Download - Out of hospital hypertonic saline
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Out-of-hospital hypertonic resuscitation following severe
traumatic brain injury:A randomized control trial
(JAMA. 2010;304(13):1455–64)
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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
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Objectives
• To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI
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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
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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
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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
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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
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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%
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Subject disposition
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Demographics and baseline characteristics (N=1282)
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Demographics and baseline characteristics (N=1282)
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Demographics and baseline characteristics (N=1282)
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Demographics and baseline characteristics (N=1282)
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Demographics and baseline characteristics (N=1282)
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Demographics and baseline characteristics (N=1282)
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Imputation vs casewise deletion
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Clinical outcomes
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Clinical outcomes
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Clinical outcomes
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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
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PICO1
P Patients with suspected severe traumatic brain injury from blunt trauma but without evidence ofhypovolaemic shockI 7.5% saline plus 6% dextran 70C 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?
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PICO2
P Patients with suspected severe traumatic brain injury from blunt trauma but without evidence ofhypovolaemic shockI 7.5% salineC 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?
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1a. R- Was the assignment of patients to treatments randomised?
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1b. R- Were the groups similar at the start of the trial?
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2a. A – Aside from the allocated treatment, were groups treated equally?
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2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?
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3. M - Were measures objective or were the patients and clinicians kept “blind” to
which treatment was being received?
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How large was the treatment effect?
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How precise was the estimate of the treatment effect?
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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?
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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
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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.