Management of Traumatic Brain Injury: Have we Learned What Works?
By Charles G. Durbin, Jr., MD
Despite major research funding, new therapeutic agents, and a better understanding of the mechanisms of neuronal cell injury, traumatic brain injury (TBI) remains the most common cause of death and disability from trauma. It is estimated that the incidence of head injury is about 150 cases per 100,000 population per year in the United States, resulting in at least 50,000 deaths and contributing to permanent disability in more than 200,000 survivors.1,2 While motor vehicle accidents are the major cause of head injury, falls and injury from projectiles account for a significant number of these injuries.
It has been recognized for many years that there are 2 major mechanisms responsible for neuronal injury in patients with TBI: primary injury, in which the actual trauma episode produces cellular injury leading to cell death, and secondary injury, in which additional cell and structural injury occurs as a result of events following the primary traumatic episode. Primary injury can be prevented or reduced by helmet use, passive and active restraints, reduced speed of impact, better automotive design, better driving habits, lower speed limits, reduction in firearm use, and other public efforts.
Secondary injury prevention has been an active area of medical research and clinical activity.3 Since the cranium is a closed, rigid box, when a rapidly expanding intracranial mass occurs following trauma, normal brain tissue is compressed, vascular supply is compromised, and irreversible injury from ischemia may occur to otherwise uninjured tissues. Relief of a mass effect on surrounding normal tissues has been the goal of early surgical and pharmacological interventions and is believed to improve the outcome of TBI. Typical traumatic expanding masses are epidural, subdural, and intraparenchymal hematomas. These are apparent on basic imaging techniques and must be identified in a timely fashion to prevent irreversible secondary injury. In addition, acute cerebrospinal fluid outflow obstruction or parenchymal edema can increase global intracranial pressure to the point where arterial inflow is inadequate and ischemic secondary brain injury results. Historically, the treatment of TBI has consisted of evacuation of clots, control of intracranial pressure, and improvement of oxygen delivery and CO2 removal from the brain.4
While this mechanical approach remains an essential component of initial treatment of the TBI patient, experimental studies suggest that therapy directed at altering brain function and metabolism may also be helpful in salvaging ischemic brain tissues. Specifically, reducing the release of excitatory neurotransmitters provides significant protection from secondary injury in most animal models tested. Preliminary human data with several of these pharmacological agents are promising. It is the purpose of this review to report the available information related to basic, commonly used treatments for patients with TBI. Some of the new agents, which have not yet been shown to be effective but which have theoretical advantages, will be mentioned but not discussed in detail.
Despite the improvement in outcome from other traumatic injuries, little or no improvement has been observed in outcome from TBI. One of the most concerning observations in the treatment of TBI is that a wide variety of basic approaches are practiced at excellent but different centers. The use of head position, monitoring (or not) of intracranial pressure, treatment directed to maintenance of cerebral perfusion pressure, hyperventilation, sedation, and paralysis have not been adequately studied. Trauma care has been improved by application of a standardized, basic approach to initial and definitive care. The integration of prehospital and hospital care for trauma victims has resulted in reduced mortality and morbidity.5 Trauma systems have been developed to provide this standardized approach during the first phase or "Golden Hour," the initial resuscitation phase of injured patients.6 In an attempt to improve the outcome of the patients with TBI, the Brain Trauma Foundation and the American Association for Neurologic Surgeons have proposed guidelines for the treatment of patients with TBI. These recommendations are evidence-based and have been recently updated.7 These recommendations are graded as "Standards," suggesting that there is sufficient high-quality evidence to support universal application; "Guidelines," suggesting a lower level but yet substantial amount of supportive evidence; and "Options," meaning there is no preponderance of support for or against the recommendation. While few of the recommendations are at the level of "Standards," most of the routine interventions used in patients are discussed in this series of papers.
There are no issues specific for TBI other than the priorities for resuscitation in general. However, the effect of inadequate resuscitation in patients with TBI seems to be greater than in those with other organ injuries. It is now well known that hypoxia (as defined as an arterial saturation less than 90% or a PaO2 less than 60 mm Hg) and hypotension (as defined by a systolic blood pressure of 90 mm Hg or less) in the TBI patient are associated with a much higher mortality and greater morbidity.8 This is true even when correction is made for severity of brain and other organ injury and other known prognostic indicators.9
During initial resuscitation, if hypoxia does not respond to increased FiO2 or if apnea is present, artificial ventilation aided by endotracheal intubation should be instituted immediately. Often an altered mental status, even if not due to TBI, affects the ability to spontaneously clear the natural airway. This potential of airway loss results in early placement of an artificial airway and initiation of mechanical ventilation. Care must be paid when starting positive pressure ventilation, as profound hypotension often occurs in these hypovolemic patients. This hypotension may be more deleterious to the patient with TBI than the potential bad effects of spontaneous ventilation, until intravascular volume is restored.
