A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury.

Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury severity impacts the overall outcome and likelihood for survival. Current treatment of acute TBI includes surgical intervention and supportive care therapies. Treatment of elevated intracranial pressure and optimizing cerebral perfusion are cornerstones of current therapy. These approaches do not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the brain. Homeostatic cellular processes governing calcium influx, mitochondrial function, membrane stability, redox balance, blood flow and cytoskeletal structure often become dysfunctional after TBI. Interruption of this cascade has been the target of numerous pharmacotherapeutic agents investigated over the last two decades. Many agents such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol were ineffective in clinical trials. While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending. Consequently, no neuroprotective treatment options currently exist that improve neurological outcome after TBI. Investigations to date have extended understanding of the injury mechanisms and sites for intervention. Examination of novel strategies addressing both pathological and pharmacological factors affecting outcome, employing novel trial design methods and utilizing biomarkers validated to be reflective of the prognosis for TBI will facilitate progress in overcoming the obstacles identified from previous clinical trials.

Intracerebroventricular administration of drugs.

Intracerebroventricular drug administration is a method that bypasses the blood-brain barrier and other mechanisms that limit drug distribution into the brain, allowing high drug concentrations to enter the central compartment. Instillation of drugs directly into the ventricles of the brain must be done carefully and with full consideration of factors affecting the efficacy and safety of this route of administration. These factors include the osmolarity, pH, volume, and presence of preservatives and diluents of the drug solution being administered. Very few studies have formally investigated intraventricular therapies, and dosing recommendations may vary widely depending on the agent and the patient. Many antimicrobials have been given intraventricularly, although very few prospective studies have evaluated this strategy. There are wide variations among the reports regarding dosage regimens and the pharmacokinetics of the antimicrobials used. Guidance on appropriate formulations and their use is lacking. Clinicians should be aware of their patients' ongoing disease processes and neurologic status, as well as pertinent physiochemical properties of drugs when formulating them for intracerebroventricular administration; a high index of suspicion should be maintained when monitoring patients for adverse drug events after instillation.

Cyclosporine A for neuroprotection: establishing dosing guidelines for safe and effective use.

Numerous neuroprotective compounds have been investigated to ameliorate secondary changes and the progression of injury after the primary insult in traumatic brain injury (TBI). This cascade of events is complex and difficult to abate once initiated following the primary injury. The clinical consequences of this secondary injury are unpredictable and often permanently incapacitating. Cyclosporine A (CsA) interrupts the endogenous mediators of secondary insult through inhibition of the mitochondrial permeability transition pore and prevention of subsequent mitochondrial dysfunction. This drug may have a role in neuroprotection but has several pharmacologic effects that must be considered when using it in the TBI population. This review discusses the physiologic responses following TBI that may affect CsA efficacy and safety when used for neuroprotective indications. So far, CsA seems to be safe in the TBI population. The role of CsA after acute TBI will be better defined after the completion of upcoming planned clinical trials.

Dosing and safety of cyclosporine in patients with severe brain injury.

OBJECT: Cyclosporine neuroprotection has been reported in brain injury models but safety and dosing guidelines have not been determined in humans with severe traumatic brain injury (TBI). The purpose of this investigation was to establish the safety of cyclosporine using 4 clinically relevant dosing schemes. METHODS: The authors performed a prospective, blinded, placebo-controlled, randomized, dose-escalation trial of cyclosporine administration initiated within 8 hours of TBI (Glasgow Coma Scale score range 4-8; motor score range 2-5). Four dosing cohorts (8 patients treated with cyclosporine and 2 receiving placebo treatment per cohort) received cyclosporine (1.25-5 mg/kg/day) or placebo in 2 divided doses (Cohorts I-III) or continuous infusion (Cohort IV) over 72 hours. Adverse events and outcome were monitored for 6 months. RESULTS: Forty patients were enrolled over 3 years (cyclosporine cohorts, 24 male and 8 female patients; placebo group, 8 male patients). Systemic trough concentrations were below 250 ng/ml during intermittent doses. Higher blood concentrations were observed in Cohorts III and IV. There was no significant difference in immunological effects, adverse events, infection, renal dysfunction, or seizures. Mortality rate was not affected by cyclosporine administration, independent of dose, compared with placebo (6 of 32 patients receiving cyclosporine and 2 of 8 receiving placebo died, p>0.05). At 6 months, a dose-related improvement in favorable outcome was observed in cyclosporine-treated patients (p<0.05). CONCLUSIONS: In patients with acute TBI who received cyclosporine at doses up to 5 mg/kg/day, administered intravenously, with treatment initiated within 8 hours of injury, the rate of mortality or other adverse events was not significantly different from that of the placebo group.

