Traumatic Brain Injury
Traumatic Brain Injury
Although the primary injury to the brain occurs at the time of impact, subsequent compromise of cerebral perfusion can extend the primary injury and create a secondary injury. Current therapy in the prehospital setting and the ED aims to minimize secondary injury by supporting systemic perfusion, reducing ICP, and optimizing cerebral perfusion pressure (CPP). The interventions to decrease intracranial hypertension that have historically been used in the ED include: head of bed elevation, supporting systolic blood pressure (SBP) > 90 mm Hg, preventing hypoxia, and ensuring normocapnic ventilation. Additionally, for patients with signs of impending herniation (such as asymmetric pupillary response, dilated and unreactive pupils, motor posturing, or rapid neurologic decline), osmotic agents (such as mannitol or HTS) should be administered.
Intracranial Pressure Reduction
Many trials have shown administration of HTS to be an effective method to reduce ICP for the brain-injured patient. Five case control studies have shown that HTS alone or with a colloid reduces ICP in both adult and pediatric patients with TBI.13-17 Five randomized controlled studies also compared HTS to mannitol,18,19 isotonic crystalloid, or hypotonic crystalloid20,21 and found HTS to be effective in reducing intracranial hypertension secondary to both traumatic and nontraumatic causes. Most studies used bolus dosing rather than continuous infusion and varied the solution concentration from 1.8% to 10% with and without colloids.
Comparison Of Hypertonic Saline To Mannitol
Despite the lack of evidence for any mortality benefit,22 mannitol is currently considered to be the gold standard for osmotic therapy in the treatment of acute intracranial hypertension, and it is endorsed by the Brain Trauma Foundation’s most recent guidelines for the management of severe TBI.23 However, HTS is being increasingly investigated as an alternative. Several retrospective studies have suggested that HTS might be effective in reducing intracranial hypertension that is refractory to the use of mannitol.24,25 Only a few rigorous prospective studies have compared the effectiveness of HTS or HTS combined with dextran to mannitol in ICP reduction. Kamel et al performed a meta-analysis of randomized clinical trials comparing HTS and mannitol for reduction of ICP.26 Only studies that administered equiosmolar doses in human subjects undergoing quantitative ICP measurements were included in this meta-analysis. Five trials comprising 112 patients with 184 episodes of intracranial hypertension were included. Despite small sample sizes and mild heterogeneity (mostly due to different formulations of HTS), they found that HTS was more effective than mannitol for the treatment of intracranial hypertension. In 2007, a Cochrane review assessed the effects of mannitol therapy for acute TBI compared to other treatment regimens. Only 1 trial was found that directly compared mannitol to HTS.27 In this study, which was performed by Vialet et al, it was suggested that mannitol therapy for intracranial hypertension may have a detrimental effect on mortality when compared to HTS therapy (relative risk for death = 1.25; 95% confidence interval, 0.47-3.33).28 Unfortunately, this study was too small to make valid conclusions, as there were only 20 patients in each arm. In 2011, Cottenceau performed a multicenter prospective study on 47 severe TBI patients in intensive care units (ICUs).29 Patients were randomized to equiosmolar doses of 20% mannitol (4 mL/kg) or 7.5% HTS (2 mL/kg). Both treatment arms effectively reduced ICP. There was a trend toward HTS being significantly stronger and of longer duration than mannitol; however, this difference was not statistically significant. There were no reported significant adverse events or differences in neurologic outcome at 6 months between the groups. While these studies suggest that HTS is a safe and effective alternative to mannitol for treating intracranial hypertension, there is limited evidence to support any superior efficacy or improved patient outcomes, and a large randomized controlled trial comparing mannitol and HTS is needed.
Few studies have examined how the use of HTS may affect mortality or long-term neurological disability for patients with TBI. In 2008, Bunn and colleagues performed a Cochrane review to determine whether the use of HTS decreases mortality in patients with hypovolemia with and without head injuries.30 They found only 1 trial that specifically studied whether prehospital resuscitation with intravenous (IV) HTS improves long-term neurological outcome in patients with severe TBI compared to resuscitation with crystalloid solutions.31 There was no difference in survival or neurologic outcome at 6 months between the 2 groups.
