Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, ...I Kur. Structural modifications of isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, and oral bioavailability.
IMPORTANCE: Trials often assess primary outcomes of traumatic brain injury at 6 months. Longer-term data are needed to assess outcomes for patients receiving surgical vs medical treatment for ...traumatic intracranial hypertension. OBJECTIVE: To evaluate 24-month outcomes for patients with traumatic intracranial hypertension treated with decompressive craniectomy or standard medical care. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of the Randomized Evaluation of Surgery With Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) randomized clinical trial data was performed for patients with traumatic intracranial hypertension (>25 mm Hg) from 52 centers in 20 countries. Enrollment occurred between January 2004 and March 2014. Data were analyzed between 2018 and 2021. Eligibility criteria were age 10 to 65 years, traumatic brain injury (confirmed via computed tomography), intracranial pressure monitoring, and sustained and refractory elevated intracranial pressure for 1 to 12 hours despite pressure-controlling measures. Exclusion criteria were bilateral fixed and dilated pupils, bleeding diathesis, or unsurvivable injury. INTERVENTIONS: Patients were randomly assigned 1:1 to receive a decompressive craniectomy with standard care (surgical group) or to ongoing medical treatment with the option to add barbiturate infusion (medical group). MAIN OUTCOMES AND MEASURES: The primary outcome was measured with the 8-point Extended Glasgow Outcome Scale (1 indicates death and 8 denotes upper good recovery), and the 6- to 24-month outcome trajectory was examined. RESULTS: This study enrolled 408 patients: 206 in the surgical group and 202 in the medical group. The mean (SD) age was 32.3 (13.2) and 34.8 (13.7) years, respectively, and the study population was predominantly male (165 81.7% and 156 80.0%, respectively). At 24 months, patients in the surgical group had reduced mortality (61 33.5% vs 94 54.0%; absolute difference, −20.5 95% CI, −30.8 to −10.2) and higher rates of vegetative state (absolute difference, 4.3 95% CI, 0.0 to 8.6), lower or upper moderate disability (4.7 −0.9 to 10.3 vs 2.8 −4.2 to 9.8), and lower or upper severe disability (2.2 −5.4 to 9.8 vs 6.5 1.8 to 11.2; χ27 = 24.20, P = .001). For every 100 individuals treated surgically, 21 additional patients survived at 24 months; 4 were in a vegetative state, 2 had lower and 7 had upper severe disability, and 5 had lower and 3 had upper moderate disability, respectively. Rates of lower and upper good recovery were similar for the surgical and medical groups (20 11.0% vs 19 10.9%), and significant differences in net improvement (≥1 grade) were observed between 6 and 24 months (55 30.0% vs 25 14.0%; χ22 = 13.27, P = .001). CONCLUSIONS AND RELEVANCE: At 24 months, patients with surgically treated posttraumatic refractory intracranial hypertension had a sustained reduction in mortality and higher rates of vegetative state, severe disability, and moderate disability. Patients in the surgical group were more likely to improve over time vs patients in the medical group. TRIAL REGISTRATION: ISRCTN Identifier: 66202560
Objectives: Increases in the extracellular concentration of the excitatory amino acids glutamate and aspartate during cerebral ischaemia in patients are well recognised. Less emphasis has been placed ...on the concentrations of the inhibitory amino acid neurotransmitters, notably γ-amino-butyric acid (GABA), despite evidence from animal studies that GABA may act as a neuroprotectant in models of ischaemia. The objective of this study was to investigate the concentrations of various excitatory, inhibitory and non-transmitter amino acids under basal conditions and during periods of cerebral ischaemia in patients with head injury or a subarachnoid haemorrhage. Methods: Cerebral microdialysis was established in 12 patients with head injury (n=7) or subarachnoid haemorrhage (n=5). Analysis was performed using high performance liquid chromatography for a total of 19 (excitatory, inhibitory and non-transmitter) amino acids. Patients were monitored in neurointensive care or during aneurysm clipping. Results: During stable periods of monitoring the concentrations of amino acids were relatively constant enabling basal values to be established. In six patients, cerebral ischaemia was associated with increases (up to 1350 fold) in the concentration of GABA, in addition to the glutamate and aspartate. Parallel increases in the concentration of glutamate and GABA were found (r=0.71, p<0.005). Conclusions: The results suggest that, in the human brain, acute cerebral ischaemia is not accompanied by an imbalance between excitatory and inhibitory amino acids, but by an increase in all neurotransmitter amino acids. These findings concur with the animal models of ischaemia and raise the possibility of an endogenous GABA mediated neuroprotective mechanism in humans.
