The human tissue bill and the mental capacity bill.
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Human Experimentation↗
Biomedical subjects
David K Menon
Publications and source records attributed to David K Menon.
Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.
OBJECTIVE: To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury. DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP. INTERVENTION: Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period. MEASUREMENTS AND RESULTS: The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine. CONCLUSIONS: If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.
Adult↗
Differentiation and migration of long term expanded human neural progenitors in a partial lesion model of Parkinson's disease.
Human neural progenitor cells (HNPCs) can be expanded in large numbers for significant periods of time to provide a reliable source of neural cells for transplantation in neurodegenerative disorders such as Parkinson's disease (PD). In the present study, HNPCs isolated from embryonic cortex were expanded as neurospheres in cell culture for 10 months. Just prior to transplantation, a proportion of the HNPCs were treated in a "predifferentiation" protocol in combination with the neurotropic factor NT4, in order to yield significant numbers of neurons. For transplantation, either undifferentiated HNPCs, or predifferentiated HNPCs were transplanted into the substantia nigra of a rat model of Parkinson's disease. At 12 weeks, there was good survival with proliferation of transplanted HNPCs occurring after transplantation but ceasing before the animals were sacrificed. Transplants of predifferentiated cells contained a higher proportion of neurons. The presence of a lesion in the striatum had a significant influence on the migration of transplanted cells from the substantia nigra into the striatum. There was no significant behavioural recovery or effect of transplanted HNPCs on the loss of dopaminergic cells from the host brain. In conclusion, HNPCs may provide a source of cells for use in the treatment of Parkinson's disease.
Animals↗
Extracellular Brain pH and Outcome following Severe Traumatic Brain Injury.
The ability to measure brain tissue chemistry has led to valuable information regarding pathophysiological changes in patients with traumatic brain injury (TBI). Over the last few years, the focus has been on monitoring changes in brain tissue oxygen to determine thresholds of ischemia that affect outcome. However, the variability of this measurement suggests that it may not be a robust method. We have therefore investigated the relationship of brain tissue pH (pH(b)) and outcome in patients with TBI. We retrospectively analyzed prospectively collected data of 38 patients admitted to the Neurosciences Critical Care Unit with TBI between 1998 and 2003, and who had a multiparameter tissue gas sensor inserted into the brain. All patients were managed using an evidence-based protocol targeting CPP > 70 mm Hg. Physiological variables were averaged over 4 min and analyzed using a generalized least squares random effects model to determine the temporal profile of pH(b) and its association with outcome. Median (IQR) minimum pH(b) was 7.00 (6.89, 7.08), median (IQR) maximum pH(b) was 7.25 (7.18, 7.33), and median (IQR) patient averaged pH(b) was 7.13 (7.07, 7.17). pH(b) was significantly lower in those who did not survive their hospital stay compared to those that survived. In addition, those with unfavorable neurological outcome had lower pH(b) values than those with favorable neurological outcome. pH(b) differentiated between survivors and non-survivors. Measurement of pH(b) may be a useful indicator of outcome in patients with TBI.
Acid-Base Equilibrium↗
Traumatic brain injury: physiology, mechanisms, and outcome.
PURPOSE OF REVIEW: This review on traumatic brain injury consolidates the substantial current literature available on the pathophysiology, mechanisms, developments, and their subsequent effects on outcome. In particular, it tries to conceptualize why our greatly improved understanding of pathophysiology and neurobiology in traumatic brain injury has not translated into clear outcome improvements. RECENT FINDINGS: Early cerebral ischaemia has been characterized further, with ischaemic brain volume correlating with 6-month outcome. The Brain Trauma Foundation has revised perfusion pressure targets, and there are additional data on the outcome impact of brain tissue oxygen response and asymmetric patterns of cerebral autoregulation. Mechanistic studies have highlighted the role of inflammation and introduced concepts such as therapeutic vaccination and immune modulation. Experimental neurogenesis and repair strategies show promise. Despite continuing gains in knowledge, the experimental successes have not yet translated to the clinic. Indeed, several major articles have attempted to understand the clinical failure of highly promising strategies such as hypothermia, and set out the framework for further studies (e.g. addressing decompressive craniectomy). High-dose mannitol has shown promise in poor grade patients, while hypertonic saline has shown better intracranial pressure control. Negative results may be the consequence of ineffective therapies. However, there is a gathering body of work that highlights the outcome impact of subtle neurocognitive changes, which may not be quantified adequately by outcome measures used in previous trials. Such knowledge has also informed improved definition of mild traumatic brain injury, and allowed validation of management guidelines. SUMMARY: The evidence base for current therapies in this heterogeneous patient group is being refined, with greater emphasis on long-term functional outcomes. Improved monitoring techniques emphasize the need for individualization of therapeutic interventions.
Animals↗
Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients.
OBJECTIVE: To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DESIGN: Prospective randomized crossover trial. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. INTERVENTIONS: Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p <.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. CONCLUSIONS: Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.
