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Investigational Neuroprotective Drugs in Traumatic Brain Injury.

Introduction

Current researchers are discovering the intricate process of neuronal cell death and establishing the role of neuroprotective agents in improving outcomes following acute traumatic brain injury. Neuroprotective agents are designed to be given soon after injury to quell the wave of mediators that initiate secondary injury. Currently there are no Food and Drug Administration (FDA) approved drugs for this indication. However, a number of investigational neuroprotective agents are under evaluation in various clinical trials (Table 1). Phase II and III drug studies are being conducted in brain-injured patients to evaluate the safety and effectiveness in reducing mortality as well as improving functional outcome. This article reviews the pathophysiology of acute neuronal injury and discusses standard and experimental drug therapy used in managing patients with traumatic brain injury.
Table 1. Investigational Neuroprotective Agents

Investigational Therapeutic Stage of clinical
 agent indication trial
(genetic name) (Phase I / II / III)

Aptiganel Stroke / Head injury III (suspended) /
 II (abandoned)
Nimodipine Head injury Abandoned
Eliprodil Stroke / Head injury II, III / II, III
HU - 211 Head trauma II
SNX - 111 Head injury / Pain III / III
CP - 0127 Head injury In development
Corticosteroids Head Injury Abandoned
Tirilizad mesylate Stroke / Head trauma III (discontinued) /
 III (discontinued)
CPC - 211 Stroke / Head injury II /II


Pathophysiology

The cascade of events occurring in the acute and later stages of central nervous system (CNS) injuries is very complex and not completely understood. In CNS trauma, the patient experiences both primary and secondary neuronal injury. Primary neuronal injury is a direct consequence of the trauma, and involves the transfer of kinetic energy to the components of the brain (nerve cells, synapses and cerebral blood vessels).[1] The key pathophysiologic process triggering secondary brain injury involves cerebral ischemia and reperfusion.[4] Ischemia occurs within six hours after the initial insult and persists for days afterward.[8] This area of the damaged brain is called the ischemic penumbra. The viability of the penumbral tissue may be regained if cerebral blood flow improves. However, during tissue reperfusion, intracellular mechanisms at the molecular level are activated mediating secondary neuronal damage.[3] Mechanisms include local tissue acidosis secondary to increased lactic acid production, release of intracellular calcium ions and production of free radicals, all of which lead to cell injury and death (Fig 1). The cumulative destructive forces at the cellular level compromise the integrity of the cerebral blood vessels and brain tissue. Cerebral capillary endothelial damage causes major shifts of intracellular and extracellular ions leading to cytotoxic and vasogenic edema.[4] Cerebral edema can cause a significant rise in intracranial pressure (ICP) interfering with cerebral blood flow and, if left unchecked, can result in brain herniation.[9]

[Figure 1 ILLUSTRATION OMITTED]

Electrolytes are linked to the processes involved in neuronal injury. The sodium-potassium ion pump maintains electrical neutrality of the cell. During reperfusion injury the sodium-potassium pump fails causing an influx of sodium and water, and an efflux of potassium and magnesium.[4] Magnesium depletion inhibits intracellular transport of calcium.[9] It has been proposed that a sustained increase in intracellular calcium ion initiates a cascade of deleterious calcium-dependent processes culminating in cell death.[15]

Calcium ion transport is effected by the excitatory amines glutamate and aspartate which are involved with normal neural transmission. Concentrations of these mediators rise dramatically following acute head injury.[9,13] Glutamate and aspartate interact with N-methyl-D-aspartate (NMDA) receptors on the cell membrane to cause an influx of calcium.[14] Increases in extracellular levels of glutamate and aspartate at the NMDA receptor correlate with injury severity and neurotoxicity.