Clinical microdialysis enables monitoring of the cerebral extracellular chemistry of neurosurgical patients. Introduction of the technique into different hospitals' neurosurgical units has resulted ...in variations in the method of application. There are several variables to be considered, including length of the catheter membrane, type of perfusion fluid, flow rate of perfusion fluid, and on-line compared with delayed analysis of samples. The objects of this study were as follows: 1) to determine the effects of varying catheter characteristics on substance concentration; 2) to determine the relative recovery and true extracellular concentration by varying the flow rate and extrapolating to zero flow; and 3) to compare substance concentration obtained using a bedside enzyme analyzer with that of off-line high-performance liquid chromatography (HPLC).
A specially designed bolt was used to conduct two adjacent microdialysis catheters into the frontal cortex of patients with head injury or poor-grade subarachnoid hemorrhage who were receiving ventilation. One reference catheter (10-mm membrane, perfused with Ringer's solution at 0.3 microl/minute) was constant for all studies. The other catheter was varied in terms of membrane length (10 mm or 30 mm), perfusion fluid (Ringer's solution or normal saline), and flow rate (0.1-1.5 microl/minute). The effect of freezing the samples on substance concentration was established by on-line analysis and then repeated analysis after storage at -70 degrees C for 3 months. Samples assayed with the bedside enzyme analyzer were reassessed using HPLC for the determination of glutamate concentrations.
Two adjacent microdialysis catheters that were identical in membrane length, perfusion fluid, and flow rate showed equivalent results. Variations in perfusion fluid and freezing and thawing of samples did not result in differences in substance concentration. Catheter length had a significant impact on substance recovery. Variations in flow rate enabled the relative recovery to be calculated using a modification of the extrapolation-to-zero-flow method. The recovery was approximately 70% at 0.3 microl/minute and 30% at 1 microl/minute (10-mm membrane) for all analytes. Glutamate results obtained with the enzyme analyzer showed good correlation with those from HPLC.
Microdialysis continuously monitors the chemistry of a small focal volume of the cerebral extracellular space. Conversely, positron emission tomography (PET) establishes metabolism of the whole ...brain, but only for the duration of the scan. The objective of this study was to apply both techniques to head-injured patients simultaneously to assess the relation between microdialysis (glucose, lactate, lactate/pyruvate L/P ratio, and glutamate) and PET (cerebral blood flow CBF, cerebral blood volume, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen) parameters. Microdialysis catheters were inserted into the frontal cerebral cortex and adipose tissue of the anterior abdominal wall of 17 severely head-injured patients. Microdialysis was performed during PET scans, with regions of interest defined by the location of the microdialysis catheter membrane. An intervention (hyperventilation) was performed in 13 patients. The results showed that combining PET and microdialysis to monitor metabolism in ventilated patients is feasible and safe, although logistically complex. There was a significant relation between the L/P ratio and the OEF (Spearman r = 0.69, P = 0.002). There was no significant relation between CBF and the microdialysis parameters. Moderate short-term hyperventilation appeared to be tolerated in terms of brain chemistry, although no areas were sampled by microdialysis where the OEF exceeded 70%. Hyperventilation causing a reduction of the arterial carbon dioxide tension by 0.9 kPa resulted in a significant elevation of the OEF, in association with a reduction in glucose, but no significant elevation in the L/P ratio or glutamate.
A prospective observational study was conducted to investigate whether episodes of ischemia are detected by continuous cerebral monitoring and whether such episodes are related to clinical outcome.
...Forty patients (35 after subarachnoid hemorrhage and 5 after complex aneurysm surgery) were monitored for a total of 174 days (mean, 4 d; range, 1-12 d). Brain tissue partial pressures of oxygen and carbon dioxide, pH, and temperature were measured continuously using Neurotrend sensors (Codman, Bracknell, England). Bedside analysis of extracellular chemistry was performed hourly using microdialysis. Glasgow Outcome Scale score was assessed at 3 to 6 months.