Successful enteral nutritional support in the neurocritical care unit.

PURPOSE: Adequate caloric intake is associated with improved outcome in neurocritical illness, but factors influencing the provision of enteral nutrition (EN) have not been systematically evaluated. The primary goal of the study was to determine the EN intake of neurosurgical intensive care unit (ICU) patients within the first week of illness and investigate the factors contributing to achieving caloric goals. METHODS: A retrospective cohort of adult patients admitted to the neurosurgery service (NS) during August 2005-August 2006 were randomly selected and stratified into three groups based on their ICU-admission Glasgow Coma Scale Score (GCS) (GCS > 11, GCS 8-11, GCS 4-7). Daily EN intake, GCS, and other clinical data were collected. RESULTS: A total of 71 patients were included (GCS > 11 = 23, GCS 8-11 = 23, GCS 4-7 = 25). Admitting diagnoses included traumatic brain injury (TBI) (32%), subarachnoid hemorrhage (SAH) (32%), and intracerebral hemorrhage (17%). The overall in-hospital mortality was 23.9%. Overall, the maximum daily mean calories provided was 1,100 kcal (mean of 55% of caloric goal on hospital day 6). The median time to feeding was approximately 3 days in each group. GCS did not appear to significantly affect the mean % of caloric goal administered in patients with a minimum daily GCS < or = 11 (P = 0.053). Multivariate analysis revealed that clinical care factors, such as time to EN orders and enteral access confirmation, were significant impediments to EN provision (P = 0.001). CONCLUSION: System-based clinical care factors appear to have great impact on the successful provision of EN in the first week of neurocritical illness.

Prevalence and characteristics of adverse drug reactions in neurosurgical intensive care patients.

OBJECTIVE: To evaluate the prevalence and characteristics of adverse drug reactions (ADRs) in neurosurgical intensive care patients. METHODS: Retrospective analysis of ADR data obtained from a spontaneous reporting system in a tertiary care university hospital. Reports of suspected ADRs in adult patients admitted emergently or electively to the neurosurgical service were included. RESULTS: Over the 3 year period, 3496 neurosurgical intensive care unit (ICU) patient admissions accounted for 5% of all hospital admissions. A total of 10% of all neurosurgical patients developed a suspected ADR, with three patients experiencing multiple reactions. Other adult ICU patients developed ADRs at a comparable rate (9%, P > 0.05). Overall, neurosurgery patients accounted for 12% of all spontaneously reported ADRs. Preventable reactions were observed in 43 (13%) cases, and treatment was required for 76%. The majority (96%) of ADRs resolved or improved at the time of the ADR report. Nausea, pruritus, thrombocytopenia, and vomiting were most frequently noted. Therapies most often associated with reported events were analgesics, antipyretics, antibiotics, anticonvulsants, and histamine H2 antagonists. The relationship between central nervous system disease and adverse event occurrence is not clear. CONCLUSION: Despite the narrow scope of drug regimens in neurosurgical ICU patients, ADRs can complicate therapy in this critically ill population. Neurosurgical ICU patients seem to experience ADRs no more frequently than their adult ICU counterparts.

Cyclosporin A disposition following acute traumatic brain injury.

Although the precise mechanism of action remains to be defined, Cyclosporin A (CsA) has demonstrated potential for neuroprotection in animal models. Predictive dosing strategies for CsA in acute traumatic brain injured (TBI) patients must account for the influence of the acute phase response on drug disposition. To characterize CsA pharmacokinetic parameters early following acute TBI, serial blood samples from patients enrolled into a Phase II dose-escalation trial were analyzed. Within eight hours of injury, thirty patients admitted with acute severe TBI were prospectively randomized into three cohorts (n = 8 CsA; n = 2 placebo per cohort) in this dose-escalation trial. Patients received one of three doses (I = 0.625 mg/kg/dose; II = 1.25 mg/kg/dose; III = 2.5 mg/kg/dose) or placebo intravenously every 12 h for 72 h. Serial blood collection began prior to dose 1 and continued for 72 h following the completion of six doses. Whole blood concentrations were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Pharmacokinetic parameters were determined for each patient by fitting the concentration-time profile to a two-compartmental model with first order elimination. Mean area under the curve and predicted maximal blood concentration increased with each dosing cohort (I = 9840 h*microg/L, 398 microg/L; II = 18300 h*microg/L, 645 microg/L; III = 32500 h*microg/L, 1300 microg/L). Whole blood clearance, steady state volume of distribution, and beta half-life were independent of dose and higher than published reports from other populations: 0.420 L/h/kg, 5.91 L/kg, and 17.3 h, respectively. These data show patients with acute severe TBI demonstrate a more rapid clearance and a larger distribution volume of CsA. Pharmacokinetic parameters derived from this study will guide dosing strategies for future prospective clinical trials evaluating CsA therapy following acute TBI.

