Mark S. Luer

Vancomycin Administration into the Cerebrospinal Fluid: A Review

OBJECTIVE: To discuss administering vancomycin directly into the cerebrospinal fluid (CSF) to treat serious central nervous system (CNS) infections. DATA SOURCES: References were obtained through an online search of MEDLINE, limited to material published in English. In addition, information was extracted from clinical trials, review articles, abstracts, and textbooks. STUDY SELECTION: Systematic evaluation of this topic in humans has not been done in a prospective manner. Related research articles describing the pathophysiology of CNS infections, intrathecal drug administration, and case reports of CSF vancomycin administration were reviewed. DATA EXTRACTION: Case reports regarding CSF vancomycin dosing were evaluated and included: Drug dosing, infecting organism, infectious disease state, infectious outcome, CSF dynamics/flow abnormalities, methods of drug administration, drug monitoring, and toxicities. DATA SYNTHESIS: The results of this review are based on qualitative evaluations of anecdotal case reports and a basic understanding of intrathecal and intraventricular drug dosing principles. CSF administration of vancomycin is an effective means of bypassing the blood-brain barrier to achieve greater drug concentrations within the CSF. Current limitations to the CSF administration of vancomycin include a lack of data describing its safety, efficacy, and pharmacokinetics. CONCLUSIONS: CNS infections may require the CSF administration of vancomycin for successful eradication. Recommendations for dosing in the literature vary. Because of the potential toxicities associated with elevated CSF concentrations of vancomycin, dosing should be conservative.

Saturable transport of gabapentin at the blood-brain barrier

Gabapentin readily crosses the blood-brain barrier and concentrates in brain tissue via an active transport process believed to be system-L. Blood-brain barrier system-L has a low K(m), making it particularly susceptible to substrate saturation. The purpose of this study was to determine whether the fraction of gabapentin crossing the blood-brain barrier remains constant over a broad range of doses. Using a rat model, microdialysis techniques were employed to determine if fluctuations in gabapentin concentrations in the brain extracellular fluid (ECF) coincided with proportional changes in plasma concentrations. Area under the concentration-time curve was calculated for plasma (AUCplasma) and brain extracellular fluid (AUCECF). The ratios of AUFECF to AUCplasma (AUCratio) and brain extracellular fluid to midpoint plasma gabapentin concentration for each collection interval (Cratio) were determined to provide indicators of the relative (i.e. fractional) amount of gabapentin crossing the blood-brain barrier. Analysis of the association between AUCECF and AUCplasma using linear regression analysis revealed a small, but significant relationship (r = 0.62; p < 0.01). Although higher AUCECF values were obtained with higher AUCplasma values, changes in AUCECF were less than proportional to observed changes in AUCplasma. Blood-brain barrier saturation of gabapentin transport was evident as the AUCratio decreased with increased AUCplasma. Collectively, these results support a trend towards saturation at higher plasma concentrations of the carrier-mediated transport mechanism of gabapentin through the blood-brain barrier.

MICRODIALYSIS IN THE HUMAN BRAIN : REVIEW OF ITS APPLICATIONS

The analysis of brain extracellular fluid can provide essential information about both the physiology and the pathology of the human nervous system. The introduction of microdialysis into the clinical sciences has provided a new opportunity to study this environment. Using microdialysis, endogenous substances can be obtained and drugs can be delivered in very close proximity to the receptors and ion channels on neuronal membranes. In this sense, microdialysis can be regarded as a novel technique since it can continuously measure interstitial brain activity in living tissue while causing minimal adverse effects. Although it has been well established as an experimental technique for neurochemistry, the true utility of microdialysis as a clinical tool is still being defined. The potential clinical applications of microdialysis to characterize the human brain extracellular environment in patients with pathologic conditions has grown rapidly. The number of publications in which microdialysis has been performed in clinical studies has been increasing during recent years and this article gives a summary of those reports where microdialysis was applied in the study of human brain disorders.

Clinical experience with transcranial cerebral oximetry.

Transcranial cerebral oximetry based on the principle of near-infrared spectroscopy has been successfully used in a variety of neurosurgical conditions, primarily those associated with disturbed cerebral circulation. The non-invasive technique of cerebral oximetry provides valuable information about brain oxygenation in patients with cerebral ischemia (due to occlusion or stenosis of the internal carotid artery). It is also used in intraoperative monitoring of carotid endarterectomy and surgical procedures performed under deep hypothermia and circulatory arrest, during neuroendovascular procedures, and in critical care settings (in patients with arterial vasospasm and during the terminal period). This article describes our preliminary clinical experience with the use of this new technique and summarizes the current literature on clinical and experimental use of transcranial cerebral oximetry.

