1. Standards
   Insufficient data to support a treatment standard for any brain-targeted therapy for patients with severe head injury.
2. Guidelines
   Data supports the use of mannitol in response to herniation at doses of 1.4-2.1 g/kg if supported by the capacity to provide high fluid volume compensation for any ensuing urine loss.
3. Options
   Hypertonic Saline

   Hypertonic saline appears to reduce ICP when given as a bolus and may be given for this purpose although an improvement in neurological outcome with resuscitation with hypertonic saline over standard fluid resuscitation has not been demonstrated.

   Hyperventilation

   Hyperventilation is to be avoided both as an intended therapy and inadvertently as part of other airway management, except in the context of visible signs of cerebral herniation, when its use may delay herniation.

   Antibiotic Prophylaxis for Penetrating Brain Injury

   Use of prophylactic broad-spectrum antibiotics is recommended for patients with penetrating brain injury.

   Treatments to optimize patient transport

   While sedation and analgesia will be given for many reasons to the brain-injured patient, no literature supports a specific brain-targeted or protective effect from these medications.

   Treating other causes of altered mental status

   Hypoglycemia can result in altered mental status and coma. Exact correlation between symptoms and serum glucose levels does not exist. Finger-stick serum glucose should be obtained as soon as possible in the patients care and any hypoglycemia corrected.

In remote environments it is easy to assume a nihilistic approach to traumatic brain injury (TBI), based on the assumption that brain-targeted therapies are not available in such remote circumstances. In fact, several very effective brain-targeted therapies can be made available to remote environments, providing the potential for some brain resuscitation. This chapter reviews the scientific basis for these therapies: hyperventilation, hyperosmolar therapy, analgesics, sedatives, lidocaine, paralysis, and control of hyperglycemia.

A MEDLINE search was conducted from 1966 to 2005 using the keywords "hyperglycemia," "hyperventilation," "glucose," "mannitol," "urea," "lidocaine," "conscious sedation," "analgesics," "hypnotics," and "sedatives," "neuromuscular blocking agents," "neuromuscular blockade," and "neuromuscular junction," in combination with "emergency medical services," "air ambulance," "emergency medical technician," "intracranial trauma," "military medicine," "recreation," "critical care," "prehospital," and "wilderness medicine." From this group, articles relevant to the field management of TBI with human data and generally more than 25 subjects with outcome related to mortality were selected. Fourteen articles met these criteria. Additional articles and animal studies are referenced only as a part of background discussion.

Treatments of Cerebral Herniation

Hyperventilation

Hyperventilation can reduce ICP by inducing cerebral vasoconstriction and thereby reducing cerebral blood volume. Because of extensive data suggesting that hyperventilation also decreases cerebral blood flow and one Class II study demonstrating poorer outcomes at 3 and 6 months in patients who were hyperventilated versus those who were not,1 prophylactic hyperventilation is discouraged and hyperventilation is reserved for patients with objective signs of cerebral herniation. In a field or prehospital environment without an ICP monitor in place, the indications that herniation is occurring are unilateral or bilateral fixed and dilated pupils, asymmetric motor posturing, or declining mental status.2

Hyperosmotic Agents

Hyperosmotic therapy was first proposed in 1919 by Weed and McKibben3 who noted that infusion of intravenous distilled water increased brain tissue mass and infusion of 30% saline dehydrated the brain. Fremont-Smith and Forbes4 began the clinical use of hyperosmolar urea the late 1920s. Javid et al.5-7 became aware of urea's dehydrating properties in 1956 and published an extensive clinical experience with it in controlling cerebral edema, popularizing its use. In 1962, mannitol was proposed as a hyperosmotic agent.8 Although urea could be given in much smaller volumes than mannitol, mannitol replaced urea as the hyperosmolar agent of choice because of concerns about rebound intracranial hypertension associated with urea's use.9,10 Recently, hypertonic saline has been proposed as an alternative hyperosmotic agent, with volume expansion qualities as well as brain dehydrating qualities.10-17

Hyperosmolar therapies reduce ICP by two distinct mechanisms. The commonly-appreciated mechanism is via the establishment of an osmolar gradient across the blood brain barrier, with the gradient favoring the flow of water out of the brain and into the circulation. This mechanism is estimated to require 15-30 minutes to act and can last 90 minutes-6 hours.

