Physiological thresholds for irreversible tissue damage in contusional regions following traumatic brain injury.

Cerebral ischaemia appears to be an important mechanism of secondary neuronal injury in traumatic brain injury (TBI) and is an important predictor of outcome. To date, the thresholds of cerebral blood flow (CBF) and cerebral oxygen utilization (CMRO(2)) for irreversible tissue damage used in TBI studies have been adopted from experimental and clinical ischaemic stroke studies. Identification of irreversibly damaged tissue in the acute phase following TBI could have considerable therapeutic and prognostic implications. However, it is questionable whether stroke thresholds are applicable to TBI. Therefore, the aim of this study was to determine physiological thresholds for the development of irreversible tissue damage in contusional and pericontusional regions in TBI, and to determine the ability of such thresholds to accurately differentiate irreversibly damaged tissue. This study involved 14 patients with structural abnormalities on late-stage MRI, all of whom had been studied with (15)O PET within 72 h of TBI. Lesion regions of interest (ROI) and non-lesion ROIs were constructed on late-stage MRIs and applied to co-registered PET maps of CBF, CMRO(2) and oxygen extraction fraction (OEF). From the entire population of voxels in non-lesion ROIs, we determined thresholds for the development of irreversible tissue damage as the lower limit of the 95% confidence interval for CBF, CMRO(2) and OEF. To test the ability of a physiological variable to differentiate lesion and non-lesion tissue, we constructed probability curves, demonstrating the ability of a physiological variable to predict lesion and non-lesion outcomes. The lower limits of the 95% confidence interval for CBF, CMRO(2) and OEF in non-lesion tissue were 15.0 ml/100 ml/min, 36.7 mumol/100 ml/min and 25.9% respectively. Voxels below these values were significantly more frequent in lesion tissue (all P < 0.005, Mann-Whitney U-test). However, a significant proportion of lesion voxels had values above these thresholds, so that definition of the full extent of irreversible tissue damage would not be possible based upon single physiological thresholds. We conclude that, in TBI, the threshold of CBF below which irreversible tissue damage consistently occurs differs from the classical CBF threshold for stroke (where similar methodology is used to define such thresholds). The CMRO(2) threshold is comparable to that reported in the stroke literature. At a voxel-based level, however (and in common with ischaemic stroke), the extent of irreversible tissue damage cannot be accurately predicted by early abnormalities of any single physiological variable.

Effects of moderate hyperventilation on cerebrovascular pressure-reactivity after head injury.

In volunteers, hyperventilation improves autoregulation. However, in head-injured patients, hyperventilation-induced deterioration and improvement of autoregulation have been reported. We have re-examined this question using an index of pressure reactivity. Thirty patients with severe or moderate head-injury were studied. Arterial blood pressure, cerebral perfusion pressure (CPP), and intracranial pressure (ICP) were recorded over 20 minute epochs separated by ten minutes of equilibration at baseline and during moderate (>3.5 kPa) hyperventilation. End-tidal CO2 was constant during each phase of data acquisition. Pressure reactivity was assessed using an index 'PRx' based on the response of ICP to spontaneous blood pressure changes. Hyperventilation decreased PaCO2 from 5.1 +/- 0.4 to 4.4 +/- 0.4 kPa (p < 0.0001). ICP decreased by 3.7 +/- 2.2 mmHg (p < 0.001). CPP increased by 5.9 +/- 8.2 mmHg (p < 0.001). Overall, PRx did not change significantly with hyperventilation. However, there was a significant negative correlation between baseline PRx and the change in PRx (r = -0.71, p < 0.0001). This suggests that patients with disturbed pressure-reactivity may improve, whereas patients with intact pressure reactivity remain largely unchanged. Our data suggest that the response of pressure reactivity to hyperventilation is heterogeneous. This could be due to hyperventilation-induced changes in cerebral metabolism, or the change in CPP.

Glucose metabolism in traumatic brain injury: a combined microdialysis and [18F]-2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) study.