Tiagabine: A Novel Antiepileptic Drug

OBJECTIVE: To provide a comprehensive review of tiagabine, including its pharmacology, toxicology, pharmacokinetics, drug interactions, efficacy, adverse effects, and dosing recommendations. DATA SOURCES: A computerized search of the MEDLINE database from 1966 to December 1997 was used to identify publications related to tiagabine and nipecotic acid derivatives. Included in this review was information gathered from scientific meetings. Manufacturers information was used when there was no primary literature. DATA SYNTHESIS: Tiagabine amplifies γ-aminobutyric acid (GABA) neurotransmission, the predominant inhibitory neurotransmitter in the brain. Its mechanism of action is selective and has shown promise as an antiepileptic drug (AED) in patients with seizures refractory to other pharmaceutical products. Tiagabine exhibits dose-independent absorption, 90–95% bioavailability, high protein binding (96%), metabolism via hepatic cytochrome P450 enzymes (CYP3A subfamily), and displays first-order elimination pharmacokinetics. The mean plasma half-life is 5–8 hours. Concomitant medications that induce hepatic metabolism enhance tiagabine elimination; metabolism is reduced in patients with hepatic dysfunction. Adverse events of tiagabine typically involve the central nervous system, have been mild to moderate in intensity, and also have been transient in nature. CONCLUSIONS: Tiagabine has demonstrated a good safety profile and, while it has not been demonstrated to be superior to other second-line AEDs for partial seizures, its safety and select mechanism of action warrant its further evaluation in the clinical setting. Tiagabine should be a good alternative add-on agent for patients with unsatisfactory seizure control or intolerable adverse effects of traditional therapies; thus, this agent should be made available to these patients.

Regional cerebral oxygen saturation during intra-arterial papaverine therapy for vasospasm: case report.

Cerebral arterial vasospasm continues to be a major secondary medical complication of aneurysmal subarachnoid hemorrhage. Despite hypervolemic hemodilution, arterial hypertension, and pharmacological therapy, morbidity and mortality due to vasospasm remain high. The authors discuss a patient with vasospasm who did not respond to traditional medical therapy and who underwent intra-arterial papaverine infusions while being monitored with transcranial cerebral oximetry. Oximetry during the procedure revealed significant improvements in brain regional saturation of oxygen, with the relief of vasospasm that correlated with clinical improvements in the patients neurological status. Transcranial cerebral oximetry was used to monitor regional oxygen saturation throughout the angiographic and interventional procedures, providing continuous, real-time, clinically relevant information about the effects of vasospasm and its treatment.

New pharmacologic strategies for acute neuronal injury.

The number of new drugs for treating neurotrauma is rapidly expanding. Emerging theories regarding the mechanisms of secondary neuronal injury provide the scientific basis for evaluating these new agents. Some of the most promising mechanisms for intervention are ionotropic channel antagonism, inhibition of lipid peroxidation, and neurotrophic factor augmentation. Many of these new agents are undergoing clinical trials to establish their roles in therapy.

New pharmacologic approaches to acute spinal cord injury

The incidence of spinal cord injury (SCI) in the United States is approximately 10,000 new cases per year. Strategies to prevent injury or salvage a few dermatomal levels may have significant effects on outcome. Several pharmacologic agents have been evaluated for their efficacy in patients with acute SCI. Methylprednisolone, when administered early, was the first drug to show significant improvement in outcome and is a standard of comparison for future agents. Several new drugs show promising results in animal models of SCI, with more extensive human trials currently under way. Results of more well‐controlled clinical trials are necessary to determine which agents have significant neurologic benefits.

Intraventricular atrial natriuretic peptide for acute intracranial hypertension.

The effect of intraventricular atrial natriuretic peptide (ANP) on elevated intracranial pressure (ICP) was evaluated in a rodent model of global ischemia and reperfusion. ANP administration into the lateral ventricle 30 minutes after reperfusion statistically significantly reduced ICP compared with both vehicle treated animals (p < 0.001) and pretreatment pressures (p < 0.001). The ICP effects of ANP did not coincide with specific changes in regional perfusion parameters measured by laser-Doppler flowmetry. Two different vehicles for ANP were used to verify that the changes in ICP observed were independent of the sodium content administered in the vehicle. Based on the reductions observed in ICP, ANP deserves further evaluation as a treatment modality for the acute elevations in ICP associated with ischemic brain injury.

Regional Cerebral Oxygen Saturation during Intra-arterial Papaverine Therapy for Vasospasm

Cerebral arterial vasospasm continues to be a major secondary medical complication of aneurysmal subarachnoid hemorrhage. Despite hypervolemic hemodilution, arterial hypertension, and pharmacological therapy, morbidity and mortality due to vasospasm remain high. The authors discuss a patient with vasospasm who did not respond to traditional medical therapy and who underwent intra-arterial papaverine infusions while being monitored with transcranial cerebral oximetry. Oximetry during the procedure revealed significant improvements in brain regional saturation of oxygen, with the relief of vasospasm that correlated with clinical improvements in the patients neurological status. Transcranial cerebral oximetry was used to monitor regional oxygen saturation throughout the angiographic and interventional procedures, providing continuous, real-time, clinically relevant information about the effects of vasospasm and its treatment.