Patients with poor World Federation of Neurosurgical Societies grades (4 and 5) or an unfavorable outcome (severe disability or death) had, on average, higher lactate and lactate/pyruvate ratio but lower glucose/lactate ratio (P < or = 0.05). Brain tissue partial pressure of oxygen decreased to below 1.1 kPa in 78% of the patients for 18% (95% confidence interval, 12-24%) of time monitored. There were 197 episodes in which brain tissue partial pressures of oxygen decreased to below 1.1 kPa for at least 30 minutes. Unfavorable outcome was associated with more of these episodes (8.8 episodes; 95% confidence interval, 4.4-13.2 episodes) than favorable outcome (2.2 episodes; 95% confidence interval, 1.1-3.3 episodes), as well as an episode of glutamate levels of more than 10 micromol/L or lactate/pyruvate ratio more than 40 (P < 0.05, chi(2) test).
Intraparenchymal oximetry and microdialysis can detect but fail to predict the development of delayed cerebral ischemia. There were associations between episodes of low brain oxygen, abnormal microdialysis, and unfavorable outcome, but these associations were weak.
Aims Promising pre‐clinical results from laboratory studies of neuro‐protective drugs for the treatment of patients with stroke and head injury have not been translated into benefit during clinical ...trials. The objective of the study was to assess the feasibility of administrating a potential neuro‐protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain.
Methods Multimodality monitoring including cerebral and peripheral microdialysis was applied to five head‐injured patients on the neuro‐intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min−1) intravenous loading infusion for 5 min followed by a slow (1 ml min−1) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bi‐spectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids.
Results Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients.
Conclusions Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro‐protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro‐protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end‐points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.
Five patients with dysembryoplastic neuroepithelial tumour (DNT) showing extensive secondary haemorrhage, a finding not previously associated with these neoplasms, are described. The clinical ...presentations, neuroimaging findings, and histopathological features of these patients are reviewed. One patient, a previously asymptomatic 12 year old girl, presented with an acute intracerebral haemorrhage into a DNT. A further four young adults with histories of intractable partial and generalised seizures dating from childhood showed significant chronic haemorrhages within DNT, the MRI appearances in one patient giving a false impression of a cavernoma. Histopathology disclosed vascular abnormalities within these tumours which, together with other factors discussed, may have predisposed these tumours to haemorrhage.
The aim of this study was to investigate potential episodes of cerebral ischemia during surgery for large and complicated aneurysms, by examining the effects of arterial temporary clipping and the ...impact of confounding variables such as blood pressure and cerebrospinal fluid (CSF) drainage.
Brain tissue PO2, PCO2, and pH, as well as temperature and extracellular glucose, lactate, pyruvate, and glutamate were monitored in 46 patients by using multiparameter sensors and microdialysis. Baseline data showed that brain tissue PO2 decreased significantly, below a mean arterial pressure (MAP) threshold of 70 mm Hg. Further evidence of its relationship with cerebral perfusion pressure was shown by an increase in mean brain tissue PO2 after drainage of CSF from the basal cisterns (Wilcoxon test, p < 0.01). Temporary clipping was required in 31 patients, with a mean total duration of 14 minutes (range 3-52 minutes), causing brain tissue PO2 to decrease and brain tissue PCO2 to increase (Wilcoxon test, p < 0.01). In patients in whom no subsequent infarction developed in the monitored region, brain tissue PO2 fell to 11 mm Hg (95% confidence interval 8-14 mm Hg). A brain tissue PO2 level below 8 mm Hg for 30 minutes was associated with infarction in any region (p < 0.05 according to the Fisher exact test); other parameters were not predictive of infarction. Intermittent occlusions of less than 30 minutes in total had little effect on extracellular chemistry. Large glutamate increases were only seen in two patients, in both of whom brain tissue PO2 during occlusion was continuously lower than 8 mm Hg for longer than 38 minutes.
The brain tissue PO2 decreases with hypotension, and, when it is below 8 mm Hg for longer than 30 minutes during temporary clipping, it is associated with increasing extracellular glutamate levels and cerebral infarction.
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