Out of hospital hypertonic saline

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Critical appraisal of http://www.ncbi.nlm.nih.gov/pubmed/20924011

Critical appraisal of http://www.ncbi.nlm.nih.gov/pubmed/20924011

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  • What does under powered mean

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  • 1. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: A randomized control trial ( JAMA. 2010;304(13):1455–64)
  • 2. Background
    • TBI results in significant mortality and morbidity
    • The primary injury to the brain occurs at the time of impact; however, subsequent compromise of cerebral perfusion can lead to an ischaemic insult that extends the 1 ° injury, creating a 2 ° brain injury
    • Current therapy focuses on minimising 2 ° injury by supporting systemic perfusion and reducing ICP
    • Hypertonic fluids have been shown to decrease ICP and improve cerebral perfusion pressure in animal models and patients with severe TBI
    • Hypertonic saline shown to have beneficial vasoregulatory, immunomodu-latory, and neurochemical effects on the injured brain
    • Previous trials suggest early administration of hypertonic fluids may improve survival but no large definitive trials have been reported and effects on neurologic outcome not known
    • Previous studies focused on patients with severe TBI + hypovolaemic shock; effect on patients with TBI - hypovolaemic shock is not known
    • Investigators hypothesised administration of hypertonic fluids ASAP after severe TBI - hemorrhagic shock would result in improved 6-month neurologic outcome
  • 3. Objectives
    • To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI
  • 4. Methods
    • Prospective, randomised, double blind, multi-centre, 3 group, controlled trial
    • 114 emergency medical services agencies in the USA and Canada
    • From May 2006 to May 2009
    • Enrolment target 2122
    • Efficacy was assessed at 6 months
  • 5. Eligibility
    • Inclusion criteria
      • Blunt mechanism
      • ≥ 15 years of age
      • GCS ≤ 8
      • No evidence of hypovolaemic shock
        • SBP > 9 0mmHg or
        • SBP between 71 and 90mmHg + HR < 108 beats/min
    • Exclusion criteria
      • Known or suspected pregnancy; prisoner
      • Severe hypothermia, out-of-hospital CPR, drowning, hanging, burns > 20%TBSA, isolated penetrating head injury
      • Inability to obtain IV access
      • Interfacility transfer
      • Injured > 4 hours from dispatch call to intervention
      • Received > 2L of crystalloid or any amount of colloid of blood products
  • 6. Randomisation and blinding
    • All study fluids were purchased from 1 supplier and provided in identical IV bags and shipped to 1 distribution centre, where they were labelled with a randomly generated numeric code
    • The randomisation was 1:1:1.4 hypertonic saline, hypertonic saline/dextran, and NS
    • Patients were individually randomised by administration of a blinded bag of study fluid
    • There was an initial unintended bias toward enrolling more patients into the NS group
  • 7. Endpoints
    • The primary efficacy endpoint was
      • superiority in neurologic status at 6 months as measured by GOSE
    • Secondary endpoints included
      • 28 day survival
      • Survival to discharge
      • ICP
      • Interventions required to manage IC hypertension
      • Fluid and blood in 1 st 24hours
      • Physiologic parameters of organ dysfunction
      • 28 day acute respiratory distress syndrome-free survival
      • Multiple organ dysfunction score
      • Nosocomial infections
    • Other endpoints
      • GOSE at discharge
      • GOSE 1month post discharge
      • DRS at discharge
      • DRS 1 month post discharge
      • DRS 6 months post injury
  • 8. Statistical Analysis
    • Sample size based on difference in proportions of GOSE ≤ 4
    • 80% power, α = 5%, absolute reduction of 7.5% from 49% for each individual agent vs control - plus a margin
    • N=2122 total patients (624:624:874)
    • 1 ° analysis planned as modified intention-to-treat
    • Planned subgroup analyses
      • head AIS ≥4
      • head AIS≥2