Systemic metabolic effects of combined insulin-like growth factor-I and growth hormone therapy in patients who have sustained acute traumatic brain injury.

OBJECT: Hypermetabolism, hypercatabolism, refractory nitrogen wasting, hyperglycemia, and immunosuppression accompany traumatic brain injury (TBI). Pituitary dysfunction occurs, affecting growth hormone (GH) and plasma insulin-like growth factor-I (IGF-I) concentrations. The authors evaluated whether combination IGF-I/GH therapy improved metabolic and nutritional parameters after moderate to severe TBI. METHODS: The authors conducted a prospective, randomized, double-blind study comparing combination IGF-I/GH therapy and a placebo treatment. Ninety-seven patients with TBI were enrolled in the study within 72 hours of injury and were assigned to receive either combination IGF-I/GH therapy or placebo. All patients received concomitant nutritional support. Insulin-like growth factor-I was administered by continuous intravenous infusion (0.01 mg/kg/hr), and GH (0.05 mg/kg/day) was administered subcutaneously. Placebo control group patients received normal saline solution in place of both agents. Nutritional and metabolic monitoring continued throughout the 14-day treatment period. The two groups did not differ in energy expenditure, nutrient intake, or use of insulin treatment. The mean daily serum glucose concentration was higher in the treatment group (123 +/- 24 mg/dl) than in the control group (104 +/- 11 mg/dl) (p < 0.03). A positive nitrogen balance was achieved within the first 24 hours in the treatment group and remained positive in that group throughout the treatment period (p < 0.05). This pattern was not observed in the control group. Plasma IGF-I concentrations were above 350 ng/ml in the treatment group throughout the study period. Overall, the mean plasma IGF-I concentrations were 1003 +/- 480.6 ng/ml in the treatment group and 192 +/- 46.2 ng/ml in the control group (p < 0.01). CONCLUSIONS: The combination of IGF-I and GH produced sustained improvement in metabolic and nutritional endpoints after moderate to severe acute TBI.

Albumin use in neurosurgical critical care.

STUDY OBJECTIVE: To examine the use of albumin in patients receiving neurosurgical intensive care. DESIGN: Survey and chart review of albumin use in neurosurgical intensive care units. SETTING: University of Kentucky Chandler Medical Center and American Brain Injury Consortium (ABIC). SUBJECTS: Thirty-eight patients who underwent neurosurgery at the University of Kentucky Chandler Medical Center; members of the ABIC. INTERVENTIONS: Chart review with attention to administration of albumin; mailed survey to 200 ABIC members. MEASUREMENTS AND MAIN RESULTS: Patients admitted to the neurosurgical intensive care unit at the University of Kentucky Chandler Medical Center over a 6-month interval were evaluated. Albumin, either 5% or 25%, was prescribed for approximately 25% of patients. The indications for use were vasospasm and maintenance of cerebral perfusion pressure. The response rate for the ABIC survey was 39%. Respondents stated that normal saline and albumin were both primary fluid choices for the treatment of vasospasm. Twenty-two percent reported a reduction in albumin prescribing following a formal warning statement issued by the Food and Drug Administration regarding the use of albumin in critically ill patients. CONCLUSIONS: Chart review revealed the primary indications for albumin in the neurosurgical intensive care unit, and our survey data demonstrated the lack of consensus among neurosurgeons regarding their fluid of choice for neurosurgery indications. Prospective, randomized investigations comparing colloids to crystalloids in patients receiving neurosurgical intensive care are required to help define the role of albumin in neurosurgery patients.