Adult↗
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↗
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↗
Incidence and mechanisms of cerebral ischemia in early clinical head injury.
Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 +/- 69 vs. 2 +/- 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 +/- 63 mL (mean +/- 95% CI), which equates to 13 +/- 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (rho = -0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this "traumatic penumbra" is poorly detected by bedside clinical monitors and has significant associations with outcome.
Adolescent↗
Hyperglycemia and brain tissue pH after traumatic brain injury.
OBJECTIVE: Hyperglycemia occurring after head injury is associated with poor neurological outcome. We tested the hypothesis that blood glucose levels are associated with brain tissue pH (pH(b)) and that the correction of hyperglycemia would result in an improvement in pH(b). METHODS: This is a retrospective analysis of a prospectively collected database. Thirty-four patients in a tertiary care neuroscience critical care unit with major traumatic brain injury underwent pH(b) monitoring. RESULTS: A total of 428 glucose measurements were recorded during pH(b) monitoring. Mean glucose level was 7.1 mmol/L (range, 2.8-21.7 mmol/L) and median (interquartile range) pH(b) was 7.11 mmol/L (7.00-7.19 mmol/L). To account for the correlated, unbalanced nature of the data, a linear generalized estimating equation model was created. This model predicted that for each 1 mmol/L increase in blood glucose, pH(b) changed by -0.011 mmol/L (95% confidence interval, -0.016 to -0.005 mmol/L; P < 0.001). This relationship remained significant in a multivariable model that included cerebral perfusion pressure, brain tissue oxygen and carbon dioxide tension, and brain temperature. Twenty-one episodes of significant hyperglycemia (>or=11.1 mmol/L) treated with intravenous insulin were identified. Insulin therapy significantly reduced blood glucose concentration from a median (interquartile range) of 11.9 mmol/L (range, 11.4-13.6 mmol/L) to 8.8 mmol/L (range, 7.3-9.6 mmol/L; P < 0.001). Baseline pH(b) was not significantly different from pH(b) associated with the subsequent glucose reading of less than 11.1 mmol/L (P = 0.29), but there was a suggestion of improvement if the change in blood glucose was large. CONCLUSION: Blood glucose is associated with brain tissue acidosis in patients with major head injury. Prospective studies are required to confirm these results and to determine whether treatment of hyperglycemia improves outcome.
Adolescent↗
Comparative tolerability of sedative agents in head-injured adults.
Sedative agents are widely used in the management of patients with head injury. These drugs can facilitate assisted ventilation and may provide useful reductions in cerebral oxygen demand. However, they may compromise cerebral oxygen delivery via their cardiovascular effects. In addition, individual sedative agents have specific and sometimes serious adverse effects. This review focuses on the different classes of sedative agents used in head injury, with a discussion of their role in the context of clinical pathophysiology. While there is no sedative that has all the desirable characteristics for an agent in this clinical setting, careful titration of dose, combination of agents, and a clear understanding of the pathophysiology and pharmacology of these agents will allow safe sedative administration in head injury.
Antipsychotic Agents↗
Calculation of doses of drugs in solution: are medical students confused by different means of expressing drug concentrations?
INTRODUCTION: Our hypothesis was that clinical medical students find the different means of expressing the concentration of drugs in solution confusing. We are concerned that lack of formal teaching on this topic may make students liable to make drug dosing errors after they have qualified. Administering the wrong volume of a drug may have serious consequences for patient safety. STUDY DESIGN AND PARTICIPANT GROUP: Web-based electronic multiple-choice examination of clinical medical students. METHODS: We asked clinical medical students at our university three multiple-choice questions concerning the concentration of lidocaine (lignocaine) and epinephrine (adrenaline) in solution and the maximal recommended dose of lidocaine. The incorrect options were wrong by factors of between 4 and 1000. RESULTS: One hundred and sixty-eight clinical students out of 350 contacted responded to an invitation to participate (response rate 48%). Twenty-seven percent answered every question incorrectly and 10% answered all three correctly. The mean score for all students was only 1.24 out of 3 (standard error 0.96). However, final-year students performed significantly better (p = 0.016), implying that some knowledge had been acquired informally. Their higher mean score resulted from correctly identifying the amount of epinephrine (p = 0.005) and lidocaine (p = 0.018) more frequently. Only 27% knew the maximal recommended dose of lidocaine, with no difference between years (p = 0.724). CONCLUSIONS: A substantial majority of medical students are unable to calculate the mass of a drug in solution correctly. There is evidence that some students are picking up this skill during the course, because final-year students performed significantly better than first-year students. Modern medical student pharmacology teaching is highly sophisticated, encompassing genomics, molecular and cell biology. The ability to calculate drug doses safely appears to have been overlooked. Students should be familiar with these concepts, so as to avoid dose errors and associated morbidity, mortality and cost when they begin prescribing. To simplify calculations, drug packaging should express the concentration of drugs in solution solely as mass per unit volume, e.g. milligrams per millilitre.
