Effect of time, injury, age and ethanol on interpatient variability in valproic acid pharmacokinetics after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CL(u)) is equal to intrinsic or metabolic clearance. OBJECTIVE: The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CL(u). In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CL(u). STUDY DESIGN: Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CL(u) was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures. RESULTS: CL and CL(u) were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The magnitude of the induction of CL was increased with decreased albumin concentrations, in addition to the presence of ethanol on admission, increased severity of head injury, tube feeding and total parenteral nutrition (TPN). The magnitude of induction of CL(u) was increased by older age, presence of ethanol on admission, increased severity of head injury, tube feeding, TPN, and if the patient had a post-injury neurosurgical procedure. The time to normalisation of CL(u) was significantly longer in patients with head injury plus other injuries compared with those with head injury alone. CONCLUSIONS: As has been reported with other drugs, TBI results in a significant increase in the metabolism of valproic acid. The patient factors identified in this study that resulted in an increase in the magnitude and time course of the induction of CL(u) (ethanol, older age, presence of a neurosurgical procedure, severity of TBI and presence of multiple non-TBI injuries) have all been reported to cause a shift to the anti-inflammatory mediators IL-4 and IL-10. This suggests that the increase in hepatic metabolism after TBI may be due to the increased presence of anti-inflammatory mediators in contrast to the inhibition effect of the pro-inflammatory mediators in non-TBI inflammation and infection.

Adenosine-induced modulation of excitatory amino acid transport across isolated brain arterioles.

OBJECT: Excitatory amino acid (EAA) uptake by neurons and glia acts synergistically with stereoselective transport across the blood-brain barrier (BBB) to maintain EAA homeostasis in the brain. The endogenous neuroprotectant adenosine counteracts many aspects of excitotoxicity by increasing cerebral blood flow and by producing pre- and postsynaptic actions on neurons. In the present study, the authors explored the effect of adenosine on EAA transport across the BBB. METHODS: The effects of adenosine on the permeability of the BBB and transport of aspartate and glutamate across the BBB were studied in a well-characterized isolated penetrating cerebral arteriole preparation suitable for simultaneous investigations of changes in diameter and permeability. At concentrations within the physiological to low pathophysiological range (10(-7)-10(-6) M), the net vectorial transport of [3H]L-glutamate or [3H]L-aspartate from blood to brain was significantly attenuated, whereas there was no effect of adenosine on paracellular BBB permeability to [14C]sucrose or [3H]D-aspartate. With higher concentrations of adenosine (10(-4) M and 10(-3) M) the net vectorial transport of [3H]L-glutamate and [3H]Laspartate returned toward baseline. At 10(-3) M, the permeability to [14C]sucrose was significantly altered, indicating a breakdown in the BBB. The effect of adenosine (10(-6) M) was blocked by theophylline, a blocker of the A1 and A2 receptors of adenosine. CONCLUSIONS: Adenosine-mediated modulation of glutamate and aspartate transport across the BBB is a novel physiological finding.

Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival.

BACKGROUND: A paucity of data exists concerning the prognostic usefulness of preoperative and postoperative imaging after resection of glioblastoma multiforme (GBM). This study aimed to connect outcome with imaging features of GBM. METHODS: Retrospective computer-assisted volumetric calculations quantified central necrotic (T0), gadolinium-enhanced (T1) and increased T2-weighted signal volumes (T2) in 70 patients with untreated GBM. Clinical and treatment data, including extent of resection (EOR), were obtained through chart review. T1 volume was used as a measure of solid tumor burden; and T2 volume, as an indicator of invasive isolated tumor cell (ITC) burden. Indicators of invasiveness included T2:T1 ratios as a propensity for ITC infiltration compared to solid tumor volumes and qualitative analysis of subependymal growth and infiltration of the basal ganglia, corpus callosum or brainstem. Cox multivariate analysis (CMVA) was used to identify significant associations between imaging features and survival. RESULTS: In the 70 patients studied, significant associations with reduced survival existed for gadolinium-enhancing tumor crossing the corpus callosum (odds ratio, 3.14) and with increased survival with gross total resection (GTR) (GTR median survival, 62 weeks versus 37 and 34 weeks for sub-total resection and biopsy, respectively). For a selected "GTR-eligible" subgroup of 52 patients, prolonged survival was associated with smaller preoperative gadolinium-enhancing volume (T1) and actual GTR. CONCLUSION: Some magnetic resonance (MR) imaging indicators of tumor invasiveness (gadolinium-enhancing tumor crossing the corpus callosum) and tumor burden (GTR and preoperative T1 volume in GTR-eligible subgroup) correlate with survival. However, ITC-infiltrative tumor burden (T2 volume) and "propensity" for ITC invasiveness (T2:T1 ratio) did not impact survival. These results indicate that while the ITC component is the ultimate barrier to cure for GBM, the pattern of spread and volumes of gadolinium-enhancing solid tumor are more robust indicators of prognosis.

Hemorrhagic complications of intracranial pressure monitors in children.

Intracranial pressure (ICP) monitoring plays a valuable role in the management of head injuries and other causes of raised ICP in the pediatric population. The purpose of this study was to investigate the incidence of hemorrhage after ICP monitor insertion, and to classify these complications in a clinically relevant manner. Hospital charts of 431 children (ages 0-16 years) admitted to a level I trauma center over a 2-year period were reviewed and 112 patients (134 insertions) who underwent intraparenchymal ICP monitoring were identified. The authors reviewed postoperative neuroradiological studies. One hundred and nineteen procedures were carried out without any hemorrhage (grade 0). After 10 insertions, a small punctate hemorrhage or localized subarachnoid hemorrhage occurred (grade 1). Three patients sustained an intracerebral hemorrhage that did not require evacuation or manifest as a new neurological deficit (grade 2). There were no hemorrhagic complications that necessitated evacuation or resulted in a noticeable change in the patient's clinical condition (grade 3). We propose a new grading system for hemorrhage after ICP monitor insertion. We found a complication rate close to 10% in our pediatric patients. Fortunately, these hemorrhages were clinically silent and no neurosurgical intervention was necessary. However, grade 1 and grade 2 hemorrhages may manifest with a false reading of high ICP, and the long-term consequences of these complications are not known. Of note, only 23% of these complications were reflected in the patients charts, which may explain the low complication rates reported in other studies that did not analyze postoperative neuroradiological studies.