Immunomodulatory Agents in Sepsis


  • huge research area
  • no definitive therapies available
  • some research very controversial


Activated Protein C

  • was widely used in Europe and US and less widely used in Australasia
  • expensive
  • PROWESS and ENHANCE study: benefit in severe sepsis with a high risk of death
  • side effects: increased risk of bleeding and ICH
  • controversy over marketing and original PROWESS study (stopped early because of benefit)
  • PROWESS SHOCK: no benefit seen
  • No longer marketed since PROWESS-SHOCK, FDA advise against its use


  • widely used
  • Annane (responders vs non-responders) vs CORTICUS (unproven benefit)
  • both studies showed that etomidate use in ICU is associated with bad outcome
  • controversies over timing, length of use, dose and tapering vs immediately stopping
  • most using hydrocortisone 50mg Q6 hourly IV


  • promising
  • study show benefit of continuing use in septic ICU patients in those already on.
  • ANZ-STATINS trial: no benefit, but improved mortality if continued in patients already on statins

Renal Replacement Therapy

  • some suggestion that early RRT may be useful as immunomodulator
  • decreases: C3a, IL-10 and C5a but probably temporary


  • sepsis induces a vasopressin deficiency state
  • research into looking at whether we should be using as the first line pressor in sepsis



  • SIC study shows possible benefit with very large doses
  • however, high mortality in each arm

Monoclonal anti-TNF alpha

  • promising
  • very expensive

Many others, all unproven or harmful:

  • G-CSF – not proven
  • IVIG – not proven
  • Ketaconazole – not proven
  • NSAIDS – not proven
  • N-acetylcysteine – not proven
  • L-NMMA – increased mortality
  • Heparin – not proven
  • Anti-thrombin III – not proven

References and Links

Journal articles and textbooks

  • Kruger P, Bailey M, Bellomo R, Cooper DJ, Harward M, Higgins A, Howe B, Jones D, Joyce C, Kostner K, McNeil J, Nichol A, Roberts MS, Syres G, Venkatesh B; ANZ-STATInS Investigators–ANZICS Clinical Trials Group. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013 Apr;187(7):743-50. doi: 10.1164/rccm.201209-1718OC. PubMed PMID: 23348980.
  • Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64. doi: 10.1056/NEJMoa1202290. Epub 2012 May 22. PubMed PMID: 22616830.
  • 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; 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]
  • Webster NR, Galley HF. Immunomodulation in the critically ill. Br J Anaesth. 2009 Jul;103(1):70-81. doi: 10.1093/bja/aep128. Epub 2009 May 27. Review. PubMed PMID: 19474216. [Free Fulltext]

Social media and web resources

CCC 700 6

Critical Care


Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a 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 three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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