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Biomedical subjects

Tim D Fryer

Publications and source records attributed to Tim D Fryer.

At least 19 recordsLinked to original sources
PubMed2007

Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism.

OBJECTIVE: To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. DESIGN: A prospective interventional study. SETTING: A specialist neurocritical care unit. PATIENTS: Ten healthy volunteers and 30 patients within 10 days of closed head injury. INTERVENTIONS: Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36+/-3 and 29+/-2 torr. MEASUREMENTS AND MAIN RESULTS: We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17+/-22 vs. 2+/-3 mL; p<or=.05), with worse matching of oxygen delivery to demand (p<.001). Hyperventilation consistently reduced cerebral blood flow (p<.001) and resulted in increases in oxygen extraction fraction and ischemic brain volume (17+/-22 vs. 88+/-66 mL; p<.0001), which were undetected by SjO2 monitoring. Mean CMRO2 was slightly increased following hyperventilation, but responses were extremely variable, with 28% of patients demonstrating a decrease in CMRO2 that exceeded 95% prediction intervals for zero change in one or more regions. CMRO2 correlated with cerebral electrophysiology, and cortical somatosensory evoked potential amplitudes were significantly increased by hyperventilation. CONCLUSIONS: The acute cerebral blood flow reduction and increase in CMRO2 secondary to hyperventilation represent physiologic challenges to the traumatized brain. These challenges exhaust physiologic reserves in a proportion of brain regions in many subjects and compromise oxidative metabolism. Such ischemia is underestimated by common bedside monitoring tools and may represent a significant mechanism of avoidable neuronal injury following head trauma.

Adolescent↗
PubMed2006

Comparison of lorazepam [7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one] occupancy of rat brain gamma-aminobutyric acid(A) receptors measured using in vivo [3H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester) binding and [11C]flumazenil micro-positron emission tomography.

The occupancy by lorazepam of the benzodiazepine binding site of rat brain GABA(A) receptors was compared when measured using either in vivo binding of [(3)H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester) in terminal studies or [(11)C]flumazenil binding in anesthetized animals assessed using a small animal positron emission tomography (PET) scanner (micro-PET). In addition, as a bridging study, lorazepam occupancy was measured using [(3)H]flumazenil in vivo binding in rats anesthetized and dosed under micro-PET conditions. Plasma lorazepam concentrations were also determined, and for each occupancy method, the concentration required to produce 50% occupancy (EC(50)) was calculated because this parameter is independent of the route of lorazepam administration. For the in vivo binding assay, lorazepam was dosed orally (0.1-10 mg/kg), whereas for the micro-PET study, lorazepam was given via the i.v. route as a low dose (0.75 mg/kg bolus) and then a high dose (0.5 mg/kg bolus then 0.2 mg/ml infusion). The lorazepam plasma EC(50) in the [(11)C]flumazenil micro-PET study was 96 ng/ml [95% confidence intervals (CIs) = 74-124 ng/ml], which was very similar to the [(3)H]flumazenil micro-PET simulation study (94 ng/ml; 95% CI = 63-139 ng/ml), which in turn was comparable with the [(3)H]flumazenil in vivo binding study (134 ng/ml; 95% CI = 119-151 ng/ml). These data clearly show that despite the differences in dosing (i.v. in anesthetized versus orally in conscious rats) and detection (in vivo dynamic PET images versus ex vivo measurements in filtered and washed brain homogenates), [(11)C]flumazenil micro-PET produces results similar to [(3)H]flumazenil in vivo binding.

Animals↗
PubMed2006

Imaging of brain hypoxia in permanent and temporary middle cerebral artery occlusion in the rat using 18F-fluoromisonidazole and positron emission tomography: a pilot study.