Following traumatic brain injury, as a consequence of ionic disturbances and neurochemical cascades, glucose metabolism is affected. [18F]-2-Fluoro-2-deoxy-D-glucose (FDG) Positron Emission Tomography (FDG-PET) provides a measure of global and regional cerebral metabolic rate of glucose (rCMRglc), but only during the time of the scan. Microdialysis monitors energy metabolites over extended time periods, but only in a small focal volume of the brain. Our objective in this study is to assess the association of parameters derived from these techniques when applied to patients with traumatic brain injury. Eleven sedated, ventilated patients receiving intracranial pressure monitoring and managed using Addenbrooke's Neurosciences Critical Care Unit protocols were monitored. Dialysate values for glucose, lactate, pyruvate, and glutamate, and the lactate to glucose (L/G), lactate to pyruvate (L/P) and pyruvate to glucose (P/G) ratios were determined and correlated with rCMRglc. FDG-PET scans were performed within 24 hours (five patients), or between 1 and 4 days (two patients) or after 4 days (six patients). Two patients were rescanned 4 and 7 days after their initial scan. A 20 mm region of interest (ROI) was defined on co-registered CT scan on two contiguous slices around the microdialysis catheter. Mean (+/-sd) for rCMRglc was 19.1 +/- 5.5 micromol/100 g/min, and the corresponding microdialysis values were: glucose 1.4 +/- 1.4 mmol/ L; lactate 5.3 +/- 3.6 mmol/L; pyruvate 164.1 +/- 142.3 micromol/L; glutamate 15.0 +/- 14.7 micromol/L; L/G 11.0 +/- 16.0; L/P 27.3 +/- 7.9 and P/G 381 +/- 660. There were significant relations between rCMRglc and dialysate lactate (r = 0.58, P = 0.04); pyruvate (r = 0.57, P = 0.04), L/G (r = 0.55, P = 0.05), and the P/G (r = 0.56, P = 0.05) but not between rCMRglc and dialysate glucose, L/P or glutamate in this data set. The results suggest that increases in glucose utilization as assessed by FDG-PET in these patients albeit in mainly healthy tissue are associated with increases in dialysate lactate, pyruvate, L/G and the P/G ratio perhaps indicating a general rise in metabolism rather than a shift towards non-oxidative metabolism. Further observations are required with regions of interest (microdialysis catheters positioned) adjacent to mass lesions notably contusions.

Imaging of cerebral blood flow and metabolism in brain injury in the ICU.

The heterogeneity of the initial insult and subsequent pathophysiology has made both the study of human head injury and design of randomised controlled trials exceptionally difficult. The combination of multimodality bedside monitoring and functional brain imaging positron emission tomography (PET) and magnetic resonance (MR), incorporated within a Neurosciences Critical Care Unit, provides the resource required to study critically ill patients after brain injury from initial ictus through recovery from coma and rehabilitation to final outcome. Methods to define cerebral ischemia in the context of altered cerebral oxidative metabolism have been developed, traditional therapies for intracranial hypertension re-evaluated and bedside monitors cross-validated. New modelling and analytical approaches have been developed.

Propofol anesthesia for craniotomy: a double-blind comparison of remifentanil, alfentanil, and fentanyl.

For patients undergoing craniotomy, it is desirable to have stable and easily controllable hemodynamics during intense surgical stimulation. However, rapid postoperative recovery is essential to assess neurologic function. Remifentanil, an ultra-short-acting mu-opioid receptor agonist, may be the ideal agent to confer the above characteristics. In this prospective randomized study, we compared the hemodynamic stability, recovery characteristics, and the dose of propofol required for maintaining anesthesia supplemented with an infusion of remifentanil, alfentanil, or fentanyl in 34 patients scheduled for supratentorial craniotomy. With routine monitors in place, anesthesia was induced with propofol (2-3 mg/kg), atracurium (0.5 mg/kg), and either remifentanil (1 microg/kg), alfentanil (10 microg/kg), or fentanyl (2 micro/kg). The lungs were ventilated with O2/air to mild hypocapnia. Anesthesia was maintained with infusions of propofol (50-100 microg/kg/min) and either remifentanil (0.2 microg/kg/min), alfentanil (20 microg/kg/h), or fentanyl (2 microg/kg/h). There were no significant differences among the groups in the dose of propofol maintenance required, heart rate, or mean arterial pressure. However, the time to eye opening (minutes) was significantly shorter in the remifentanil compared to the alfentanil group (6+/-3; 21+/-14; P = 0.0027) but not the fentanyl group (15+/-9). We conclude that remifentanil is an appropriate opioid to use in combination with propofol during anesthesia for supratentorial craniotomy.

Imaging after brain injury.

