Monitoring vigabatrin in head injury patients by cerebral microdialysis: obtaining pharmacokinetic measurements in a neurocritical care setting

AimsThe aims were to determine blood–brain barrier penetration and brain extracellular pharmacokinetics for the anticonvulsant vigabatrin (VGB; γ-vinyl-γ-aminobutyric acid) in brain extracellular fluid and plasma from severe traumatic brain injury (TBI) patients, and to measure the response of γ-aminobutyric acid (GABA) concentration in brain extracellular fluid.MethodsSevere TBI patients (n = 10) received VGB (0.5 g enterally, every 12 h). Each patient had a cerebral microdialysis catheter; two patients had a second catheter in a different region of the brain. Plasma samples were collected 0.5 h before and 2, 4 and 11.5 h after the first VGB dose. Cerebral microdialysis commenced before the first VGB dose and continued through at least three doses of VGB. Controls were seven severe TBI patients with microdialysis, without VGB.ResultsAfter the first VGB dose, the maximum concentration of VGB (C_max) was 31.7 (26.9–42.6) μmol l⁻¹ (median and interquartile range for eight patients) in plasma and 2.41 (2.03–5.94) μmol l⁻¹ in brain microdialysates (nine patients, 11 catheters), without significant plasma–brain correlation. After three doses, median C_max in microdialysates increased to 5.22 (4.24–7.14) μmol l⁻¹ (eight patients, 10 catheters). Microdialysate VGB concentrations were higher close to focal lesions than in distant sites. Microdialysate GABA concentrations increased modestly in some of the patients after VGB administration.ConclusionsVigabatrin, given enterally to severe TBI patients, crosses the blood–brain barrier into the brain extracellular fluid, where it accumulates with multiple dosing. Pharmacokinetics suggest delayed uptake from the blood.     

Cerebral microdialysis methodology--evaluation of 20 kDa and 100 kDa catheters

Microdialysis monitoring of cerebral metabolism is now performed in several neuro-intensive care units. Conventional microdialysis utilizes CMA70 catheters with 20 kDa molecular weight cut-off membranes enabling the measurement of small molecules such as glucose, lactate, pyruvate and glutamate. The CMA71 100 kDa molecular weight cut-off microdialysis catheter has recently been introduced to allow detection of larger molecules such as cytokines. The objective of this study was to perform in vitro and in vivo testing of the CMA71 microdialysis catheter, comparing its performance with the CMA70. In vitro comparison studies of three of each catheter using reference analyte solutions, demonstrated equivalent recovery for glucose, lactate, pyruvate and glutamate (range 94-97% for CMA70 and 88-103% for CMA71). In vivo comparison involved intracranial placement of paired CMA70 and CMA71 catheters (through the same cranial access device) in six patients with severe traumatic brain injury. Both catheters were perfused with CNS Perfusion Fluid without dextran at 0.3 microl min-1 with hourly sampling and bedside analysis on a CMA600 microdialysis analyser. The two catheters yielded equivalent results for glucose, lactate, pyruvate, glutamate and lactate/pyruvate ratio. CMA71 microdialysis catheters can, therefore, be used for routine clinical monitoring of extracellular substances, as well as for their intended research role of larger molecular weight protein sampling.     

Intersubject variability and reproducibility of 15O PET studies.

Oxygen-15 positron emission tomography (15O PET) can provide important data regarding patients with head injury. We provide reference data on intersubject variability and reproducibility of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolism (CMRO2) and oxygen extraction fraction (OEF) in patients and healthy controls, and explored alternative ways of assessing reproducibility within the context of a single PET study. In addition, we used independent measurements of CBF and CMRO2 to investigate the effect of mathematical correlation on the relationship between flow and metabolism. In patients, intersubject coefficients of variation (CoV) for CBF, CMRO2 and OEF were larger than in controls (32.9%+/-2.2%, 23.2%+/-2.0% and 22.5%+/-3.4% versus 13.5%+/-1.4%, 12.8%+/-1.1% and 7.3%+/-1.2%), while CoV for CBV were lower (15.2%+/-2.1% versus 22.5%+/-2.8%) (P<0.001). The CoV for the test-retest reproducibility of CBF, CBV, CMRO2 and OEF in patients were 2.1%+/-1.5%, 3.8%+/-3.0%, 3.7%+/-3.0% and 4.6%+/-3.5%, respectively. These were much lower than the intersubject CoV figures, and were similar to alternative measures of reproducibility obtained by fractionating data from a single study. The physiological relationship between flow and metabolism was preserved even when mathematically independent measures were used for analysis. These data provide a context for the design and interpretation of interventional PET studies. While ideally each centre should develop its own bank of such data, the figures provided will allow initial generic approximations of sample size for such studies.     

