Corticosteroid Therapy for Shock

OVERVIEW

Corticosteroids are widely used in patients with refractory septic shock, as well as other selected causes of shock. Despite numerous trials, the role of corticosteroids in septic shock remains a controversial issue… still!

TYPICAL USES OF CORTICOSTEROIDS FOR SHOCK

  • anaphylaxis
  • hypothalamic-pituitary-adrenal insufficiency (e.g. pituitary apoplexy, Addison’s disease)
  • known previous steroid dependence
  • recent steroid administration (ie. a course > 1 week in last 6 months)
  • refractory septic shock

RELATIVE ADRENAL INSUFFICIENCY (RAI) AND SEPTIC SHOCK

The RAI concept is based on the following:

  • cortisol levels are increased in response to stress
  • the greater the stress, the greater the expected cortisol rise
  • as sepsis is a potent stressor, cortisol levels should be very high
  • adrenalectomised animal models of sepsis die

This was supported by some important studies

  • Jurney 1987 found that septic shock patients were either ‘responders’ or ‘non-responders’ to ACTH
  • the use of the short synACTHen test became the cornerstone of RAI when Annane et al 2002 found that ‘responders’ have better outcomes when treated with steroids than ‘non-responders’ — e.g. patients with a cortisol level <250 nM after 250 mcg synACTHen do worst

Problems with the RAI concept:

  • leads to the prediction that patient’s with lower levels of cortisol should have higher mortality in septic shock… BUT the opposite is found!
  • Short SynACTHen tests are nearly uninterpretable in septic shock patients – what is an appropriate cut off?
  • the RAI hypothesis is too simplistic – free cortisol is biologically active, yet we only measure total cortisol (cortisol bind globulin levels change in sepsis)
  • response to cortisol may vary at any level: receptor levels and responsiveness, translocation into the nucleus, variations in the many hundreds of gene products that are transcribed

SHORT SYNACTHEN TEST

The synacthen test is used to test adrenal reserve

  • Synacthen is tetracosactrin, the first 24 amino acids of ACTH
  • Primarily used in patients with suspected endocrinological disorders who are not critically ill

Short synacthen test procedure:

  • take a basal sample for cortisol (time = 0 min)
  • give 250 mcg Synacthen IV (can also be given IM)
  • blood cortisol sample is taken at 30 min and 60 min

Result interpretation:

  • healthy individuals
    • basal plasma cortisol >170 nM and rises to >580 nM
  • hypoadrenalism
    • inadequate rise in serum cortisol in response to synacthen
    • <250 nM (= 9 mcg/dL) used in the Annane trial (2002) of corticosteroids for septic shock to identify ‘relative adrenal insufficiency’

HISTORY OF TRIALS OF STEROIDS IN SEPTIC SHOCK

1970s

  • high dose 30mg/kg methylprednisolone was used for septic shock
  • supported by animal studies and early human studies
  • e.g. Schumer et al 1976: DB RCT, n = 172, methylprednisolone vs dexamethasone versus saline; outcome: increased mortality in the saline arm
  • methylprednisolone became standard of care

1980s

  • supraphysiological doses used in several trials
  • no survival benefit, increased morbidity due to secondary infections

Jurney et al, 1987

  • single center prospective observational study
  • suggested that patients in septic shock fall into two groups based on response to ACTH: ‘responders’ and ‘non-responders’
  • led to the concept of ‘relative adrenal insufficiency’ (RAI)

Cronin et al, CCM 1995

  • meta-analysis
  • outcome: increased mortality for steroids in septic shock
  • high dose steroids were no longer considered the standard of care for septic shock as a result

Annane et al, JAMA 2002

  • RCT
  • patients with septic shock who were non-responders to an ACTH stimulation test
  • intervention: low dose steroids (hydrocortisone and fludrocortisone)
  • control: placebo
  • outcome: significant decrease in mortality compared with placebo and shorter vasopressor duration; no difference in adverse effects
  • supported the concept of ‘relative adrenal insufficiency’, suggesting a role for ‘physiological’ doses of corticosteroids

CORTICUS trial, NEJM 2008

  • MC RCT
  • outcomes:
    • hydrocortisone did not improve survival or reversal of shock in patients with septic shock, however reversal occurred more quickly
    • no difference between ‘responders’ and ‘non-responders’
  • patients were not as sick as in the Annane study and CORTICUS was underpowered

COIITTS trial, JAMA 2010

  • MC RCT
  • outcomes:
    • fludrocortisone (mineralocorticoid) in addition to hydrocortisone did not produce a survival advantage
    • steroids increased the superinfection rate

SSC Guidelines 2012:

  • Recommend against using hydrocortisone IV to treat adult septic shock if fluid resuscitation and pressors are able to reverse hemodynamic instability, if unable to do so hydrocortisone 200 mg IV daily may be used at that point (grade 2C)
  • Recommend against ACTH stimulation test in adults with septic shock (grade 2B)
  • Recommend against using hydrocortisone when vasopressors aren’t required (grade 2D)
  • Recommend against using corticosteroids in sepsis without shock (grade 1D)

