nuclear factor kappa B [NF-KB]) and anti-inflammatory (glucocorticoid-glucocorticoid receptor alpha [G-GRA], inhibitory factor kappa B [I-KB]) systems(2) maintained by the neuroendocrine and immune systems in the body.

It is well recognised that conditions of ‘stress’ results in a relative adrenal insufficiency.(3,4) This increases the presence of pro-inflammatory mediators (NF-KB) therefore worsening the systemic inflammatory response(5) and even contributing to cell, tissue and organ damage.(6) These physiological rationales support the use of steroids in periods of severe stress such as sepsis shock.

Saldago et al(7) demonstrated adrenal suppression in approximately 23% of patient with septic shock using a modified version of the Synacthen test. Other diagnostic methods have been used however the Consensus Task Force of the American College of Critical Care Medicine recommend the same diagnostic criteria as Saldago et al. They recommend a serum cortisol increase of less than 9 μg/dl after a 250 μg ACTH stimulation test or a random total cortisol level less than 10 μg/dl implies “critical illness-related corticosteroid insufficiency”.

The aim of this report is to evaluate the evidence for or against the use of corticosteroids in the treatment of septic shock which has swung back and forth several times.

High dose corticosteroids
High dose corticosteroids was demonstrated to have significant survival benefit in patients with septic shock by Schumer(8). However it was a single centred retrospective study and later Sprung et al demonstrated no survival benefit in a prospective RCT.(9)

Low dose corticosteroids
Oppert et al randomised 40 patients with vasopressor dependent septic shock and demonstrated an improvement in shock reversal, decreased proinflammatory cytokines as well as no increase in secondary infection.(10) This was further confirmed by Annane et al(11) where 300 patients were randomised to hydrocortisone 50mg QDS and fludrocortisone 50 mcg OD versus placebo. It too demonstrated improved survival and shock reversal. Adrenal insufficiency was evident in 76.5% of these patients. The major contribution to this adrenal insufficiency is also a major criticism in this trial which was the
use of etomidate to facilitate endotracheal intubation in the majority of the patients.

Sligl et al, however, performed a meta-analysis on eight studies demonstrating no statistically significant difference in mortality in using corticosteroids.(12)

In 2008 the CORTICUS trial published its results randomising 499 patients and demonstrating no improvement in shock reversal or 28 day survival. Instead it found increased frequency of complications including hyperglycaemia, hypernatraemia and superinfections.(9)

Learning points
Use of steroids in septic shock remains a contentious issue. It is due to this that the surviving sepsis guidelines 2012 do not recommend its use if haemodynamic stability is achieved using adequate fluid resuscitation and vasopressor therapy. If shocked patient remain haemodynamically unstable they recommend intravenous hydrocortisone alone at a dose of 200mg per day. It is not without side effects and therefore patients require regular electrolyte and glucose measurement and treatment. The downside of insulin therapy is the frequent occurrence of hypoglycaemia which unless continuous blood glucose monitoring becomes standard practice will be impossible to avoid. Once initiated, corticosteroids are to be slowly weaned after 7 days therapy.

Fludrocortisone in addition to hydrocortisone has not shown to have any survival benefit according to the COIITSS trial and instead demonstrated higher incidence of infection.

1. Annane D, Bellissant E, Cavaillon JM: Septic shock. Lancet 2005, 365:63-
2. Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in
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3. Kashiwabara M, Miyashita M, Nomura T, Makino H, Matsutani T, Kim C,
Takeda S, Yamashita K, Chaudry IH, Tajiri T: Surgical trauma-induced
adrenal insufficiency is associated with postoperative inflammatory
responses. J Nippon Med Sch 2007, 74(4):274-283.
4. Hoen S, Asehnoune K, Brailly-Tabard S, Mazoit JX, Benhamou D, Moine
P, Edouard AR: Cortisol response to corticotropin stimulation in trauma
patients: influence of hemorrhagic shock. Anesthesiology 2002, 97(4):807-
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and treatment with glucocorticoids during critical illness. Nat Clin Pract
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Effect of corticosteroids on nuclear factor-kappaB activation and
hemodynamics in late septic shock. Crit Care Med 2001, 29(5):1074-1077.
7. Salgado DR, Verdeal JCR, Rocco JR. Adrenal function testing in patients
with septic shock. Crit Care 2006;10:R149.
8. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg.
9. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM,
Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids
in patients with septic shock: a prospective, controlled study. N Engl J Med
10.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.
11.Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM,
Capellier G, Cohen Y, Azoulay E, Troche G, et al. Effect of treatment with
low doses of hydrocortisone and fludrocortisones on mortality in patients
with septic shock. JAMA 2002;288:862–871.
12.Sligl WI, Milner DA Jr, Sundar S, et al: Safety and efficacy of
corticosteroids for the treatment of septic shock: A systematic review and
meta-analysis. Clin Infect Dis 2009; 49:93-101.
13.The COIITSS Study Investigators. Corticosteroid treatment and intensive
insulin therapy for septic shock in adults: a randomized controlled trial.
JAMA 2010;303:341–348.

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