The role of tissue oxygen monitoring in patients with acute brain injury

Cerebral ischaemia is implicated in poor outcome after braininjury, and is a very common post-mortem finding. The inabilityof the brain to store metabolic substrates, in the face of highoxygen and glucose requirements, makes it very susceptible toischaemic damage. The clinical challenge, however, remains thereliable antemortem detection and treatment of ischaemic episodesin the intensive care unit. Outcomes have improved in the traumaticbrain injury setting after the introduction of progressive protocol-driventherapy, based, primarily, on the monitoring and control ofintracranial pressure, and the maintenance of an adequate cerebralperfusion pressure through manipulation of the mean arterialpressure. With the increasing use of multi-modal monitoring,the complex pathophysiology of the injured brain is slowly beingunravelled, emphasizing the heterogeneity of the condition,and the requirement for individualization of therapy to preventsecondary adverse hypoxic cerebral events. Brain tissue oxygenpartial pressure (     

Interaction between brain chemistry and physiology after traumatic brain injury: impact of autoregulation and microdialysis catheter location

Bedside monitoring of cerebral metabolism in traumatic brain injury (TBI) with microdialysis is gaining wider clinical acceptance. The objective of this study was to examine the relationship between the fundamental physiological neuromonitoring modalities intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygen (P(bt)O(2)), and cerebrovascular pressure reactivity index (PRx), and cerebral chemistry assessed with microdialysis, with particular focus on the lactate/pyruvate (LP) ratio as a marker of energy metabolism. Prospectively collected observational neuromonitoring data from 97 patients with TBI, requiring neurointensive care management and invasive cerebral monitoring, were analyzed. A linear mixed model analysis was used to account for individual patient differences. Perilesional tissue chemistry exhibited a significant independent relationship with ICP, P(bt)O(2) and CPP thresholds, with increasing LP ratio in response to decrease in P(bt)O(2) and CPP, and increase in ICP. The relationship between CPP and chemistry depended upon the state of PRx. Within the studied physiological range, tissue chemistry only changed in response to increasing ICP or drop in P(bt)O(2)<1.33 kPa (10 mmHg). In agreement with previous studies, significantly higher levels of cerebral lactate (p<0.001), glycerol (p=0.013), LP ratio (p<0.001) and lactate/glucose (LG) ratio (p=0.003) were found in perilesional tissue, compared to "normal" brain tissue (Mann-Whitney test). These differences remained significant following adjustment for the influences of other important physiological parameters (ICP, CPP, P(bt)O(2), P(bt)CO(2), PRx, and brain temperature; mixed linear model), suggesting that they may reflect inherent tissue properties related to the initial injury. Despite inherent biochemical differences between less-injured brain and "perilesional" cerebral tissue, both tissue types exhibited relationships between established physiological variables and biochemistry. Decreases in perfusion and oxygenation were associated with deteriorating neurochemistry and these effects were more pronounced in perilesional tissue and when cerebrovascular reactivity was impaired.     

Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra

Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (+/-SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1alpha 19.7+/-7.6%, IL-1beta 23.9+/-10.5%, and IL-1ra 20.9+/-6.3%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1alpha 5.6+/-14.8 pg/mL, IL-1beta 10.4+/-14.7 pg/mL, and IL-1ra 2796+/-2918 pg/mL. IL-1ra was consistently much higher than IL-1alpha and IL-1beta. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1beta and increasing IL-1ra (Spearman r=0.59, p=0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r=-0.57, p=0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1beta ratio, were associated with better outcome (Mann Whitney, p=0.018 and p=0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1beta in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.     

An investigation of auto-reactivity after head injury

Murine models of CNS injury show auto-reactive T cell responses directed at myelin antigens, associated with improved neuronal survival and functional recovery. This pilot study shows, for the first time, that similar immune responses against myelin occur in human traumatic brain injury (TBI), with an expansion of lymphocytes recognising myelin basic protein observed in 40% of patients studied. "Reactive" patients did not have greater contusion volume on imaging, but were younger than the "unreactive" subgroup and tended towards a more favorable outcome. These findings are consistent with the concept of "beneficial autoimmunity".     

Cerebrovascular reactivity during hypothermia and rewarming

Background: Experimental evidence from a murine model of traumatic braininjury (TBI) suggests that hypothermia followed by fast rewarmingmay damage cerebral microcirculation. The effects of hypothermiaand subsequent rewarming on cerebral vasoreactivity in humanTBI are unknown. Methods: This is a retrospective analysis of data acquired during a prospective,observational neuromonitoring and imaging data collection project.Brain temperature, intracranial pressure (ICP), and cerebrovascularpressure reactivity index (PRx) were continuously monitored. Results: Twenty-four TBI patients with refractory intracranial hypertensionwere cooled from 36.0 (0.9) to 34.2 (0.5)°C [mean (SD),P < 0.0001] in 3.9 (3.7) h. Induction of hypothermia [averageduration 40 (45) h] significantly reduced ICP from 23.1 (3.6)to 18.3 (4.8) mm Hg (P < 0.05). Hypothermia did not impaircerebral vasoreactivity as average PRx changed non-significantlyfrom 0.00 (0.21) to –0.01 (0.21). Slow rewarming up to37.0°C [rate of rewarming, 0.2 (0.2)°C h^–1] didnot increase ICP [18.6 (6.2) mm Hg] or PRx [0.06 (0.18)]. However,in 17 (70.1%) out of 24 patients, rewarming exceeded the braintemperature threshold of 37°C. In these patients, the averagebrain temperature was allowed to increase to 37.8 (0.3)°C(P < 0.0001), ICP remained stable at 18.3 (8.0) mm Hg (P= 0.74), but average PRx increased to 0.32 (0.24) (P < 0.0001),indicating significant derangement in cerebrovascular reactivity.After rewarming, PRx correlated independently with brain temperature(R = 0.53; P < 0.05) and brain tissue O₂ (R = 0.66; P <0.01). Conclusions: After moderate hypothermia, rewarming exceeding the 37°Cthreshold is associated with a significant increase in averagePRx, indicating temperature-dependent hyperaemic derangementof cerebrovascular reactivity.