In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. Previous human studies using 18F-fluoromisonidazole and positron emission tomography (18F-FMISO PET) have shown high tracer retention indicative of tissue hypoxia, which had normalized at repeat scan >48 h later. In the only validation study of 18F-FMISO, using ex vivo autoradiography in thread middle cerebral artery occluded (MCAo) rats, there was unexpected high uptake as late as 22 h after reperfusion, raising questions about the use of 18F-FMISO as a hypoxia tracer. Here we report a pilot study of 18F-FMISO PET in experimental stroke. Spontaneous hypertensive rats were subjected to distal clip MCAo. Three-hour dynamic PET was performed in 7 rats: 3 normals, 1 with permanent MCAo (two sessions: 30 mins and 48 h after clip), and 3 with temporary MCAo (45 mins, n=1; 120 mins, n=2; scanning started 30 mins after clip removal). Experiments were terminated by perfusion-fixation for standard histopathology. Late tracer retention was assessed by both compartmental modelling and simple side-to-side ratios. In the initial PET session of the permanent MCAo rat, striking trapping of 18F-FMISO was observed in the affected cortex, which had normalized 48 h later; histopathology revealed pannecrosis. In contrast, there was no demonstrable tracer retention in either temporary MCAo models, and histopathology showed ischemic changes only. These results document elevated 18F-FMISO uptake in the stroke area only in the early phase of MCAo, but not after early reperfusion nor when tissue necrosis has developed. These findings strongly support the validity of 18F-FMISO as a marker of viable hypoxic tissue/penumbra after stroke.

Anesthesia↗
PubMed2006

Differences in orbitofrontal activation during decision-making between methadone-maintained opiate users, heroin users and healthy volunteers.

OBJECTIVE: Previously, we reported that opiate users enrolled in methadone treatment made 'risky' choices on a decision-making task following a loss of points compared with heroin users and healthy volunteers. One possible explanation for this behaviour is that methadone users were less sensitive to punishment on immediately preceding unsuccessful trials. METHODS: We sought to explore this finding from a neural perspective by performing a post hoc analysis of data from a previous [see text] positron emission tomography study. We restricted the analysis to the opiate groups and controls, assessing differences between opiate users on methadone and those on heroin. RESULTS: We found significant over-activation in the lateral orbitofrontal cortex (OFC) in methadone users compared with both heroin users and controls concomitant with the greatest overall tendency to 'play risky'. Heroin users showed significant under-activation in this area compared with the other two groups whilst exhibiting the greatest overall tendency to 'play safe'. Correlational analysis revealed that abnormal task-related activation of the left OFC was associated with the dose of methadone in methadone users and with the duration of intravenous heroin use in heroin users. 'Playing safe' following a loss of points was also negatively correlated with the activation of pregenual anterior cingulate and insula cortex in controls, but not in opiate users. CONCLUSION: Our findings suggest that the interplay between processes involved in integrating penalty information for the purpose of response selection may be altered in opiate users. This change was reflected differentially in task-related pattern of OFC activation depending on the opiate used.

Adult↗
PubMed2006

Local relationships between restricted water diffusion and oxygen consumption in the ischemic human brain.

BACKGROUND AND PURPOSE: MR is widely used to depict still ischemic but viable tissue in acute stroke. However, the relationship between the apparent diffusion coefficient (ADC) and energy failure from reduced oxygen supply are unknown in man. METHODS: Acute carotid-territory stroke patients were studied prospectively with both diffusion tensor-imaging and back-to-back steady-state 15O-PET. Substantial numbers of voxels with oxygen extraction fraction >0.70 (ie, significant ongoing hypoxia) were identified in 3 patients (imaged at 7, 16 and 21 hours after stroke onset). In this voxel population, the quantitative relationships between the ADC and cerebral metabolic rate of oxygen (CMRO2), and ADC and cerebral blood flow (CBF), were assessed. RESULTS: The ADC remained essentially unchanged until CBF reached values approximately 20 mls/100g per min, beyond which it declined linearly. In contrast, except when severely reduced, the ADC was a poorer predictor of CMRO2. For both CBF and CMRO2, however, the relationship with ADC became steeper with longer times since onset, ie, the same ADC reflected lower perfusion and CMRO2 with elapsed time. CONCLUSIONS: Despite the small sample and late times from stroke onset, the findings indicate that the degree of restricted water diffusion reliably reflects the severity of oxygen deprivation below the penumbral threshold but is less strongly related to metabolic disruption, which may explain why the ADC does not reliably predict tissue outcome. However, the same degree of diffusion restriction may correspond to greater severity of tissue disruption with elapsing time, which has relevance for stroke therapy. Time elapsed since stroke onset should be taken into account when interpreting ADC declines and in voxel-based infarct prediction models.