Initial management of brain-injured patients includes maintaining a euvolemic, hyperosmolar state to avoid increased cerebral blood volume that can elevate intracranial pressure. In addition, resuscitation following trauma is key to prevent post-injury hypotension that may worsen outcome.[5] A decrease in mean arterial blood pressure (MAP) will decrease cerebral perfusion pressure (CPP) and compromise blood flow to areas of ischemia. If there is clinical or objective evidence of an elevated ICP, the patient may be managed with hyperventilation, surgical intervention or drug therapy. Sedatives and paralytics agents are adjunctive drugs that are used in the intensive care unit. Sedatives such as lorazepam (Ativan[R]), midazolam (Versed[R]) and propofol (Diprivan[R]) have shown a beneficial effect in decreasing ICP and cerebral oxygen utilization.[25] The use of neuromuscular blocking agents may be indicated when ICP cannot be controlled by other means.[18] Accepted therapy for treating elevated ICP may consist of osmotic and loop diuretics, and barbiturates. Barbiturate coma is not a first-line approach and should be used with caution in hemodynamically unstable patients.[7]

Traditional Drug Therapy

Osmotic Diuretics

Mannitol is an osmotic diuretic. It elevates the osmotic pressure of the plasma shifting fluid from the extravascular to the intravascular space. It also acts as a plasma-volume expander by decreasing the blood viscosity and increasing oxygen delivery to the brain.[6] Mannitol is preferred over other diuretics for controlling elevated ICP associated with cerebral edema.

Mannitol is administered as an intravenous (IV) bolus over 3 - 5 minutes to treat acute elevations in ICP or as an IV infusion over 30 - 60 minutes. The dosage range is 0.25 - 1 gram/kg body weight administered as a 15%, 20% or 25% solution. Solutions should be inspected for evidence of crystal formation. An in-line 5 micron filter set should always be used to remove crystals.

Mannitol may also be given to hypovolemic, head-injured patients in conjunction with crystalloid and colloid solutions to maintain plasma serum osmolality between 300 and 320 mOsm per liter. This practice maximizes the therapeutic effect and minimizes decreased renal blood flow. The duration of action for mannitol is variable lasting from 90 minutes up to 4 - 6 hours depending upon the dose and clinical condition of the patient. Rebound elevations of ICP may occur if the osmotic agent accumulates in the brain's extravascular space. The accumulation may lead to a reverse osmotic shift, thus increasing brain swelling.

After receiving mannitol, patients should be monitored for electrolyte imbalances (hypokalemia, hyponatremia), declining renal function (increased serum creatinine, decrease in urine output) and signs of heart failure or pulmonary congestion. Adverse reactions such as seizures, urinary retention, fever, chills and urticaria may occur, as well as extravasation from the intravenous site causing local edema and necrosis.

Another osmotic diuretic, glycerol has been used to lower ICP by osmotic brain dehydration; it also decreases cerebrospinal fluid (CSF) production and increases cerebral blood flow to ischemic brain tissue.[23] Glycerol is given orally; intravenous preparation is not commercially available.24 Glycerol can be given intermittently at doses between 0.5 - 1 gram/kg every 4 - 6 hours. It should be used cautiously in patients with cardiac, renal or hepatic disease, or in patients with urinary retention. Adverse reactions include confusion, headache, nausea and vomiting.

Loop Diuretics

Furosemide (Lasix[R]) is a loop diuretic that inhibits sodium and water reabsorption within the kidney tubule at the loop of Henle. It has been proposed that furosemide lowers ICP by carbonic anhydrase inhibition resulting in decreased CSF production, or, via suppression of cerebral sodium uptake.[23] The use of furosemide may be advantageous in patients with co-existing cerebral and pulmonary edema. It is a potent diuretic that may precipitate massive diuresis resulting in intravascular depletion and hypotension when used alone or in combination with mannitol. However, there is limited data to support this combination. Monitoring hemodynamics closely with a pulmonary artery catheter in this setting is strongly suggested to avoid severe hypotension.[27]

Intravenous doses of 0.5 - 1 mg/kg will lower ICP within minutes.[26] The maximum decrease in ICP occurs within 25 - 30 minutes.[26] Adverse effects include electrolyte abnormalities such as hypokalemia, hyponatremia, hypochloremia, hypercalciuria, hypomagnesemia and hyperuricemia, renal dysfunction and metabolic alkalosis.

