320 likes | 432 Views
Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: A randomized control trial. ( JAMA. 2010;304(13):1455–64). Background. TBI results in significant mortality and morbidity
E N D
Out-of-hospital hypertonic resuscitation following severe traumatic brain injury:A randomized control trial (JAMA. 2010;304(13):1455–64)
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
Objectives • To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI
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
Eligibility • Inclusion criteria • Blunt mechanism • ≥ 15 years of age • GCS ≤ 8 • No evidence of hypovolaemic shock • SBP > 90mmHg 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
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
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 1st 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
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 χ2 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%
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
PICO1 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?
PICO2 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?
1a. R- Was the assignment of patients to treatments randomised?
2a. A – Aside from the allocated treatment, were groups treated equally?
2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?
3. M - Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received?
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?
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
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.