Traumatic Brain Injury Literature Summaries

Reviewed and revised Chris Nickson and Sarah Yong


Roberts I, Yates D, Sandercock P, et al: CRASH trial collaborators: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004 Oct 9-15;364(9442):1321-8. [PMID 15474134]

Edwards P, Arango M, Balica L, et al: CRASH trial collaborators: Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroidin adults with head injury-outcomes at 6 months. Lancet. 2005 Jun 4-10;365(9475):1957-9. [PMID 15936423]

  • n = 10,000
    inclusion: all severity of HI
  • 48 hours of IV steroids vs placebo
    -> stopped early as…
    -> increased mortality within 14 days
    -> increases mortality @ 6 months
    -> increased risk of severe disability


Clifton GL et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001 Feb 22;344(8):556-63. [PMID 11207351]

  • MRCT, US, 9 centers
  • n = 392
  • inclusion: severe TBI
  • normothermia VS moderate hypothermia (T 33C for 48 hrs)
    -> improves ICP but no reduction in mortality
    -> patients older than 45 do worse with induced hypothermia
    -> if they arrive hypothermic -> do not warm to 37 C (poorer outcome)
    -> if you have a low temperature on arrival you have a more significant TBI


Brain Trauma Foundation Guidelines – Guidelines for the Management of Severe TBI

  • consensus guidelines
  • covers:
    -> classification
    -> resuscitation
    -> management of ICP
    -> seizure prophylaxis
    -> poor outcome prediction
    -> CPP lowered to 60mmHg from 70mmHg (increased risk of ARDS)


Robertson CS, Hannay J, Yamal JM et al and the EPO Severe TBI Trial Investigators. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomised clinical trial. JAMA 2014, 312 (1): 36 – 47. PMID: 25058216

  • Prospective RCT, 2×2 factorial design, 2 US level 1 trauma centres
    • N = 200
    • Closed head injury, moderate to severe, unable to follow commands after resuscitation, within 6 hrs of injury
  • Background
    • Anaemia is common in TBI and many contribute to secondary brain injury
    • Suggestion from smaller studies that EPO associated with neuroprotective effects in TBI: anti-inflammatory, anti-apoptotic, vascular neuroprotective effects
    • Red cell transfusion in TBI is controversial with little evidence to guide practice
  • Intervention
    • EPO Vs placebo
    • Hb transfusion threshold 7 vs 10 g/dL
  • Outcomes
    • Glasgow Outcome Scale at 6 months post-injury, dichotomised as
      • Favourable: good recovery and moderate disability, or
      • Unfavourable: severe disability, vegetative, dead
    • Results
      • No improvement in neurologic outcomes with EPO
      • No improvement in neurologic outcomes with maintaining Hb > 10g/dL
      • Higher rate thromboembolic events with transfusion threshold > 10g/dL
    • Comments
      • No benefit with higher transfusion threshold (this may cause harm) nor EPO in TBI
      • EPO formulation changed during trial: initial EPO-1 regiment showed promising neurological outcome results compared to EPO-2 or placebo, however the switch resulted in insufficient numbers to assess
      • Switched from EPO-1 to EPO-2 in response to the EPO Stroke Trial, which showed patients with regimen similar to EPO-1 had higher mortality

EPO-TBI – ANZICS Trial currently in progress

  • currently recruiting
  • moderate to severe TBI: EPO vs placebo
  • there is some data that EPO can prevent the degree of secondary brain injury


Cooper, D, J, et al Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011 Apr 21;364(16):1493-502 [PMID 21434843]

  • ANZICS Trial
  • 15 tertiary centres (Australia, NZ and Saudi Arabia)
  • n = 155
  • early bifrontotemporoparietal decompression (within 6 hours) vs conventional treatment
  • inclusion: age 15-59 years, severe, nonpenetrating severe TBI
  • exclusion: not for full active treatment, dilated, unreactive pupils, mass lesions that required surgery, spinal cord injury, cardiac arrest at the scene.
  • randomized at:
    • -> > 20mmHg
    • -> > 15min
    • -> post first tier ICP management: sedation, normal PaCO2, mannitol, hypertonic saline, paralysis and EVD
  • post surgery or not second tier management introduced: mild hypothermia (35 C), barbiturates
  • patients could undergo life threatening decompression after 72 hours.
  • primary outcome: functional out come as per Extended Glasgow Outcome Scale
  • secondary outcomes: hourly ICP, intracranial hypertension index, proportion of survivors with a EGOS of 2-4 (severe disability and requiring assessment with ADLs), days in ICU, days in hospital, mortality at 6 months.

-> less raised ICP
-> shorter duration of MV
-> shorter stay in ICU
-> no change in duration in hospital
-> more medical and surgical complications
-> worse functional outcome @ 6 months (when adjusting for pupil reactivity this difference disappeared)


  • no patients lost to follow up
  • adequately powered base on adjusted interim analysis (except more of the craniectomy group has unreactive pupils)
  • 96% success with interventions
  • only 5% of the standard care group had a violation (received decompression within 72 hours of admission)


  • surgical technique not standardised.
  • craniectomy group may have been sicker (pupil reactivity difference)
  • one centre recruited 1/3 of the patients
  • non-blinding for obvious reasons
  • change of primary outcome during trial (although when analysed this did not change outcomes)


  • evacuate haematoma.
  • control ICP as much as I can medically.
  • use decompressive craniectomy as a rescue therapy.
  • less is more.
  • await RESCUE-ICP trial


Whyte, Cook, VENKATESH, The Use of Hypertonic Saline for Treating Intracranial Hypertension After TBI Anesth Analg 2006

– review presenting advantages and use of HTS in TBI

References and Links

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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