Barbiturates

Barbiturates are sedative-hypnotic drugs. Clinical application of barbiturate coma for treating intracranial hypertension began approximately three decades ago.[28] The mechanism for lowering ICP has not been completely established. The most accepted mechanism of action is the suppression of both the cerebral metabolic rate of oxygen utilization ([CMRO.sub.2]) and cerebral blood flow (CBF) to well-perfused brain tissue. This diverts blood flow (steal phenomenon) into ischemic regions resulting in a decrease in the ICP and improvement in cerebral global perfusion.[23,29,33]

Pentobarbital is initiated by IV at 20 - 30 mg/kg given over 1 - 2 hours followed by a maintenance infusion ranging between 0.5 - 3.5 mg/kg/hr.[34,35] Discontinuation of a pentobarbital infusion may begin once the ICP [is less than] 20 mm Hg for 48 hours, the drug may be tapered over a 3 day period.[10] Thiopental is administered as a IV loading dose of 20 mg/kg over 1 hour followed with a maintenance dose of 2 - 12 mg/kg/hr.[36] Pentobarbital and thiopental can cause severe tissue damage due to extravasation. Barbiturates should be infused separately through a central IV line to avoid incompatibilities with other IV solutions.

These agents are distinguished by their pharmacodynamic and pharmacokinetic profile. The onset of effect of thiopental is rapid, occurring seconds after a bolus dose. This drug is highly lipid soluble, and the effects dissipate when the drug redistributes into fat and muscle, thus shortening the duration of pharmacological coma. Complete elimination of thiopental and phenobarbital from the body can take several days. Pentobarbital has been studied frequently and is favored over the other agents due to its relatively short half-life of 16-19 hours. The half-life of thiopental is 38-86 hours whereas the half-life of phenobarbital is 60-100 hours. No clear correlation has been established between serum pentobarbital levels and either therapeutic efficacy or systemic toxicity.[28] However, blood level monitoring is essential to insure clearance of the drug from the body when evaluating a patient for determination of brain death.

The electroencephalogram (EEG) should be monitored continuously during a barbiturate coma. Electrical activity in the brain is represented by repeating patterns on the EEG graph. Barbiturates reduce the frequency of this pattern, known as burst suppression, resulting in a drug-induced coma. The dose is titrated to achieve the minimum number of electrical bursts per minute (ie, 1 - 5 bursts per minute) that correlate with ICP control.

During a barbiturate coma, the patient must be mechanically ventilated. Continuous monitoring of cardiovascular hemodynamics, pulse oximetry, electrocardiogram, ICP and hourly EEG should be performed while the patient is maintained in a barbiturate coma. The ICP should be kept below 15 mm Hg. The mean arterial pressure (MAP) should be kept between 60 - 90 mm Hg and the cerebral perfusion pressure (CPP) should be maintained above 60 mm Hg. Patients should be monitored for cardiovascular complications such as hypotension and myocardial depression, as well as hypothermia and infection.[28]

Investigational Pharmacologic Therapy

A number of compounds to prevent the cascade of events involved in secondary neuronal injury are being investigated. These agents may protect or reverse the damage to the ischemic penumbra. Table 1 lists novel investigational agents that have been evaluated. High-dose corticosteroids and the calcium-channel blocking agent, nimodipine, have also been studied in brain injury. Since processes involved in traumatic brain injury are similar to those in stroke, a number of agents are being studied for both indications.

Aptiganel (Cerestat[R], Cambridge Neuroscience) is an NMDA receptor antagonist that has been proposed to increase perfusion to the brain following ischemic injury. Subjects were given a 15 mg IV bolus followed by a 3 mg/hr infusion over 3 days starting within eight hours of initial traumatic brain injury. Although animal studies were promising, the Phase III trial conducted in 343 subjects with traumatic brain injury was abandoned after interim analysis showed no benefit over placebo.[30] A recent Phase III trial in the use of aptiganel in stroke has been temporarily suspended because of concerns over drug adverse effects. This agent is also being evaluated for other neurologic disorders.