Head injury remains an important cause of death and disability in young adults. This review will discuss the role of structural imaging using computed tomography (CT) and magnetic resonance imaging (MRI) and physiological imaging using CT perfusion, 131Xe CT, MRI and spectroscopy (MRS), single photon emission computed tomography, and positron emission tomography (PET) in the assessment, management, and prediction of outcome after head injury. CT allows rapid assessment of brain pathology which ensures patients who require urgent surgical intervention receive appropriate care. Although MRI provides greater spatial resolution, particularly within the posterior fossa and deep white matter, a complete assessment of the burden of injury requires imaging of cerebral physiology. Physiological imaging techniques can only provide 'snap shots' of physiology within the injured brain, but they can be repeated, and such data can be used to assess the impact of therapeutic interventions. Perfusion imaging based on CT techniques (xenon CT and CT perfusion) can be implemented easily in most hospital centres, and provide quantitative perfusion data in addition to structural images. PET imaging provides unparalleled insights into cerebral physiology and pathophysiology, but is not widely available and is primarily a research tool. MR technology continues to develop and is becoming generally available. Using a complex variety of sequences, MR can provide data concerning both structural and physiological derangements. Future developments with such imaging techniques should improve understanding of the pathophysiology of brain injury and provide data that should improve management and prediction of functional outcome.

Analysis of acute traumatic axonal injury using diffusion tensor imaging.

Traumatic axonal injury (TAI) contributes significantly to mortality and morbidity following traumatic brain injury (TBI), but is poorly characterized by conventional imaging techniques. Diffusion tensor imaging (DTI) may provide better detection as well as insights into the mechanisms of white matter injury. DTI data from 33 patients with moderate-to-severe TBI, acquired at a median of 32 h postinjury, were compared with data from 28 age-matched controls. The global burden of whole brain white matter injury (GB(WMI)) was quantified by measuring the proportion of voxels that lay below a critical fractional anisotropy (FA) threshold, identified from control data. Mechanisms of change in FA maps were explored using an Eigenvalue analysis of the diffusion tensor. When compared with controls, patients showed significantly reduced mean FA (p < 0.001) and increased apparent diffusion coefficient (ADC; p = 0.017). GB(WMI) was significantly greater in patients than in controls (p < 0.01), but did not distinguish patients with obvious white matter lesions seen on structural imaging. It predicted classification of DTI images as head injury with a high degree of accuracy. Eigenvalue analysis showed that reductions in FA were predominantly the result of increases in radial diffusivity (p < 0.001). DTI may help quantify the overall burden of white matter injury in TBI and provide insights into underlying pathophysiology. Eigenvalue analysis suggests that the early imaging changes seen in white matter are consistent with axonal swelling rather than axonal truncation. This technique holds promise for examining disease progression, and may help define therapeutic windows for the treatment of diffuse brain injury.

Predicting the response of intracranial pressure to moderate hyperventilation.

BACKGROUND: Hyperventilation may cause brain ischaemia after traumatic brain injury. However, moderate reductions in PaCO(2) are still an option in the management of raised intracranial pressure (ICP) under some circumstances. Being able to predict the ICP-response to such an intervention would be advantageous. We investigated the ability of pre-hyperventilation ICP and cerebrospinal compensatory reserve to predict the reduction in ICP achievable with moderate hyperventilation in head injured patients. METHODS: Thirty head injured patients requiring sedation and mechanical ventilation were investigated. ICP was monitored via an intraparenchymal probe and intracranial cerebrospinal compensatory reserve was assessed using an index (R(ap)) based on the relationship between mean ICP and its pulse amplitude. Measurements were made at a constant level of PaCO(2) during a 20-minute baseline period. The patients were then subjected to an acute decrease in PaCO(2) of approximately 1 kPa and, after an equilibration period of 10 minutes, measurements were again made at a constant level of PaCO(2) for a further 20 minutes. A multiple linear regression model, incorporating baseline PaCO(2), ICP, and R(ap) was used to identify the relevant predictors of ICP reduction. FINDINGS: Baseline ICP and R(ap) were both significant predictors of ICP-reduction (p=0.02 and 0.001 respectively) with R(ap) being the more powerful parameter. CONCLUSIONS: A model based on cerebrospinal compensatory reserve and ICP can predict the achievable ICP-reduction and may potentially be used to optimise patient selection and intensity of hyperventilation.

A comparison of remifentanil and fentanyl in patients undergoing carotid endarterectomy.

