Steroids and Septic Shock Literature Summaries

Bone R.C. et al (1987) “A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock” NEJM, 317:653-658 PMID 3306374

• RCT
• n = 382 with sepsis and organ dysfunction
• methylprednisolone (30mg/kg) vs placebo
  -> no difference in mortality
  -> increased mortality in a subgroup with renal impairment

Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995 Aug;23(8):1430-9. PMID: 7634816.

-> trend towards detrimental effects in those treated with steroids

Jurney TH, Cockrell JL Jr, Lindberg JS, Lamiell JM, Wade CE. Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality. Chest. 1987 Aug;92(2):292-5. PubMed PMID: 3038477.

• suggested there might be a small proportion of patients who are non-responders (unable to increase their cortisol levels in stress -> relative adrenal insufficiency)
• these patient have high mortality and may improve with low dose steroid administration
• ‘normal’ response in sepsis: cortisol >500 nmol/L (random) or a rise of > 200nmol/L following ACTH administration
  -> non-responders might benefit from steroid replacement

Annane D, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71. Erratum in: JAMA. 2008 Oct 8;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe]. PubMed PMID: 12186604. [Free Fulltext]

• MC DB RCT
• n = 300 refractory septic shock patients in 19 French ICUs
• low dose hydrocortisone (50 mg IV q6h) + fludrocortisone  (50 mcg/d) for 7 daysVS placebo
• outcomes:
  -> BUT, non-responders to Synacthen test + given steroid -> significant decrease in 28d mortality (P = 0.02): 53% vs 63% in favour of the intervention; but no difference at 1 year
  -> duration of vasopressor therapy shorter
  -> more rapid reversal of shock
  -> increased wound infections in the placebo group
• commentary:
  — all patients were mechanically ventilated
  — refuted by the CORTICUS study

Sprung CL, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366. PubMed PMID: 18184957. [Free Fulltext]

• 2008 – CORTICUS
• MC DB RCT
• low dose hydrocortisone (50mg q6h tapered over 6 days) vs placebo
  -> no survival benefit (32% vs 34%)
  -> no difference in whether or not shock was reversed (76% vs 70%)
  -> shock reversed more quickly (2.8 vs 5.8 days)
  -> more superinfections, hyperglycaemia, hypernatremia
• commentary and criticisms:
  — stopped early due to slow recruitment
  — inadequately powered (target sample size was 800)
  — no differences according to whether patients were ‘responders’ or ‘non-responders’
  — enrolment was <72h compared with <8h in Annane 2002
  —Annane 2002 included sicker patients (based on SAPS scores) that had higher mortality

COIITSS Study Investigators, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010 Jan 27;303(4):341-8. doi: 10.1001/jama.2010.2. Erratum in: JAMA. 2010 May 5;303(17):1698. PubMed PMID: 20103758. [Free Fulltext]

• MCRCT
• 4 groups with septic shock:
  — intensive insulin therapy + hydrocortisone VS  conventional  insulin therapy + hydrocortisone VS same treatments with fludrocortisone
• inclusion criteria: adult, septic shock, MODS, hydrocortisone
• exclusion criteria: no consent, moribund, pregnant, co-enrolement
• primary end points = hospital mortality and 90 day mortality
• secondary end points = 28, 90 and 180 day mortality, ventilator free days, ICU length of stay, hospital length of stay, hypoglycaemia, infectious complications, weakness
• n = 509
• ITT analysis

Intensive Insulin Group
-> double hypoglycaemic rate
-> no increase in mortality
-> no difference in secondary outcomes
-> no difference in synth-ACTH-en responders
-> no difference in fludrocortisone patients

Fludrocoritisone Results
-> no increase in mortality
-> no difference in inotropes
-> excess superinfection rate

Conclusions – in septic shock patients treated with hydrocortisone there was:

• no benefit from intensive insulin therapy, it led to increased episodes of hypoglycemia
• no benefit from fludrocortisone, it led to increased rates of superinfection

Criticisms

• did not reach required recruitment levels
• not blinded
• tested multiple variables

AN APPROACH TO STEROIDS IN SEPTIC SHOCK

• don’t use in low risk patients
• consider in high risk patients (multi-organ failure) acknowledging that septic shock may reverse more quickly but will not change mortality
• use low dose
• vigilance for super infection
• don’t use a short synACTHen test
• eagerly await the ADRENAL study!

References and Links

LITFL

• CCC – Corticosteroids for Refractory Shock
• CCC – Steroid conversion
• CCC – Corticosteroids Overview
• CCC – Adrenal Insufficiency
• Basic Science – Pharm 101: Corticosteroids

Journal articles

• Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71. Erratum in: JAMA. 2008 Oct 8;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe]. PubMed PMID: 12186604. [Free Full Text]
• Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995 Aug;23(8):1430-9. PubMed PMID: 7634816.
• Jurney TH, Cockrell JL Jr, Lindberg JS, Lamiell JM, Wade CE. Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality. Chest. 1987 Aug;92(2):292-5. PubMed PMID: 3038477.
• Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976 Sep;184(3):333-41. PubMed PMID: 786190; PubMed Central PMCID: PMC1344393.
  Sprung CL, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366. PubMed PMID: 18184957. [Free Fulltext]
• COIITSS Study Investigators, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010 Jan 27;303(4):341-8. doi: 10.1001/jama.2010.2. Erratum in: JAMA. 2010 May 5;303(17):1698. PubMed PMID: 20103758. [Free Fulltext]

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