Aged, 80 and over↗
PubMed2006

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.

Adolescent↗
PubMed2006

Imaging endothelin ET(B) receptors using [18F]-BQ3020: in vitro characterization and positron emission tomography (microPET).

The endothelin (ET) receptor system has been shown to play a role in a number of vascular diseases. We have synthesized 18F-and 11C-labeled radioligands to enable in vivo imaging of the fundamental processes involved in ET receptor pharmacology in normal and diseased tissue using positron emission tomography (PET). One aim is to elucidate the proposed role of the ET(B) subtype as clearing receptor, removing ET-1 from the circulation, and whether this is an important mechanism to limit the detrimental effects caused by upregulated ET-1 in disease. To image ET(B) receptors we have labeled the selective agonist BQ3020 with 18F. In vitro characterization verified that [18F]-BQ3020 bound with a single subnanomolar affinity (K(D) = 0.34 +/- 0.10 nM, B(max) = 9.23 +/- 3.70 fmol/mg protein) to human left ventricle. Binding of [18F]-BQ3020 to human kidney was inhibited by ET-1 and unlabeled BQ3020 but not by the ET(A) selective antagonist FR139317, confirming that selectivity for the ET(B) receptor was retained. In vitro autoradiography revealed, as expected, high levels of ET(B) receptor densities in lung and kidney medulla, whereas kidney cortex and heart showed lower levels of ET(B) receptor densities. Furthermore, a high level of [18F]-BQ3020 binding was found to colocalize to macrophages in atherosclerotic coronary arteries. MicroPET studies demonstrated high uptake of [18F]-BQ3020 in ET(B) receptor-rich tissue, including lung, liver and kidney. The in vivo biodistribution of [18F]-BQ3020 was comparable to that previously obtained for [18F]-ET-1, supporting our hypothesis that the ET(B) receptor plays a significant role in the uptake of ET-1. In conclusion, [18F]-BQ3020 has retained high affinity and selectivity, allowing imaging of ET(B) receptor distributions in vitro and in vivo in human and animal tissue. Furthermore, in vitro data suggest that [18F]-BQ3020 potentially can be used to image atherosclerotic lesions in vivo using PET.

Animals↗
PubMed2005

Declarative memory impairments in Alzheimer's disease and semantic dementia.

Semantic dementia (SD) and Alzheimer's disease (AD) are both disorders in which early pathology affects the temporal lobe yet they produce distinct syndromes of declarative memory impairment-loss of established semantic knowledge with relatively preserved episodic memory in the former and the converse in the latter. Groups with mild SD and mild AD who showed a double dissociation in these two aspects of declarative memory were studied-the SD group's episodic memory and the AD group's semantic knowledge each being comparable to controls. Positron emission tomography and volumetric magnetic resonance imaging were used to map deficits in regional cerebral metabolic rate and mesial temporal lobe (MTL) atrophy, respectively. Episodic memory impairment in AD was associated with dysfunction of an integrated network (mesial temporal lobe, mamillary bodies, dorso-mesial thalamus and posterior cingulate). Semantic memory impairment in SD was associated with bilateral rostral temporal lobe hypometabolism. The SD group had comparable MTL atrophy and hypometabolism to that found in AD but the remainder of their limbic-diencephalic network was preserved suggesting that the latter explains their ability to acquire new episodic memories. The results challenge the view that amnesia in early AD can be explained by the degree of MTL damage alone while showing that semantic impairment can occur with damage restricted to the rostral temporal lobes.