Osmolar agents, however, can act in a much shorter time frame via a second mechanism. These agents also improve the rheology of the blood via plasma expansion, reduced hematocrit, and reduced blood viscosity resulting in more efficient cerebral blood flow. This increased efficiency means that at any given CPP, the cerebrovascular resistance will be higher, the cerebral blood volume will be lower, and ICP will therefore be lower while cerebral blood flow remains unaltered.18 Mannitol and hypertonic saline are believed to utilize both of these mechanisms.19

Mannitol

Mechanism of Action

Mannitol has long been accepted as an effective tool for reducing intracranial pressure.20-24 Numerous mechanistic laboratory studies support this conclusion. Its impact on outcome has never, however, been directly demonstrated via a Class I trial testing mannitol against placebo. Schwartz et al.23 conducted a Class III study comparing mannitol to pentobarbital which failed to demonstrate the superiority of pentobarbital and which did demonstrate better outcomes and maintenance of CPP in the mannitol group.

Cruz et al.25-27 has published three Class II studies demonstrating benefit of high dose mannitol versus conventional dose mannitol in the very early stages (emergency department) of a patient's treatment. Patient populations with acute subdural hematomas, temporal lobe hemorrhages, and diffuse brain swelling were studied. Patients who received early high dose mannitol had better preoperative improvement of pupillary widening and better Glasgow Outcome Scores at 6 months. Fortune et al.28 compared mannitol, hyperventilation, and ventricular drainage in 22 patients. Mannitol was most effective in reducing ICP.

Rate of Infusion

There is a commonly held belief that mannitol administration can cause or exacerbate hypotension in the early resuscitation of trauma victims. There is Class III data that infusion of mannitol at rates of 0.2-0.8 g/kg/min can lead to transient drops in blood pressure.29-31 From these observations, a recommended rate of no higher than 0.1 g/kg/min or 1 g/kg delivered over 10 minutes or more is recommended.18 Careful monitoring of urine output with aggressive replacement of this fluid loss is also recommended to prevent hypotension associated with the use of mannitol.

Sayre et al.32 tested the hypothesis that mannitol would exacerbate hypotension in a prehospital environment in a Class II study. Patients were randomized to a mannitol or normal saline group. Mannitol was allowed to be given rapidly over as little as 5 minutes. No difference in heart rate or blood pressure was observed over the 2-hour subsequent observation period between the two groups.

Dose

Mannitol can be given in response to an elevated ICP or as a continuous drip in a more prophylactic fashion. Class II data have found bolus administration to be effective and some Class III data have found no difference between the two routes.20,22,24,33-35

Mannitol and other hyperosmotics are known to be able to briefly open the blood brain barrier. Furthermore, at rates of administration which exceed the rate of excretion of mannitol, mannitol can accumulate in the extracellular space. These factors lead to the accumulation of mannitol in the extracellular space and a reverse osmotic gradient which can lead to a "rebound effect" or movement of water into the brain. Class III data suggests that this effect is more likely with continuous infusion of mannitol as opposed to bolus administration.36,37 In a field or prehospital environment the time need to see a rebound effect would normally not be present.

Class II and Class III data have shown that doses of 0.25-1.0 g/kg of mannitol may be needed to achieve a reduction in ICP. This required dose varies from patient to patient and even may vary from time to time in the same patient.22,37,33

In a field or prehospital environment, mannitol cannot usually be given based on a measured ICP. Data from Cruz et al.25-27 (Class II) show that doses from 1.4-2.1 g/kg can be effective in response to the clinical findings of pupillary widening, declining mental status or asymmetric motor examination, as opposed to ICP.

Hypertonic Saline

Hypertonic saline offers an attractive alternative to mannitol as a brain-targeted hyperosmotic therapy. Its ability to reduce elevated ICP has been demonstrated with Class II and III data in the ICU and in the operating room.15-17,38 Several issues require clarification in discussing hypertonic saline as a brain-targeted therapy.

The first is that hypertonic saline is also a potential low volume resuscitation fluid. Its actions in this role are discussed elsewhere in these Guidelines. While the qualities that make it useful as a low volume resuscitation fluid and as a brain-targeted therapy are related, this discussion will be limited to its role as a brain-targeted therapy.