BACKGROUND AND AIM: We investigated the haemodynamic stability and emergence characteristics of isoflurane/nitrous oxide anaesthesia supplemented with remifentanil or fentanyl in patients undergoing carotid endarterectomy. METHODS: Anaesthesia was induced with propofol (1-2 mg kg-1) and either remifentanil (0.5 microgram kg-1) or fentanyl (1 microgram kg-1), followed by an infusion of remifentanil (0.2 microgram kg-1 min-1) or fentanyl (2 micrograms kg-1 h-1). RESULTS: There were no significant differences between the groups in haemodynamic variables, postoperative pain, nausea or vomiting. After induction there was a significant decrease in mean arterial pressure for both groups (P < 0.001) and a decrease in heart rate (P = 0.001) in the remifentanil group. In both groups these haemodynamic changes continued during maintenance of anaesthesia (P < 0.05). The time to eye opening after surgery was significantly shorter with remifentanil compared with fentanyl (6.62 +/- 3.89 vs. 18.0 +/- 15.18 min, P = 0.015). CONCLUSION: Remifentanil appears to be a comparable opioid to fentanyl when supplementing isoflurane/nitrous oxide anaesthesia for carotid endarterectomy.

Assessment of the Caradyne WhisperFlow for administration of continuous positive airway pressure in a 3 Tesla magnetic resonance scanner.

Demand for magnetic resonance investigations in critically ill patients is increasing. While these patients frequently need ventilatory support, not all of them require controlled ventilation and many may be treated with continuous positive airway pressure. Controlled ventilation, with the concurrent need for sedation, may be inappropriate when airway physiology is being studied and may retard weaning. No commercially available ventilator designed for the magnetic resonance environment can deliver high flow continuous positive airway pressure. We tested the Caradyne Whisperflow flow generator and five Whisperflow valves (2.5-15 cmH2O airway pressure) within a 3 Tesla environment for safety and possible dysfunction. All components had minimal ferromagnetic properties and tests showed no clinically relevant change in flow delivery or oxygen concentration in the magnetic field. In addition, the airway pressure generated by the valves was not affected by the magnetic field. We conclude that the tested system can be safely used in a 3 Tesla magnetic resonance environment.

Modification of gibberellin production and plant development in Arabidopsis by sense and antisense expression of gibberellin 20-oxidase genes.

Gibberellin (GA) 20-oxidase catalyses consecutive steps late in GA biosynthesis in plants. In Arabidopsis, the enzyme is encoded by a gene family of at least three members (AtGA20ox1, AtGA20ox2 and AtGA20ox3) with differential patterns of expression. The genes are regulated by feedback from bioactive GAs, suggesting that the enzymes may be involved in regulating GA biosynthesis. To investigate this, we produced transgenic Arabidopsis expressing sense or antisense copies of each of the GA 20-oxidase cDNAs. Over-expression of any of the cDNAs gave rise to seedlings with elongated hypocotyls; the plants flowered earlier than controls in both long and short days and were 25% taller at maturity. GA analysis of the vegetative rosettes showed a two- to threefold increase in the level of GA4, indicating that GA 20-oxidase normally limits bioactive GA levels. Plants expressing antisense copies of AtGA20ox1 had short hypocotyls and reduced rates of stem elongation. This was reflected in reduced levels of GA4 in both rosettes and shoot tips. In short days, flowering was delayed and the reduction in the rate of stem elongation was greater. Antisense expression of AtGA20ox2 had no apparent effects in long days, but stem growth in one transgenic line grown in short days was reduced by 20%. Expression of antisense copies of AtGA20ox3 had no visible effect, except for one transgenic line that had short hypocotyls. These results demonstrate that GA levels and, hence, plant growth and development can be modified by manipulation of GA 20-oxidase expression in transgenic plants.

Effects of propofol on cerebral oxygenation and metabolism after head injury.

BACKGROUND: Flow-metabolism coupling is thought to be deranged after traumatic brain injury, while the effects of propofol on flow-metabolism coupling are controversial. We have used a step increase in target plasma propofol concentration in head injured patients to explore flow-metabolism coupling in these patients. METHODS: Ten patients with a moderate to severe head injury received a step increase in propofol target controlled infusion of 2 microg x ml(-1). Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Arterial-jugular venous oxygen differences (AVDO(2)) were measured and all patients had cortical function monitoring (EEG). RESULTS: The step increase in propofol led to a large increase in EEG burst-suppression ratio (0% (range 0-1.1) to 46.1% (range 0-61.7), P<0.05); however, this did not significantly change tissue gas levels, tissue chemistry, or AVDO(2). CONCLUSIONS: Flow-metabolism coupling remains intact during a step increase in propofol after traumatic brain injury. The EEG burst-suppression induced by propofol after traumatic brain injury does not appear to be a useful therapeutic tool in reducing the level of regional ischaemic burden.