Intravenous nimodipine (Nimotop[R]) is a calcium-channel blocking agent that has selective effects on cerebral arteries. The drug was evaluated as a prevention for secondary injury. It was found to be beneficial in reducing mortality and improving recovery in a subset of patients with subarachnoid hemorrhage (SAH).[11] Hypotension was seen frequently in this study resulting in drug discontinuation. Nimodipine is not available as an IV preparation in the United States. It has only been approved as a capsule given orally to prevent cerebral vasospasm following SAH. Widespread application of nimodipine in traumatic brain injury is not recommended at this time.

Eliprodil (Synthelabo) is a new agent with a dual mechanism of action. It is a neuronal calcium channel-inhibitor and a NMDA receptor antagonist that has been associated with amnestic and psychostimulatory effects. Results on drug safety and efficacy will be available within the year. A European clinical trial in acute ischemic stroke was halted because of lack of efficacy. Phase II and III studies in the United States are presently ongoing.[31] Results from these trials may determine the future role of this agent.

HU - 211 (Pharmos) is a synthetic nonpsychotropic cannabinoid derivative which has been shown to act as a noncompetitive NMDA receptor antagonist. It binds to the opened NMDA receptor thus preventing the potentially toxic flux of ions into the neuron thereby decreasing cerebral edema. These agents are devoid of the mood-altering effects that occur with other cannabinoids such as marijuana. It is presently undergoing a Phase II clinical trial in six trauma centers in Israel in patients with severe head injury.[32] Preliminary results from animal studies have demonstrated improvement in motor function when the drug is administered within 2 - 3 hours after injury.

SNX - 111 (Neurex / Warner Lambert) is a neuron-specific calcium antagonist being evaluated in patients with head trauma. Phase I and II studies have been promising. Presently, eight-hundred patients are expected to be enrolled in a Phase III trial.[12] The trial is expected to be completed within two years, and an interim analysis will be performed after approximately 200 patients are enrolled. Separate trials are underway to evaluate its role in neuropathic and severe intractable pain.

CPC - 211 (Cypros) reduces lactic acid production in the brain. Drugs in this new class facilitate anaerobic glycolysis to support the generation of metabolic energy under ischemic conditions. Phase II studies in stroke victims have begun and additional trials in head injury are underway.[19] It is too early to determine the role of this agent until results are available from these trials.

Corticosteroids, such as methylprednisolone and dexamethasone, have been studied in traumatic brain injury because they act as free radical scavengers with antioxidant effects at high doses. High dose methylprednisolone (ie, 30 mg/kg bolus followed by 5.4 mg/kg/hr for 23 hours) has been shown to be beneficial in improving motor and sensory recovery following spinal cord injury.[2] Unfortunately, the use of corticosteroids has been disappointing in patients with cerebral edema as a result of ischemia. At this time, there is no definitive evidence in humans describing any clinical benefit of corticosteroids in the setting of traumatic brain injury.[21]

Tirilazad mesylate (Freedox[R], Pharmacia & Upjohn) is a nonglucocorticoid 21-aminosteroid lipid peroxidation inhibitor that has been studied in brain and spinal cord injury. It is believed to block lipid peroxidation thus limiting neuronal injury by decreasing free radical formation. Although neurologic recovery and survival have occurred in head-injured mice, the efficacy in humans is controversial. The phase III multicenter trial in North America was halted due to high mortality rate in the treated group after approximately 98% of the study was completed.[22] Although human studies in patients with subarachnoid hemorrhage have been promising, it's role in stroke and spinal cord injuries are pending. The future role in traumatic brain injury is unknown.

CP - 0127 (Cortech) is a bradykinin antagonist developed for traumatic brain injury and other indications. Bradykinin, an inflammatory mediator, causes cerebral vasodilation and may represent a pivotal endogenous mediator of acute neuronal injury. A pilot study in brain injury showed encouraging results; however, unexplained mortality has been shown in test animals.[20] Also, negative results on mortality were observed in patients with sepsis. Phase I and II testing of this agent in over 600 patients did not produce any adverse effects. Until clinical trials for traumatic brain injury are complete, the future role of this agent for acute neuronal injury is delayed.

