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 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

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%

Subject disposition

Demographics and baseline characteristics (N=1282)

Imputation vs casewise deletion

Clinical outcomes

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> % HS vs 56.1% NS, p>0.05 –Multiple hot deck imputation 53.7% HS+dextran vs 51.5% NS, p> % 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

PICO 1 PPatients with suspected severe traumatic brain injury from blunt trauma but without evidence of hypovolaemic shock I7.5% saline plus 6% dextran 70 CNormal saline O6-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?

PICO 2 PPatients with suspected severe traumatic brain injury from blunt trauma but without evidence of hypovolaemic shock I7.5% saline CNormal saline O6-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?

1b. R- Were the groups similar at the start of the trial?

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?

How large was the treatment effect?

How precise was the estimate of the treatment effect?

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.