Hypotension should never be attributed to TBI alone and other sources for blood loss or abnormal vascular resistance (ie, spinal cord injury or sepsis) should be identified. In the setting of TBI, hypotonic solutions should be avoided. Normal or even hypertonic saline may be of value in initial resuscitation in the hypotensive, multiply injured patient. This is not a mandatory recommendation, however, and rapid restoration of intravascular volume in the patient in shock with whatever isotonic fluid is immediately available takes priority over using one of these high-sodium fluids. After initial resuscitation, selection of fluids should be made with the intent of restoring or maintaining a serum sodium concentration in the range of 145 mEq/L or higher. Hyponatremia increases cerebral edema.
Initial TBI Treatment
Following restoration of intravascular volume, intubation, and ventilation, if depressed mental status remains an issue in the multiply injured patient (ie, patients with a Glasgow Coma Scale score of 8 or less), treatment to prevent or reverse transtentorial cerebral herniation should be instituted. This includes institution of sedation, possibly inducing pharmacologic paralysis, and mild hyperventilation (to PaCO2 between 35-40 mm Hg or a slightly alkalotic pH). Propofol may be the sedative of choice (if hypotension is not a problem), as it can be withdrawn periodically to allow a complete neurologic examination. However, narcotics can be used for sedation and reversed if necessary with naloxone. If herniation is suspected or progressive deterioration attributable to the TBI continues, mannitol boluses can be used (up to 1 g/kg) to reduce edema while preparing to perform a computed tomography (CT) scan. If there is no suspicion of impending herniation, neither mannitol nor paralysis should be used. Prolonged therapeutic paralysis should be avoided as this results in a higher incidence of pneumonia than sedation alone.
To identify surgical lesions, a CT scan should be considered in any patient with an altered mental status following initial resuscitation. Operative intervention should be accomplished as soon as feasible. Following surgery, or if herniation is reversed with medical treatment, intracranial pressure (ICP) monitoring should be initiated and further treatment decisions should be made based on ICP, cerebral perfusion pressure calculations, or both. These initial management steps are outlined in Figure 1. (Click here.)
Hypertension often accompanies severe TBI, and systolic pressures greater than 160-180 mm Hg can cause further disruption of the blood brain barrier which may lead to worsening edema, ischemia, or additional intracranial bleeding. Hypertension of this level should be treated. During stimuli, reactive hypertension can also be deleterious and must be avoided. This especially applies to endotracheal intubation, where the expected rise in blood pressure should be blunted with appropriate anesthetic agents. Ultrashort acting barbiturates, such as thiopental, are effective since they blunt the hypertension as well as reduce cerebral blood flow and reduce ICP.
Once a mainstay of TBI management, hyperventilation (to PaCO2 < 30 mm Hg) is reserved for episodes of uncontrolled increases in ICP until some other intervention (eg, mannitol infusion) is applied and effective. Sustained hyperventilation is associated with a worse outcome, probably because it diminishes blood flow in normal brain rather than damaged tissues and may augment ischemia.10 Prophylactic hyperventilation must be avoided in the management of TBI—this is now considered a standard of care by the Brain Trauma Foundation. This is particularly important in the first 24 hours following injury. In the presence of extremely elevated ICP, hyperventilation should only be used transiently to reduce the ICP while other measures are instituted.
The need for ICP monitoring following TBI has been debated throughout the world of neurosurgery. A minority opinion is that effective management should be provided based on changes in the neurologic exam and not on a measured ICP. The risk of monitoring is not trivial, and some believe it is inappropriate to treat an elevated ICP without a neurologic correlate. If the ICP remains elevated after maximum conventional therapy, outcome is so poor even with additional therapy (eg, barbiturate coma or profound hypothermia), that knowing the ICP adds little to management. Good centers with similar clinical outcomes throughout the world disagree about the use of this monitor.11
The Brain Trauma Foundation proposes the following guideline for ICP monitoring: 1) If the GCS remains 8 or less following resuscitation and the CT is abnormal, ICP monitoring is indicated; 2) If the patient has severe head injury but a normal CT scan, monitoring is indicated if 2 or more of the following are present: age > 40 years, unilateral or bilateral posturing, and systolic blood pressure less than 90 mm Hg at any time since injury. These are based upon the belief that therapy directed at increased ICP should be titrated to ICP (ie, hyperventilation and mannitol), and prognosis can also be improved by knowing this pressure. A ventriculostomy, which can be used to reduce ICP by draining a small amount of cerebral spinal fluid (CSF), can be used to monitor ICP but carries significant risk of causing injury or promoting infection.