Many pharmacologic agents have been investigated for acute neuronal injury with mixed or inconsistent results. Factors responsible for variable study outcomes may be severity of injury, inadequate dose or therapeutic concentration of the pharmacologic agent and delayed timing of drug delivery. Future efforts should consider administration of drug combinations to target different mechanisms in neuronal injury. Until a better understanding of the pathophysiologic and biochemical indices of acute neuronal injury are available, complete neurologic recovery remains elusive.

Each compound has distinct effects that may improve cognitive and motor deficits after acute neuronal injury. There are several excellent reviews describing other mediators (phospholipases, oxygen free-radicals, antioxidants, platelet-activating factor) and their implications in CNS trauma.[4,8,9,13-17]

Role of the Nurse

There may be a number of barriers to the use of neuroprotective agents in patients with brain injury. Currently, there are no neuroprotective drugs approved by the FDA to treat brain injuries. If a patient meets the inclusion criteria for an investigational protocol, the patient (if capable) or family member will be approached to give informed consent to participate in the study. Some states may allow an emergency waiver of informed consent after adhering to strict FDA guidelines (Code of Federal Regulations). Whether or not the patient is enrolled, the risk of mortality varies with the severity of brain injury, therefore the nurse should offer realistic expectations for outcome when meeting with the patient and family members.

The nurse providing care to the patient should not forget the nursing process: assessment, planning, implementation and evaluation. In an investigational study, the side effect profile of the drug may not have been completely elucidated. It is imperative to perform a thorough assessment of the patient and document any findings. Side effects, or adverse events (AEs), may include but are not limited to those AEs listed in the protocol. AEs may include allergic reactions such as rash, hives and cardiovascular collapse. Therefore, vital signs should be monitored closely during drug administration to detect immediate reactions to the drug.

A number of trials presented were terminated due to increased mortality in the study group. Serious Adverse Events (SAEs) including death, rehospitalization, prolonged hospitalization, persistent or significant disability, congential anomaly or cancer must be reported to the sponsoring pharmaceutical company within 24 hours. Some studies are designed to follow patients during and after hospitalization to assess survival and functional recovery. An open line of communication should be kept with the research coordinator to insure documentation and timely reporting of all events.

Investigational studies are regulated by the FDA and require substantial documentation. All doses that are administered should be signed out, and any missed doses should be noted with an explanation. In some cases when additional injuries are present, patients will be transported to the operating room (OR) for surgery. An explicit report of participation in a research protocol to anesthesia personnel may prevent missed or interrupted doses. If the drug is given as an IV infusion, one IV port should be reserved for the study drug as compatibility data is usually not complete during early phases of research. All IV ports should be taped to discourage unintentional injection.

Summary

Primary neuronal injury due to acute traumatic brain-injury may cause significant damage to the CNS. However, impaired cognitive and behavioral function also occurs following secondary neuronal injury. Neuroprotective agents should be administered soon after the acute event to prevent this secondary phase. NMDA receptor antagonists, free radical scavengers and bradykinin antagonists are designed to protect the neuron from the damaging effects of mediators. Calcium-channel blocking agents and drugs promoting anaerobic glycolysis are designed to stop the intracellular processes causing ischemia. The standard treatment options for patients with brain injuries are limited. Thus, the possibility exists for poor outcomes. At this time, since there are no approved neuroprotective drugs available, experimental treatment offers a chance for improved outcomes.

References

[1.] Bouma GJ, Muizelaar JP, Choi SC et al: Cerebral circulation and metabolism after severe traumatic brain injury: The elusive role of ischemia. J Neurosurg 1991;75:685-693.

[2.] Bracken MB, Shepard MJ, Collins WF et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. New Engl J Med 1990; 322:1405-14.

[3.] Bricolo AP, Glick RP: Barbiturate effects on acute experimental intracranial hypertension. J Neurosurg 1988; 55:397-406.