      • documented IC haemorrhage
      • emergent craniotomy
    • Secondary outcomes assessed using t tests or χ 2 analyses as appropriate
    • Unplanned analysis also performed using multiple hot deck imputed primary outcome values due to 15% missing data
    • All analyses assessed using two-sided superiority tests, α = 5%
  • 9. Subject disposition
  • 10. Demographics and baseline characteristics (N=1282)
  • 11. Demographics and baseline characteristics (N=1282)
  • 12. Demographics and baseline characteristics (N=1282)
  • 13. Demographics and baseline characteristics (N=1282)
  • 14. Demographics and baseline characteristics (N=1282)
  • 15. Demographics and baseline characteristics (N=1282)
  • 16. Imputation vs casewise deletion
  • 17. Clinical outcomes
  • 18. Clinical outcomes
  • 19. Clinical outcomes
  • 20. Results
    • Study terminated as deemed futile with
      • 1331 randomised (373 HS+dextran, 353 HS, 603 NS)
      • 1282 “enrolled” (359 HS+dextran, 341 HS, 582 NS)
    • 6-month neurological outcome (GOSE ≤4)
      • Casewise deletion
        • 59.9% HS+dextran vs 56.1% NS, p>0.05
        • 58.4% HS vs 56.1% NS, p>0.05
      • Multiple hot deck imputation
        • 53.7% HS+dextran vs 51.5% NS, p>0.05
        • 54.3% HS vs 51.5% NS, p>0.05
    • Survival at 28 days
      • 74.3% HS+dextran vs 75.1% NS, p>0.05
      • 75.7% HS vs 75.1% NS, p>0.05
  • 21. PICO 1
    • P Patients with suspected severe traumatic brain injury from blunt trauma but without evidence of hypovolaemic shock
    • I 7.5% saline plus 6% dextran 70
    • C Normal saline
    • O 6-month extended Glascow outcome score
    • Research question:
    • In patients with suspected severe traumatic brain injury from blunt trauma but without evidence of hypovolaemic shock does pre-hospital administration of 7.5% saline plus 6% dextran 70 result in improved 6-month extended Glascow outcome scores compared with placebo?
  • 22. PICO 2
    • P Patients with suspected severe traumatic brain injury from blunt trauma but without evidence of hypovolaemic shock
    • I 7.5% saline
    • C Normal saline
    • O 6-month extended Glascow outcome score
    • Research question:
    • In patients with suspected severe traumatic brain injury from blunt trauma but without evidence of hypovolaemic shock does pre-hospital administration of 7.5% saline result in improved 6-month extended Glascow outcome scores compared with normal saline?
  • 23. 1a. R- Was the assignment of patients to treatments randomised ?
  • 24. 1b. R- Were the groups similar at the start of the trial?
  • 25. 2a. A – Aside from the allocated treatment, were groups treated equally?
  • 26. 2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?
  • 27. 3. M - Were measures objective or were the patients and clinicians kept “ blind ” to which treatment was being received?
  • 28. How large was the treatment effect?
  • 29. How precise was the estimate of the treatment effect?
  • 30. Will the results help me in caring for my patient? (External validity/Applicability)
    • The questions that you should ask before you decide to apply the results of the study to your patient are:
      • Is my patient so different to those in the study that the results cannot apply?
      • Is the treatment feasible in my setting?
    • Will the potential benefits of treatment outweigh the potential harms of treatment for my patient?
  • 31. Criticisms
    • No adjustment for or discussion of multiple hypothesis testing
    • Quoting mean ± SD for non-normal data and quoting median and IQR in an each way bet!
    • Randomisation process poorly described with some error in the original process which was then compensated for somehow
    • Some lack of clarity around the imputation process employed
  • 32. Bottom line
    • A well conducted study with some data presentation issues that has not shown a 6-month neurological outcome advantage in patients with severe blunt traumatic brain injury without hypovolaemia, for pre-hospital administration of either 7.5% saline plus 6% dextran 70 or 7.5% saline alone, over normal saline.
    • Lack of control over in-hospital treatment may have confounded results.