Cerebral Perfusion Pressure (CPP)
Treatment of TBI in patients with increased ICP can be directed at reducing ICP, maintaining CPP, or both. ICP should normally be kept below 20-25 mm Hg. In patients with values at this level or above but no signs of herniation, CPP can be augmented with intravascular volume expansion and/or vasopressors. CPP is normally above 70 mm Hg. Some have suggested better outcomes with a CPP greater than 80 mm Hg. There is no standard recommended for CPP nor is there a recommendation as to the most effective way for achieving a particular end point. Direct acting alpha agonists (ie, phenylephrine) are effective at increasing blood pressure. They do not cause cerebral vasoconstriction as there do not appear to be active alpha receptors on cerebral vessels. They also do not cause tachycardia and therefore maintain a more favorable myocardial oxygen supply/demand ratio. In high doses, they can cause organ ischemia, primarily the kidney and gut, and adding a beta agent to increase cardiac output may be preferable under some circumstances.
Uncontrolled Intracranial Hypertension
In the case that ICP cannot be maintained below 25 mm Hg despite use of mannitol, CSF drainage, sedation, paralysis, and transient hyperventilation, several heroic options have been tried. The mortality in this group of patients (10-15% of all TBI who survive initial injury) is estimated to be 85-100% without additional treatment. A flow chart suggested for the treatment of patients with uncontrolled intracranial hypertension is presented in Figure 2. (Click here.)
Barbiturate Coma. Probably the best studied treatment is the use of high-dose barbiturates. Barbiturates are known to reduce cerebral metabolism and cerebral blood flow proportionately. They can reversibly induce bust suppression on the EEG and minimize cerebral oxygen demand. They are also oxygen free-radical scavengers and may contribute by reducing oxidative secondary injury. They can reduce elevated ICP. They are not indicated unless medical and surgical measures have failed and ICP is greater than 35 mm Hg. If barbiturates lower ICP in this group of ill patients, then mortality is less than if they don’t (nonresponders). Barbiturates cause cardiac depression and hypotension in the majority of patients in whom coma is induced. Vasopressors and cardiostimulants are almost always needed.
A suggested formula for inducing coma with pentobarbital is as follows:
- Loading Dose: 10 mg/kg over 30 minutes followed by 5 mg/kg/h for 3 doses
- Maintenance: 1 mg/kg/h
This dosing plan produces minimal effects on blood pressure and achieves therapeutic benefit in several hours. Invasive cardiovascular monitoring with an indwelling arterial catheter and a Swan-Ganz catheter are usually needed. Serum levels of barbiturates do not correlate with clinical effectiveness, but when discontinuing the drug, they have predictive value. Patients usually require many days for the drug levels to drop low enough to perform a valid neurologic examination. This is a problem when brain death is suspected as the neurologic examination is unreliable.
Deep Hypothermia. Profound hypothermia (core temperature 25-30°C) has been used to control elevated ICP. However, any improvement in mortality is negligible. As with barbiturate coma, profound cardiac disturbances are encountered and often result in cardiovascular collapse. Hypothermia also predisposes to infection and rampant sepsis is another event that worsens survival. For these reasons, profound hypothermia has been abandoned as therapy for elevated ICP.
Moderate Hypothermia. A great deal of interest has arisen in using moderate hypothermia (32-34°C) in patients with TBI. While not reducing the global brain metabolic rate significantly, release of excitatory neuromediators may be reduced and this could improve outcome. An initial report suggested a better clinical outcome 3 and 6 months following injury with modest hypothermia.12 This study was flawed and follow-up studies failed to show any improvement.13,14 The value of moderate hypothermia in TBI awaits further study. A corollary is true, however, that hyperthermia increases cerebral injury and must be avoided. Intravascular cooling devices have been proposed for this purpose, although no efficacy data on this approach have yet been published.
Decompressive Craniectomy. Since the skull is a closed box, removal of part of the skull bone can allow mass expansion without increasing pressure. This can prevent secondary injury. Craniectomy has been performed along with removal of blood clots or other masses and intact neurological survival has been seen. Craniectomy for diffuse edema without a resectable mass lesion is less well supported with data. Most American neurological surgeons do not advocate decompressive craniectomy under these circumstances,15 however, one active German group has reported surprising success, especially when performed early in the course of brain swelling.16 More study is needed before this invasive, aggressive approach can be advocated.
Following TBI, especially if there is any intraparenchymal blood, the risk of seizures is great. Early seizures may augment injury by increasing cerebral blood flow (CBF) and ICP although this has not been proven. Prophylaxis for early seizures with phenytoin (Dilantin) or carbamazepine (Tegretol) is indicated and effective. These drugs have no effect in preventing the late development of a seizure disorder and should be discontinued 7-10 days following injury.