[4.] Bullock R: Mannitol and other diuretics in severe neurotrauma. New Horizons 1995; 3:448-452.

[5.] Bullock R, Chesnut RM, Clifton G et al: Resuscitation of blood pressure and oxygenation. Pages 1-11 in: Guidelines for the Management of Severe Head Injury. Brain Trauma Foundation, 1995.

[6.] Bullock R, Chesnut RM, Clifton G et al: The use of mannitol in severe head injury. Pages 1-12 in: Guidelines for the Management of Severe Head Injury. Brain Trauma Foundation, 1995.

[7.] Bullock R, Chesnut RM, Clifton G et al: The use of barbiturates in the control of intracranial hypertension. Pages 1-17 in: Guidelines for the Management of Severe Head Injury. Brain Trauma Foundation, 1995.

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[16.] Hall ED: The role of oxygen radicals in traumatic injury: Clinical implications. J Emerg Med 1993;11:31-36.

[17.] Hallenbeck JM, Dutka AJ: Background review and current concepts of reperfusion injury. Arch Neurol 1990; 47: 1245-1254.

[18.] Hsiang JK, Chesnut RM, Crisp CB et al: Early, routine paralysis for intracranial pressure control in severe head injury: Is it necessary? Crit Care Med 1994; 22:1471-1476.

[19.] NDC Health Information Services: Intellect Update: Product Research and Approval Report: Vol XVII, No 10, Maldonado M, Benecke H, Horna MJ (editors). Source Informatica, 1997.

[20.] NDC Health Information Services: Intellect Update: Product Research and Approval Report: Vol XVII, No 10, Maldonado M, Benecke H, Horna MJ (editors). Source Informatica, 1997.

[21.] Kelly DF: Steroids in head injury. New Horizons 1995; 3:453-45.

[22.] Luer MS, Rhoney DH, Hughes M, Hatton J: New pharmacological strategies for acute neuronal injury. Pharmacotherapy 1996; 16(5):830-848.

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[25.] Mirski MA, Muffelman B, Ulatowski JA, Hanley DF: Sedation for the critically ill neurologic patient. Crit Care Meal 1995; 23:2038-2053.

[26.] Ochial C, Asano T, Takakura K et al: Mechanisms of cerebral protection by pentobarbital and nizofenane correlated with the course of local cerebral blood flow changes. Stroke 1982; 13:788-796.

[27.] Pitts LH, McIntosh TK: Dynamic changes after brain trauma. Pages 65-100 in: Handbook of Clinical Neurology: Head InJury, Vol 57, Vinken PJ, Bruyn GW, Klawans HL (editors). Elsevier Science Publishing, 1990.

[28.] Quandt CM, de los Reyes RA, Diaz FG: Barbiturate-induced coma for the treatment of cerebral ischemia: Review of outcome. Clin Pharm 1982; 1:549-551.

[29.] Rockoff MA, Marshall LF, Shapiro HM: High-dose barbiturate therapy in humans: A clinical review of 60 patients. Ann Neurol 1979; 6:194-199.

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[34.] Tourtellotte WW, Reinglass JL, Newkirk TA: Cerebral dehydration action of glycerol. 1. Historical aspects with emphasis on the toxicity and intravenous administration. Clin Pharm Ther 1972; 13:159-172.

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[36.] Young W: The post-injury response in trauma and ischemia. Secondary injury or protective mechanisms? Centr Nerv Sys Trauma 1987; 4:27-51.

Questions or comments about this article may be directed to: Grace L. Earl, Pharm D, Clinical Pharmacist, Cooper Health System, Pharmacy Department, Camden, New Jersey 08103. Michael J. Cawley, Pharm D, is an assistant professor at Philadelphia College of Pharmacy and Science in Philadelphia, Pennsylvania.

Robert K. Marburger, RN, CCRC, is a research coordinator at the Regional Trauma Center of Southern New Jersey, Cooper Health System in Camden, New Jersey.

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Author:Cawley, Michael J.; Marburger, Robert K.; Earl, Grace L.
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Dec 1, 1998
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