Trauma Literature Summaries

OVERVIEW

• Tranexamic acid (TXA) for traumatic haemorrhage
• Steroids for acute spinal injury

TRANEXAMIC ACID FOR TRAUMATIC HAEMORRHAGE

CRASH-2 Trial Collabaorators (2010) “Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial” Lancet 276:23-32

• DB MCRCT (274 hospitals, 40 countries)
• n = 20,211 adults within 8 hours of injury (blunt and penetrating) at risk of severe hemorrhage or in hemorrhagic shock
• Intervention: tranexamic acid 1g over 10 min then 1g over 8h IV
• Control: placebo
• Primary outcome: all cause mortality  within 4 weeks of injury (bleeding, vascular occlusion – MI, CVA, PE, MOF, HI, other)
• secondary outcomes: vascular occlusive events (MI, CVA, PE, DVT), surgical intervention (neurosurgery, thoracic, abdominal, pelvic), receipt of blood transfusion, units of blood products transfused, degree of dependency, FVIIa use and GI bleeding
• Results:
  -> all cause mortality reduced in the TXA2 group
  -> decreased mortality due to bleeding (RR 0.85) (which was 35% of deaths)
  -> trend toward more vascular occlusive events in placebo group
  -> no difference in transfusion and need for surgery
  -> trend towards early treatment being more effective
  -> NNT 65, ARR 1.5%, RR 0.91
• Commentary and criticisms:
  — TXA2 group got more FVIIa
  — most benefit appeared to be in the severe shock group
  — many of the centers were in developing countries

CRASH 2 a priori subgroup analysis 2011

• benefit for tranexamic acid was greater if given early
• NNT 125 (RR 0.68) for death from bleeding if given within 1 hour
• benefit up to 3 hours post-injury
• causes harm if given later than 3 hours

MATTERS study

• retrospective observational study (i.e. low quality evidence)
• benefit found for tranexamic acid in the military setting (Camp Bastion, Afghanistan)
• included patients who required transfusion and were given tranexamic acid
• decreased amount of transfused PRBCs needed if tranexamic acid given

MATTERS 2 study

• retrospective observational study (i.e. low quality evidence)
• military setting (Camp Bastion, Afghanistan)
• synergistic decrease in mortality with tranexamic acid and cryoprecipitate
• mortality was 14.4% for TXA + cryo vs 28.8% if neither used
• despite higher ISS scores (severity of injury) in the intervention group

STEROIDS FOR ACUTE SPINAL INJURY

12/8/10

Bracken MB, Shepard MJ, Collins WF, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. (NASCIS2) N Engl J Med 1990; 322:1405-1411.

• DB MC RCT
• n = 487
• methylprednisolone (30 mg/kg IV bolus then 5.4 mg/kg/h for 23 hours) vs naloxone vs placebo
• primary outcome of change in motor and sensory scores at 1 year showed no difference
• post hoc subgroup analysis suggested high dose methylprednisolone within 8 hours of injury was beneficial
  -> mild improvement in motor and sensory scores @ 6 months and 1 year
• commentary and criticisms
  — this followed up NASCIS 1 which compared high dose and low dose methylprednisolone (no placebo)
  — this study lead to steroid use being considered standard of care, despite the negative primary outcome
  — posthoc subgroup analyses should be considered hypothesis forming at best (data dredging at worst)

Miller SM: Methylprednisolone in acute spinal cord injury: A tarnished standard. J Neurosurg Anesthesiol 2008; 20:140-142.

George ER, Scholten PJ, Buechler CM: Failure of methylprednisolone to improve the outcome of spinal cord injury. Am Surg 1995; 61:659-663.

Pointillart V, Petitjean ME, Wiart L: Pharmacotherapy of spinal cord injury during the acute phase. Spinal Cord 2000; 38:71-76.

-> criticisms of NASCIS: study design flawed, statistical analysis flawed, conflicting evidence

Bracken MB: Steroids for acute spinal cord injury. Cochrane Database Syst Rev 2002.CD001046

-> supports use of methylprednisolone
-> written by the author of the NASCIS papers!!!

Tsutsumi S, Ueta T, Shiba K, et al: Effects of the Second National Acute Spinal Cord Injury Study of high-dose methylprednisolone therapy on acute cervical spinal cord injury results in spinal injuries center. Spine 2006; 31:2992-2996.

-> supports use of methylprednisolone

Leypold BG, Flanders AE, Schwartz ED, et al: The impact of methylprednisolone on lesion severity following spinal cord injury. Spine 2007; 32:373-378. [PMID 17268271]

-> patients who had methylprednisolone had significantly less intramedullary haemorrhage than those who were no treated.

Eck JC, Nachtigall D, Humphreys SC, et al: Questionnaire survey of spine surgeons on the use of methylprednisolone for acute spinal cord injury. Spine 2006; 31:E250-253. [PMID 16641765]

• N = 305 spine surgeons
  -> 90% would initiate methylprednisolone especially within the 8 hour window
  -> reasons given: institutional protocol, medicolegal reasons
  -> only 24% used steroids because of a belief in improved outcomes!

Bracken (1997) NASCIS 3– early steroids in spinal injury for longer than NASCIS 2 – JAMA

• methylprednisome started within 8 hours of spinal injury and given for 48 hours, compared to tirilazid
  -> primary outcome showed no difference
  -> some improvement in motor score and functional outcome
  -> increased sepsis and pneumonia seen
• again, benefit only on post-hoc subgroup analysis
• not placebo controlled (steroid use was considered ‘proven’ prior to this study

Summary of evidence for steroids for spinal cord injury

• there is no concrete evidence that methylprednisolone has a useful role in neurological protection in early spinal cord injury
• the NASCIS studies are fatally flawed
• adverse effects include increased sepsis and hyperglycemia
• steroid use could be considered on a case-by-case basis, but situations where the risk-benefit balance favours administration would be rare