Corticosteroids in TBI
The use of steroids is not recommended for improving outcome or reducing intracranial pressure in patients with severe head injury. Investigation of the role of the 21-aminosteroid, tirilizad, is ongoing. While not apparently offering any benefits in most patients with TBI, those with traumatic subarachnoid hemorrhage may benefit from this compound. The role of adrenal insufficiency in critical illness is being appreciated and some multiply injured patients with TBI may benefit from replacement therapy.
Experimental Therapy for TBI
Hypertonic Saline. The use of hypertonic saline for initial trauma resuscitation or for treating uncontrolled intracranial hypertension is a promising therapy.17 Animal experience and initial human trials suggest that outcome is improved by administering small volumes of hypertonic saline (7.5-23%) at the accident scene. This seems to be effective by preserving vascular integrity and dehydrating injured tissues. It may also be effective by more effectively ameliorating the shock state. When used for uncontrolled intracranial hypertension, hypertonic saline is as effective as barbiturate coma in reducing ICP.18 Appropriate dose and timing of the treatment have not been determined.
Anti-inflammatory Agents. It has been recently recognized that TBI elicits an inflammatory response in the brain. The production of toxic mediators may augment secondary injury. Anti-inflammatory agents are effective at limiting injury in animal models.
Neuroprotective Agents. Recognition of the role of excitatory mediators in increasing neurologic injury has led to the idea that agents that would interfere with these mediators could improve outcome. NMdA antagonists, calcium channel antagonists, steroids, nitric oxide synthase inhibitors, 5-hydroxy-tryamine receptor antagonists are all undergoing trials in humans with cerebral injuries. It is too early to recommend any of these for clinical use.
Induced Hypertension. Since CBF is often reduced following TBI and angiographic vasospasm can be demonstrated, treatment by inducing hypertension (as with vasospasm associated with subarachnoid hemorrhage) could be helpful. Other than a case report, this therapy remains speculative and cannot be recommended at this time.19
The outcome following TBI is improved with initial effective resuscitation, prevention of hypotension, avoidance of hypoxia and hypercarbia, and identification and removal of surgical lesions. Following the period of resuscitation, those patients with severe TBI (GCS < 8) benefit from therapy to reduce intracranial hypertension directed by intracranial pressure measurements. Effective measures include removal of hematomas, infusion of mannitol, and temporary hyperventilation to prevent herniation. Prolonged or prophylactic hyperventilation is harmful and must be avoided. Hypothermia, moderate or profound, has not been shown to be helpful, but hyperthermia should be aggressively treated. Steroids are not useful. Anticonvulsants may reduce the incidence of early seizures but should not be continued for prolonged periods in the absence of seizure activity. Other techniques for lowering ICP of unproven value include barbiturate coma, profound hypothermia, and decompressive craniectomy. These should only be used with increased monitoring (ie, jugular venous saturation monitoring, pulmonary artery catheter monitoring, or CBF monitoring) and when all other therapy has failed.
1. Max W, et al. J Head Trauma Rehabil. 1991;6:67-91.
2. Thurman DJ, et al. J Head Trauma Rehabil. 1999;14: 602-615.
3. Robertson CS, et al. Crit Care Med. 1999;27:2086-2095.
4. Chestnut RM, et al. J Trauma. 1993;34:216-222.
5. Shackford S, et al. Arch Surg. 1987;122:523-527.
6. American College of Surgeons. Committee on Trauma. ATLS Course Manual. Chicago, Ill: American College of Surgeons; 1997.
7. Anonymous. J Neurotrauma. 2000;17(6-7).
8. Pigula FA, et al. J Pediatr Surg. 1993;28:310-316.
9. Marmorou A, et al. J Neurosurg. 1991;75:S159-S166.
10. Muizelaar J, et al. J Neurosurg. 1991;75:731-739.
11. Anonymous. J Neurotrauma. 2000;17(6-7):479-491.
12. Marion DW, et al. J Neurosurg. 1993;79(3):354-362.
13. Shiozaki T, et al. J Neurosurg. 1999;91(2):185-191.
14. Clifton GL, et al. N Engl J Med. 2001;344(8):556-563.
15. Munch E, et al. Neurosurgery. 2000;47(2):315-322;discussion 322-323.
16. Guerra WK, et al. J Neurosurg. 1999;90(2):187-196.
17. Doyle JA, et al. J Trauma. 2001;50(2):367-383.
18. Suarez J, et al. Crit Care Med. 1998;26:1118-1122.
19. Ferring M, et al. Intensive Care Med. 1999;25:1006-1009.