Shortly after the Cochrane review by Bunn et al, the National Institutes of Health sponsored the largest and most important study to date with respect to these outcomes. This multicenter randomized double-blind placebo-controlled trial enrolled 1331 patients from the prehospital setting.32 Patients with concomitant hypotension were excluded. Patients were randomized to receive a 250-mL prehospital bolus of 7.5% HTS, 7.5% HTS with 6% dextran 70, or normal saline and were followed for 6 months. The study was stopped after an interim analysis determined that HTS provided no improvement in either mortality or neurologic outcome and that enrolling new patients would not change the outcome of the study.
In 2011, Tan et al conducted a systematic literature review to investigate whether the infusion of HTS or colloid solutions results in better outcomes than standard isotonic crystalloid solutions for patients with TBI. They identified 9 randomized controlled trials and 1 cohort study that examined the effects of infusion of hypertonic solutions (with or without the addition of colloids) for prehospital volume resuscitation.33 Studies that included patients who had sustained a TBI, with and without other injuries, were included in the review. None of these trials reported better survival and functional outcomes with HTS compared to the use of standard isotonic crystalloid solutions.
In 2007, the Brain Trauma Foundation, in conjunction with the American Association of Neurological Surgeons and the Congress of Neurological Surgeons, published guidelines regarding the use of hyperosmolar therapy for the management of severe TBI. The guideline authors only examined literature on adult human hospitalized patients. The major outcomes they reviewed included reduction in ICP, changes in CPP, changes in cerebral blood flow, and long-term morbidity and mortality. They concluded that the current evidence is not strong enough to make recommendations on the use, concentration, or method of administration of HTS in traumatic intracranial hypertension.23 Until more conclusive evidence regarding the use of HTS for ICP management for patients with severe TBI emerges, future guidelines are unlikely to be different from the current guidelines.
Traumatic Brain Injury With Concurrent Hypotension
Trauma patients with TBI often have accompanying injuries that lead to hypotension. Volume resuscitation in this patient population can be challenging, as the isotonic crystalloid solutions that are traditionally used to restore end-organ perfusion and prevent secondary anoxic brain injury could, theoretically, exacerbate cerebral edema. It would seem intuitive that these patients would be an ideal cohort to benefit from HTS. Unfortunately, there is no strong evidence to support this. One multicenter trial using 7.5% HTS with dextran suggested a mortality benefit in hypotensive patients who sustained a TBI. However, the strength of this conclusion is weak, as the improvement was in comparison with predicted survival, not a direct comparison with the control group.34 Wade et al performed a manufacturer-supported cohort analysis of 223 patients with TBI and hypotension from 6 previous prospective randomized double-blind trials. These trials compared 7.5% HTS with dextran versus a “standard-of-care isotonic crystalloid” (usually lactated Ringer’s). They showed a trend toward survival until discharge (38% vs 27%; P = 0.08).35 Cooper et al from Australia performed a double-blind randomized controlled trial focusing on the effect of prehospital resuscitation with 7.5% HTS on neurologic outcomes in patients with severe TBI and an SBP < 100 mm Hg.31 A total of 229 patients were enrolled. Though there was no significant neurologic difference between the groups at 6 months, there was a trend toward survival in the HTS group (55% for the HTS group and 47% for the control group; P = 0.25). While these studies show promise for the treatment of the hypotensive TBI patient with HTS, it is difficult to draw definitive conclusions from such small sample sizes.
Summary Of The Use Of Hypertonic Saline In Severe Traumatic Brain Injury
Although the strength of the current literature is weak, it suggests that HTS is as effective as mannitol for treating intracranial hypertension from TBI. Currently, there is no convincing evidence to suggest that osmotic therapy (whether HTS or mannitol) results in improved long-term neurologic outcome or overall mortality benefit. HTS may be an acceptable alternative to mannitol, and indications for its use by the emergency physician would include significantly deteriorating neurologic status or signs of herniation. While there is no agreement as to the dose or concentration of HTS to use, most studies administered a 250 mL bolus of 7.5% HTS with dextran.
Jeffrey A. Holmes, MD
February 4, 2013