Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial.

Cooper DJ, Myles PS, McDermott FT, et al.

JAMA. 2004 Mar 17;291(11):1350-7. [abstract]

Reviewed by Gurpreet Mander MD, Hope Children's Hospital, Oak Lawn, IL

Review posted August 11, 2004

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I. What is being studied?:

The study objective:

Prehospital HTS (7.5%) resuscitation may decrease secondary brain injury compared with standard resuscitation protocols.

The study design:

Randomized prospective, double blind controlled trial. Conducted between December 1998 and April 2002, in Melbourne Australia.

The patients included:

Patients were eligible for the study if at any time during prehospital care the following were present: Coma due to blunt head trauma, a Glasgow Coma Scale (GCS) < 9 and hypotension (systolic BP < 100mm Hg)

Patients with multisystem trauma were also included.

The patients excluded:

Those with penetrating trauma, age less than 18 years, pregnant, those without an IV access, those with a serious premorbid disease, peripheral edema, absent sinus rhythm and cardiac arrest. Patients received from close proximity of the referring hospital (scoop and run) were also excluded.

The interventions compared:

Patients were randomly assigned to receive a 250 ml IV infusion of HTS or LR initially followed by the use of standard resuscitation fluids. The study fluid was given as rapidly as possible. Paramedics than administered a crystalloid, LR or a colloid solution or both according to medically determined protocols.

The outcomes evaluated:

Primary outcome evaluated was Glasgow outcome score at 6 months. A score of 1 indicates dead; 2, vegetative; 3 lower severe disability; 4 upper severe disability; 5 lower moderate disability; 6, upper moderate disability; 7, lower good recovery and 8, upper good recovery.

Secondary outcomes

• First ICP and CPP recorded after ICP catheter insertion
• Duration of ICP elevation and inadequate CPP
• Worst oxygenation (Pao2/FiO2 ratio)
• Duration of inotropic support
• Duration of mechanical ventilation
• Serum sodium
• Hospital mortality rate

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was done in blocks of four and was stratified by ambulance. As ambulances transported patients to specific hospitals, allocation was also stratified by hospital.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes, at 6 months. All patients were accounted for, as they either died (45% in HTS group, and 50% in saline group) or were analyzed at 6 months. There were two patients lost to follow up.

Were patients analyzed in the groups to which they were randomized?

Yes. There were no cross-overs.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. This was a double blind study. The blinding mechanisms seemed appropriate and unbiased. The reviewers were blind as well. However, from the higher serum sodium values on hospital admission, caregivers might have been able to distinguish treated patients from controls.

4. Were the groups similar at the start of the trial?

The treatment groups had equivalent baseline characteristics. There were no differences in intubation rates, scene times or transport times, the total fluids received and the body temperature. The median injury score in both groups was 38, and the maximum abbreviated injury score was the same in both groups.

There was no difference with respect to probability of survival as measured by the Trauma Injury Severity Score (TRISS).

5. Aside from the experimental intervention, were the groups treated equally?

Not certain. After hospital admission patient care was at the discretion of the attending physicians. They generally followed the guidelines of the Brain Trauma foundation.

There is no reason to believe that they were treated differently however. The do not specify what treatments were given except mechanical ventilation and pressor support. These treatments were equal between groups.

III. What were the results?

1. How large was the treatment effect?

There were no significant differences between the groups with respect to the primary end point, the GOSE or other measures of functional neurological outcome at either 3 or 6 months after injury. The median GOSE at 3 months was 5 (IQR 3-5) for the HTS group and 5 (IQR 4-5) for the control group. At 6 months the median score was 5 (IQR 3-6) for the HTS group and 5 (IQR 5-6) for the control group.

Survival was 55% vs. 47%.

No difference in the rates of favorable outcome, defined by GOSE of 5 or more for HTS (RR 0.99; 95% CI, 0.76-1.30; P = 0.96) vs. control.

No differences in secondary outcomes were seen.

2. How precise was the estimate of the treatment effect?

The study was designed with an 80 % power to detect a 20% improvement in the five-level GOSE.

Even though not statistically significant, a small trend towards greater survival for HTS was seen.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

This is an adult study that excluded patients under 18 yrs. Therefore the applicability to the pediatric patients is unclear.

Even though there were no differences in the outcome between the two groups it cannot be take as definitive proof that HTS is not better than LR. Mixed fluid therapy could have influenced the result

There was a non-significant higher rate of survival with HTS corresponding to an odds ratio of 1.26 (95% CI, 0.75-2.11) at hospital discharge and 1.38 (95 % CI, 0.82-2.32) at 6 months

These are reasons why a true difference may have been missed: It is also difficult to interpret mixed fluid therapy. Could the lack of effect be due to the dilutional effect of other fluids? The post intervention therapy could have made a difference in the results. The lack of a standardized protocol for in hospital treatment could also have made a difference on the final results.

2. Were all clinically important outcomes considered?

No. Both long term neurologic outcomes and changes in clinical parameters were considered. One of the potential side effects of HTS is an increase in serum sodium. This was significantly higher in the HTS group for about 12 hrs after admission (mean of 149 vs. 141). The possibility of renal damage and Central Pontine Myelinolysis needs to be considered. Previous studies using long-term infusions of HTS (3%) in head trauma have showed no side effects with prolonged elevations of serum sodium(3). The effects of an acute elevation in serum sodium when using 7% HTS need to be studied.

3. Are the likely treatment benefits worth the potential harms and costs?

No strong evidence to date supports the routine use of HTS over isotonic crystalloids for initial resuscitation of patients with hypotension and traumatic brain injury. There also is a scarcity of well-designed studies looking at the use of HTS-dextran-based strategies (1,2). This study demonstrates however, that there does not seem to be any obvious harm from using HTS in the trauma setting.

Until further data is available HTS should be considered with caution for resuscitation of patients with hypotension and traumatic brain injury.

References:

1. Dubick M, Wade C. A review of the efficacy and safety of 7.5% NaCl/6% dextran 70 in experimental animals and in humans. J Trauma. 1994:36:323-330. [abstract]
2. Mattox KL, Maningas PA, Moore EE, et al. Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. The U.S.A. Multicenter Trial. Ann Surg 1991 May;213(5):482-91.[abstract]
3. Gabriel EJ, Ghajar J, Jogada A, Pons PT, Scalea T. Guidelines for the Prehospital Management of Traumatic Brain Injury. New York, NY: Brain Trauma foundation. 2000:7-49.

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