Secondly, there is no consensus on what is meant by "hypertonic saline." Concentrations of 3%, 7.2%, 7.5%, 10%, and 23.4% have all been used. There is no consensus on the optimum concentration for reduction of ICP.11,15-17

Lastly, hypertonic saline is dosed in different ways. In some studies, it is given as an infusion, the goal of which is to elevate serum sodium to 155-160 mEq/L, although some investigators have gone as high as 180 mEq/L. This elevated serum sodium is thought to help stabilize ICP and reduce the therapeutic intensity required to prevent elevated ICP.39,40 This modality would not be used in the prehospital or field environment. A field environment would utilize hypertonic saline as a bolus, taking advantage of the rapid rheologic improvement and improved cerebral blood flow, which like mannitol, hypertonic saline can create. Multiple animal studies and several human studies have demonstrated that hypertonic saline, as a bolus, can reduce ICP in a monitored environment such as the operating room or ICU where ICP monitoring is present.40-42 Comparison of these studies is difficult since they do not use the same concentrations or protocols.

No study has demonstrated an effect on clinical indicators of herniation such as pupillary widening or posturing such as Cruz demonstrated for mannitol. One study looked at the impact of prehospital hypertonic saline on neurological outcome. Hypertonic saline did not demonstrate any advantage over normal saline on neurological outcome when given as a prehospital resuscitation fluid.43

Lidocaine

Expert opinion supports the use of lidocaine to prophylax against ICP elevations during interventions, in particular intubation. No data exists to support this recommendation.

Antibiotic Prophylaxis for Penetrating Brain Injury

The evidence-based Guidelines for the Management of Penetrating Brain Injury recommends the use of prophylactic broad-spectrum antibiotics in patients who are the victims of penetrating brain injury (PBI). Although there is no evidence directly supporting the use of antibiotics for PBI in a field environment, there is evidence that prophylactic antibiotics do reduce postoperative cranial infections.44,45 From this data, the Guidelines authors reasoned that the early administration of broad spectrum antibiotics would also reduce cerebral infections in the field environment. They recommend prophylactic antibiotics at the level of an option.46 Patients with CSF leaks and air sinus wounds have been identified as being at especially high risk for cerebral abscess after PBI.46,47

Treatments to optimize patient transport

Sedation and Analgesia

While sedation and analgesia will be given for many reasons to the brain-injured patient, no literature supports a specific brain-targeted or protective effect from these medications.

Managing Hypoglycemia

There is literature to suggest that poor control of hyperglycemic patients in the ICU results in poorer outcomes for brain-injured patients.48 In addition, patients with higher serum glucose on admission to the hospital appear to have worse clinical outcomes.48-52 Early hyperglycemia appears to be part of the early stress response to head injury.51,52 Whether early elevated serum glucose contributes to poor outcome or is simply associated with poor neurological outcome is not clear.48-52 Patients with serum glucose greater than 200 mg/dl, and probably 150 mg/dl, early in their hospital course appear to have poorer outcomes.48-52

Hypoglycemia can result in altered mental status and coma. Exact correlation between symptoms and serum glucose levels does not exist, but levels < 80 mg/dl can be symptomatic, and < 30 mg/dl can be seriously symptomatic.53,54 While there are technical flaws that can occur with finger stick glucose monitoring, this technique remains the best available method early in a patient's care to detect and correct hypoglycemia. As soon as this technology becomes available to the patient, a finger stick serum glucose should be obtained and any hypoglycemia corrected.55-57

The brain-targeted therapies possible away from a treatment facility in a prehospital or remote environment are hyperventilation, hyperosmolar therapy, sedation, and control of glucose. Hyperventilation will delay herniation but can also impact outcomes by creating ischemia, limiting its use to patients who show clinical evidence of herniation. Hyperosmolar therapy has been shown to improve outcome. Unfortunately, the hyperosmolar agent demonstrated to provide benefit, mannitol, is a high volume agent. The lower volume agent, hypertonic saline, has shown neither benefit nor detriment over isotonic solutions. While analgesics, sedatives and lidocaine will continue to be part of the early care of brain-injured patients, no evidence exists for a specific beneficial brain effect. Prevention of hypoglycemia should continue to be a priority. The impact on neurological outcome of limiting hyperglycemia is still to be determined. Although obtaining tight control of serum glucose in the prehospital environment may not be practical in all cases, checking and managing serum glucose as soon as practical in the patient's course is advisable.

1. Much of what is known about bolus hypertonic saline as a brain-targeted therapy is from animal models. More human data are needed.
2. The early management of glucose in the field needs to be better defined in terms of ultimate outcome.
3. A better way to manage ventilation without the benefit of blood gas analysis is needed.
4. Exploration of alternative, low volume hyperosmolar agents, such as urea, could prove productive.