Alzheimer Disease↗
PubMed2005

Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Carotid endarterectomy is currently guided by angiographic appearance on the assumption that the most stenotic lesion visible at angiography is likely to be the lesion from which future embolic events will arise. However, risk of plaque rupture, the most common cause of atherosclerosis-related thromboembolism, is dictated by the composition of the plaque, in particular the degree of inflammation. Angiography may, therefore, be an unreliable method of identifying vulnerable plaques. In this study, plaque inflammation was quantified before endarterectomy using the combination of 18F fluorodeoxyglucose positron (FDG)-emission tomography (PET) and high-resolution MRI (HRMRI). METHODS: Twelve patients, all of whom had suffered a recent transient ischemic attack, had a severe stenosis in the ipsilateral carotid artery, and were awaiting carotid endarterectomy underwent FDG-PET and HRMRI scanning. A semiquantitative estimate of plaque inflammation was calculated for all of the lesions identified on HRMRI. RESULTS: In 7 of 12 patients (58%), high FDG uptake was seen in the lesion targeted for endarterectomy. In the remaining 5 patients, FDG uptake in the targeted lesion was low. In these 5 patients, 3 had nonstenotic lesions identified on HRMRI that exhibited a high level of FDG uptake. All 3 of the highly inflamed nonstenotic lesions were located in a vascular territory compatible with the patients' presenting symptoms. CONCLUSIONS: Our data suggest that angiography may not always identify the culprit lesion. Combined FDG-PET and HRMRI can assess the degree of inflammation in stenotic and nonstenotic plaques and could potentially be used to identify lesions responsible for embolic events.

Aged↗
PubMed2005

Monte Carlo simulation and scatter correction of the GE advance PET scanner with SimSET and Geant4.

For Monte Carlo simulations to be used as an alternative solution to perform scatter correction, accurate modelling of the scanner as well as speed is paramount. General-purpose Monte Carlo packages (Geant4, EGS, MCNP) allow a detailed description of the scanner but are not efficient at simulating voxel-based geometries (patient images). On the other hand, dedicated codes (SimSET, PETSIM) will perform well for voxel-based objects but will be poor in their capacity of simulating complex geometries such as a PET scanner. The approach adopted in this work was to couple a dedicated code (SimSET) with a general-purpose package (Geant4) to have the efficiency of the former and the capabilities of the latter. The combined SimSET+Geant4 code (SimG4) was assessed on the GE Advance PET scanner and compared to the use of SimSET only. A better description of the resolution and sensitivity of the scanner and of the scatter fraction was obtained with SimG4. The accuracy of scatter correction performed with SimG4 and SimSET was also assessed from data acquired with the 20 cm NEMA phantom. SimG4 was found to outperform SimSET and to give slightly better results than the GE scatter correction methods installed on the Advance scanner (curve fitting and scatter modelling for the 300-650 keV and 375-650 keV energy windows, respectively). In the presence of a hot source close to the edge of the field of view (as found in oxygen scans), the GE curve-fitting method was found to fail whereas SimG4 maintained its performance.

Algorithms↗
PubMed2005

The diffusion-weighted lesion in acute stroke: heterogeneous patterns of flow/metabolism uncoupling as assessed by quantitative positron emission tomography.

BACKGROUND: To investigate what the hyperintense lesion in diffusion-weighted imaging (DWI) of acute ischaemic stroke represents metabolically, we prospectively imaged acute carotid-territory stroke patients with DWI along with fully quantitative positron emission tomography (PET), which gives physiological maps of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2) and the oxygen extraction fraction (OEF). METHOD: Of 10 patients who consented, 5 (3 males, 2 females, 53-84 years, NIHSS 6-16) completed the imaging protocol of back-to-back DWI and PET within 21 (mean 15.7, range 7-21) h of stroke onset. All images were co-registered with the DWI lesion forming a region of interest (ROI) that was transferred to the PET parametric maps (OEF, CBF, CMRO2). Patterns of blood flow and metabolism were assessed within the DWI ROI. RESULTS: Within the DWI lesions, the following patterns were observed: very low CBF and CMRO2/variable OEF; low CBF/high OEF, and high CBF/low OEF. There was a heterogeneity of patterns between and within DWI lesions. In addition, areas of hyperperfusion (with low OEF) and areas of hypoperfusion (with high OEF) were seen outside the DWI lesions. CONCLUSION: The DWI lesion does not have a single flow/metabolism counterpart, suggesting that it reflects various stages of the ischaemic process.

Acute Disease↗
PubMed2005

Positron emission tomography using 18F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ET B receptors in vivo.