ADRENAL trial (2018)

  • Multicenter international double-blind randomised placebo-controlled trial
  • 69 ICUs, mostly in Australia
  • n= 3658 adult patients with septic shock requiring vasopressors and mechanical ventilation
  • intervention: IV hydrocortisone 200mg/day, given as continuous infusion for 7 days or until ICU discharge
  • comparison: placebo + standard therapy
  • outcomes:
    • No difference in the primary outcome of 90-day mortality
      • 511 of 1832 patients (27.9%) in the hydrocortisone group died vs 526 of 1826 (28.8%) in the placebo group
      • Odds ratio (OR), 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50
      • Absolute risk reduction (ARR) 0.91%; 95% CI -2.01% to 3.83%; P=0.56 (Fisher’s exact)
    • Multiple secondary outcomes were assessed, those that were significant were:
      • Median days to resolution of shock
        • 3 vs 4 days (Hazard ratio [HR] 1.32; 95% C.I. 1.23-1.41, P=<0.001)
      • Median time to cessation of initial mechanical ventilation
        • 6 vs. 7 days (HR 1.13; 95% C.I. 1.05-1.22, P=<0.001)
      • Median time to discharge from the ICU
        • 10 vs. 12 days (HR 1.14, 95% C.I. 1.06-1.23, P=<0.001)
      • Use of blood transfusion
        • 37.0% vs. 41.7% (OR 0.82; 95% C.I. 0.72-0.94, P=0.004)
      • Number of patients with adverse events were significantly greater in hydrocortisone group
        • 21 (1.1%) vs. 6 (0.3%), p=0.009
        • e.g. hyperglycaemia, hypernatraemia, encephalopathy
  • Commentary and criticisms
    • Very well designed trial with excellent internal validity
    • Secondary outcomes should not change practice
      • they are not patient-orientated outcomes (duration of mechanical ventilation and ICU LOS are arguable)
      • “shock resolution” is based on when vasopressors are stopped, it is possible that steroids simply “buff the numbers” rather than help the patient
      • some are dependent on clinician decision making (e.g. when to extubate, when to discharge) and may be influenced by “the numbers being buffed”
      • they may be statistical quirks due to the large number of secondary outcomes assessed (* other secondary outcomes were not statistically significant)
    • Used continuous infusions of hydrocortisone rather than intermittent boluses; they were stopped abruptly at 7 days or ICU discharge (not weaned)
    • Did not assess long-term functional outcomes or neuromuscular weakness
    • appropriateness of antibiotic therapy was not assessed
    • no differences whether Sepsis 2.0 or Sepsis 3.0 definition criteria were applied
  • Conclusion
    • No mortality benefit at 90 days from IV hydrocortisone for septic shock in mechanically ventilated patients

THE ‘MARIK PROTOCOL’ 

Marik et al (2016)

  • Single centre, unblinded and retrospective before-and-after observational study
  • n-47 patients with severe sepsis or septic shock and a procalcitonin (PCT) >2 ng/ml
  • Intervention: Vitamin C + Hydrocortisone + Thiamine in addition to standard treatment
    • 1.5g QID Vitamin C intravenously for 4 days or until ICU discharge
    • Hydrocortisone 50mg QID intravenously for 7 days or until ICU discharge followed by a taper over 3 days
    •  200mg thiamine BD for 4 days or until ICU discharge
  • Control arm was placebo
  • Primary outcome
    • Hospital mortality – 8.5% (4 of 47) in the treatment group compared to 40.4% (19 of 47) in the control group (p < 0.001)
  • Commentary and criticism:
    • There is a biological rationale for a synergistic effect of hydrocortisone, with Vitamin C, and thiamine (e.g. many studies have found low levels of vitamin C and thiamine in septic patients, possible combined role in maintaining endothelial integrity)
    • The study design lacks internal validity and is at very high risk of systematic bias
  • Conclusion
    • The results, while promising, are merely hypothesis generating and should not change practice pending better-designed studies

AN APPROACH

Corticosteroids should not be used routinely for patients with septic shock

  • the weight of evidence does not support a benefit in terms of patient-orientated outcomes
  • ACTH stimulation tests are not useful in this patients
  • hydrocortisone 200 mg IV daily is an option for septic shock patients who are refractory to vasopressors (e.g. adults requiring IV noradrenaline at 20-30 micrograms/h) and no other cause found; despite an absence of convincing supportive evidence of benefit

Corticosteroids should be used in patients who have shock and a specific indication for corticosteroid therapy

  • e.g. anaphylaxis, known steroid dependence (e.g. for chronic immunosuppression), known hypoadrenalism, other steroid-responsive conditions like asthma or rheumatoid arthritis

References and Links

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. [free full text]
  • 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 full text]
  • 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 full text]

FOAM and web resources


CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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