Assessment of the Ventrix parenchymal intracranial pressure monitoring probe (NL950-P) and Monitor (NL950-100) in a 3 Tesla magnetic resonance scanner.

Magnetic resonance (MR) imaging and spectroscopy provide important information in patients with acute head injury. However, optimal patient management requires intracranial pressure (ICP) monitoring. There are few reports on the use of ICP sensors in an MR environment. We tested the Ventrix parenchymal intracranial pressure monitoring probe and monitor (Integra Neurosciences, USA), modified by the use of a fibre-optic extension cable, within a 3 Tesla MR system. The device performed well in the MR environment, but one element within the fibre-optic extension was significantly ferromagnetic. The ICP probe produced a small susceptibility artefact on spin echo images, and a larger artefact on gradient echo images. The MR safety of the integrated system is probably acceptable, but could be easily improved with minor modifications. Although the system is MR compatible and produces generally acceptable imaging even at 3 Tesla, there is significant degradation of image quality during gradient echo sequences.

TETRASPORE encodes a kinesin required for male meiotic cytokinesis in Arabidopsis.

A key step in pollen formation is the segregation of the products of male meiosis into a tetrad of microspores, each of which develops into a pollen grain. Separation of microspores does not occur in tetraspore (tes) mutants of Arabidopsis thaliana, owing to the failure of male meiotic cytokinesis. tes mutants thus generate large 'tetraspores' containing all the products of a single meiosis. Here, we report the positional cloning of the TES locus and details of the role played by the TES product in male cytokinesis. The predicted TES protein includes an N-terminal domain homologous to kinesin motors and a C-terminus with little similarity to other proteins except for a small number of plant kinesins. These include the Arabidopsis HINKEL protein and NACK1 and two from tobacco (Nishihama et al., 2002), which are involved in microtubule organization during mitotic cytokinesis. Immunocytochemistry shows that the characteristic radial arrays of microtubules associated with male meiotic cytokinesis fail to form in tes mutants. The TES protein therefore is likely to function as a microtubule-associated motor, playing a part either in the formation of the radial arrays that establish spore domains following meiosis, or in maintaining their stability.

Cerebrovascular pressure reactivity is related to global cerebral oxygen metabolism after head injury.

BACKGROUND: After head injury, impaired cerebrovascular autoregulation has been associated with abnormally high or low cerebral blood flow. The physiological relevance of cerebral blood flow levels is difficult to assess in these patients, whose cerebral metabolic rate for oxygen (CMRO(2)) is known to be abnormal. Investigation of these relations requires quantitative measures of cerebral blood flow and CMRO(2), to allow assessment of oxygen supply and demand relations. OBJECTIVES: To investigate the relation between dysautoregulation and global cerebral oxygen metabolism following head injury. METHODS: Using positron emission tomography, global cerebral blood flow, CMRO(2), and oxygen extraction fraction were determined in 22 patients who were investigated in 26 examinations on days 1 to 11 (mean (SD), 3.5 (2.3)) after head injury. Cerebrovascular pressure reactivity was assessed using a pressure reactivity index, calculated as the moving linear correlation coefficient between mean arterial blood pressure and intracranial pressure. Outcome was assessed six months after injury using the Glasgow outcome scale. RESULTS: Low CMRO(2) was associated with disturbed pressure reactivity (inverse function, R(2) = 0.21, p = 0.018) and there was a correlation between disturbed pressure reactivity and oxygen extraction fraction (quadratic function, R(2) = 0.55, p = 0.0001). There was no significant relation between pressure reactivity and cerebral blood flow. An unfavourable outcome was associated with disturbed pressure reactivity. There was no significant relation between outcome and CMRO(2) or oxygen extraction fraction. CONCLUSIONS: There is a close relation between dysautoregulation and abnormal cerebral metabolism but not blood flow. Further studies are needed to determine whether metabolic dysfunction is a result of or a cause of disturbed pressure reactivity, and to establish if there is a relation between cerebral oxygen metabolism and outcome.

Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent.

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.