Our aim was to synthesise an (18)F analogue of endothelin-1 (ET-1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ET(B) subtype as a clearing receptor in organs expressing high densities including kidney and lung.[(18)F]-ET-1 was characterised in vitro and bound with a single subnanomolar affinity (K(D)=0.43+/-0.05 nM, B(max)=27.8+/-2.1 fmol mg(-1) protein) to human left ventricle (n=4). The in vivo distribution of [(18)F]-ET-1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis. Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [(125)I]-ET-1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements.[(18)F]-ET-1 binding in lungs could not be displaced by the ET(B) selective antagonist BQ788, in agreement with the proposed internalisation of ET-1 by ET(B) receptors. In contrast, infusion of BQ788 prior to injecting [(18)F]-ET-1 significantly reduce the amount of radioligand visualised in the ET(B) rich lung and kidney by 85% (P< 0.05, n=3) and 55% (P<0.05, n=3), respectively. Under conditions of ET(B) receptor blockade, the heart could be visualised by microPET imaging.These results suggest that clearance by ET(B) receptors in the lung and kidney prevents binding of ET-1 to receptors in the heart.

Animals↗
PubMed2005

Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury.

OBJECTIVE: In this study we have used O positron emission tomography, brain tissue oxygen monitoring, and cerebral microdialysis to assess the effects of cerebral perfusion pressure augmentation on regional physiology and metabolism in the setting of traumatic brain injury. DESIGN: Prospective interventional study. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Eleven acutely head-injured patients requiring norepinephrine to maintain cerebral perfusion pressure. INTERVENTIONS: Using positron emission tomography, we have quantified the response to an increase in cerebral perfusion pressure in a region of interest around a brain tissue oxygen sensor (Neurotrend) and microdialysis catheter. Oxygen extraction fraction and cerebral blood flow were measured with positron emission tomography at a cerebral perfusion pressure of approximately 70 mm Hg and approximately 90 mm Hg using norepinephrine to control cerebral perfusion pressure. All other aspects of physiology were kept stable. MEASUREMENTS AND MAIN RESULTS: Cerebral perfusion pressure augmentation resulted in a significant increase in brain tissue oxygen (17 +/- 8 vs. 22 +/- 8 mm Hg; 2.2 +/- 1.0 vs. 2.9 +/- 1.0 kPa, p < .001) and cerebral blood flow (27.5 +/- 5.1 vs. 29.7 +/- 6.0 mL/100 mL/min, p < .05) and a significant decrease in oxygen extraction fraction (33.4 +/- 5.9 vs. 30.3 +/- 4.6 %, p < .05). There were no significant changes in any of the microdialysis variables (glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol). There was a significant linear relationship between brain tissue oxygen and oxygen extraction fraction (r = .21, p < .05); the brain tissue oxygen value associated with an oxygen extraction fraction of 40% (the mean value for oxygen extraction fraction in normal controls) was 14 mm Hg (1.8 kPa). The cerebral perfusion pressure intervention resulted in a greater percentage increase in brain tissue oxygen than the percentage decrease in oxygen extraction fraction; this suggests that the oxygen gradients between the vascular and tissue compartments were reduced by the cerebral perfusion pressure intervention. CONCLUSIONS: Cerebral perfusion pressure augmentation significantly increased levels of brain tissue oxygen and significantly reduced regional oxygen extraction fraction. However, these changes did not translate into predictable changes in regional chemistry. Our results suggest that the ischemic level of brain tissue oxygen may lie at a level below 14 mm Hg (1.8 kPa); however, the data do not allow us to be more specific.

Adolescent↗
PubMed2004

Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2) and oxygen extraction fraction (OEF) using 15O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 +/- 4 to 90 +/- 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO2 were associated with the greatest reduction in OEF (r2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 +/- 16 to 5 +/- 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 +/- 1.5 versus 4.3 +/- 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO2 and neuronal electrical function will require further study.

Adolescent↗
PubMed2004

Diffusion limited oxygen delivery following head injury.

OBJECTIVE: To use a range of techniques to explore diffusion limitation as a mechanism of cellular hypoxia in the setting of head injury. DESIGN: A prospective interventional study. SETTING: A specialist neurocritical care unit. PATIENTS: Thirteen patients within 7 days of closed head injury underwent imaging studies. Tissue for ultrastructural studies was obtained from a cohort of seven patients who required surgery. INTERVENTIONS: Cerebral tissue PO2 (PtO2) was obtained using a multiple-variable sensor, and images of oxygen extraction fraction (OEF), derived from positron emission tomography, were used to calculate cerebral venous PO2 (PvO2). These data were used to derive the PvO2-PtO2 gradient in a region of interest around the sensor, which provided a measure of the efficiency of microvascular oxygen delivery. Measurements were repeated after PaCO2 was reduced from 37 +/- 3 to 29 +/- 3 torr (4.9 +/- 0.4 to 3.9 +/- 0.4 kPa) to assess the ability of the microvasculature to increase oxygen unloading during hypocapnia-induced hypoperfusion. Pericontusional tissue was submitted to electron microscopy to illustrate the structural correlates of physiologic findings. MEASUREMENTS AND MAIN RESULTS: Tissue regions with hypoxic levels of PtO2 (<10 torr) had similar levels of PvO2 compared with nonhypoxic areas and hence displayed larger PvO2-PtO2 gradients (27 +/- 2 vs. 9 +/- 8 torr, p <.001). Despite similar cerebral blood flow reductions with hyperventilation, hypoxic regions achieved significantly smaller OEF increases compared with normoxic regions (7 +/- 5 vs. 16 +/- 6 %, p <.05). Pericontusional tissue showed varying degrees of endothelial swelling, microvascular collapse, and perivascular edema. CONCLUSIONS: Increased diffusion barriers may reduce cellular oxygen delivery following head injury and attenuate the ability of the brain to increase oxygen extraction in response to hypoperfusion. Global or regional OEF underestimates tissue hypoxia due to such mechanisms.

Adolescent↗
PubMed2004

In vivo imaging of cardiovascular endothelin receptors using the novel radiolabelled antagonist [18F]-SB209670 and positron emission tomography (microPET).

The aim of this study was to develop an F-labelled analogue of SB209670 with subnanomolar affinity for the endothelin receptor and to test whether it would have the required pharmacokinetic properties to permit binding and imaging of endothelin receptors in rat heart in vivo using small animal positron emission tomography (PET) imaging. [18F]-SB209670 could be produced in a total radiochemical yield of 14.9 +/- 3.8% in 162 +/- 7 minutes (n = 6). The radiochemical purity of the isolated radioligand was 99% and the specific activity was 100-150 GBq/micromol. In vitro characterization using ligand-binding assays demonstrated that [18F]-SB209670 bound with a single subnanomolar affinity to human heart tissue (n = 3) with a KD = 0.67 +/- 0.14 nM and a Bmax = 168.3 +/- 29.3 fmol/mg protein. The binding was time-dependent with a half-time (t(1/2)) for association of 3.8 minutes and an association rate constant (kobs) of 0.182 +/- 0.032/min. In vivo distribution in the rat was studied using microPET. Dynamic imaging revealed a fast clearance of [F]-SB209670 from the circulation by the liver, indicative of a high degree of metabolism. However, visualization of uptake in the rat heart was achievable and dynamic PET data together with the in vitro results suggest that [F]-SB209670 binds rapidly and primarily to endothelin-A receptors in the heart.

Animals↗
PubMed2004

Defining ischemic burden after traumatic brain injury using 15O PET imaging of cerebral physiology.

Whereas postmortem ischemic damage is common in head injury, antemortem demonstration of ischemia has proven to be elusive. Although 15O positron emission tomography may be useful in this area, the technique has traditionally analyzed data within regions of interest (ROIs) to improve statistical accuracy. In head injury, such techniques are limited because of the lack of a priori knowledge regarding the location of ischemia, coexistence of hyperaemia, and difficulty in defining ischemic cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) levels. We report a novel method for defining disease pathophysiology following head injury. Voxel-based approaches are used to define the distribution of oxygen extraction fraction (OEF) across the entire brain; the standard deviation of this distribution provides a measure of the variability of OEF. These data are also used to integrate voxels above a threshold OEF value to produce an ROI based upon coherent physiology rather than spatial contiguity (the ischemic brain volume; IBV). However, such approaches may suffer from poor statistical accuracy, particularly in regions with low blood flow. The magnitude of these errors has been assessed in modeling experiments using the Hoffman brain phantom and modified control datasets. We conclude that this technique is a valid and useful tool for quantifying ischemic burden after traumatic brain injury.

Adult↗