Clinical Competence↗
Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients.
OBJECTIVE: To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine. DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP). INTERVENTION: Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrations MEASUREMENTS AND RESULTS: Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r2=0.431), and systemic vascular resistance index (r2=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of approximately 50 nM/l (corresponding to an infusion rate of approximately 15 microg.kg(-1).min(-1)). CONCLUSIONS: Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.
Adult↗
Cost-effective outcome for treating poor-grade subarachnoid hemorrhage.
BACKGROUND AND PURPOSE: The goal of this study was to prospectively assess outcome and cost for poor-grade subarachnoid hemorrhage patients presenting to a regional neurosurgical center (Addenbrooke's Hospital, Cambridge, UK) between 1994 and 2001. Outcome measures were clinical outcome at 6 months, number needed to treat (NNT) for favorable outcomes, and cost analysis. METHODS: Poor-grade patients (World Federation of Neurological Surgeons grades 4 and 5) were transferred to the neurocritical care unit after intubation and ventilation. After resuscitation and drainage of ventricular cerebrospinal fluid for 24 hours, sedation was stopped, and patients were assessed clinically. Patients with a Glasgow Motor Score (GMS) > or =4 underwent angiography and surgical treatment of culprit aneurysms. Patients with a subsequent GMS of 6 were not deemed poor grade and were discounted from the study. RESULTS: We deemed 166 ventilated patients genuinely poor grade (mean age, 53.4 years; 94 women [56.6%]). Of these, 88 patients (4<GMS<6; 53%) progressed to angiography and possible definitive treatment. Seventy-five patients had an identifiable aneurysm, but only 64 survived for treatment. Operative mortality was 31.3%, and of the 44 survivors, 22 (34.4% of operated patients) achieved a favorable outcome. Favorable outcomes were more frequently seen in women than men (21.3% versus 6.9%) but were unrelated to patient age. The NNT for 1 favorable outcome was 7 (male NNT, 15; female NNT, 5) at a cost of pound 84 336 per favorable outcome (female, pound 60 240; male, pound 180 720). CONCLUSIONS: Poor-grade aneurysmal subarachnoid hemorrhage is associated with a high mortality but a significant subset of patients can achieve favorable outcomes.
Adolescent↗
Assessment of cerebrovascular autoregulation in head-injured patients: a validation study.
BACKGROUND AND PURPOSE: Cerebrovascular autoregulation is frequently measured in head-injured patients. We attempted to validate 4 bedside methods used for assessment of autoregulation. METHODS: PET was performed at a cerebral perfusion pressure (CPP) of 70 and 90 mm Hg in 20 patients. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) were determined at each CPP level. Patients were sedated with propofol and fentanyl. Norepinephrine was used to control CPP. During PET scanning, transcranial Doppler (TCD) flow velocity in the middle cerebral artery was monitored, and the arterio-jugular oxygen content difference (AJDo2) was measured at each CPP. Autoregulation was determined as the static rate of autoregulation based on PET (SROR(PET)) and TCD (SROR(TCD)) data, based on changes in AJDo2, and with 2 indexes based on the relationship between slow waves of CPP and flow velocity (mean velocity index, Mx) and between arterial blood pressure and intracranial pressure (pressure reactivity index, PRx) RESULTS: We found significant correlations between SROR(PET) and SROR(TCD) (r2=0.32; P<0.01) and between SROR(PET) and PRx (r2=0.31; P<0.05). There were no significant associations between PET data and autoregulation as assessed by changes in AJDo2. Global CMRo2 was significantly lower at the higher CPP (P<0.01). CONCLUSIONS: Despite some variability, SROR(TCD) and PRx may provide useful approximations of autoregulation in head-injured patients. At least with our methods, CMRo2 changes with the increase in CPP; hence, flow-metabolism coupling may affect the results of autoregulation testing.
Adolescent↗
Images in clinical medicine. Carotid-artery thrombosis secondary to basal skull fracture.
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Adolescent↗
Non-neurological organ dysfunction in neurocritical care.
PURPOSE: To determine the incidence of non-neurological organ dysfunction in patients with severe neurological injury. MATERIALS AND METHODS: Modified daily SOFA (mSOFA) scores were retrospectively calculated for 55 consecutive patients with severe head injury or subarachnoid hemorrhage. mSOFA was defined as the sum of the 5 non-neurological component SOFA scores, maximum mSOFA as the sum of the most abnormal non-neurological SOFA component scores and delta mSOFA as the difference between maximum mSOFA and admission mSOFA. Organ failure was defined as a SOFA component score > or =3. RESULTS: Median (IQR) admission, maximum and delta mSOFA scores were 4 (3-6), 8 (6-9), and 2 (1-5), respectively. Respiratory and cardiac failure developed in 80% and 82% of patients, respectively. No patient developed renal or hepatic failure. Three patients developed hematological failure. There was no difference between survivors and nonsurvivors with respect to admission mSOFA (P =.45), maximum mSOFA (P =.54), or delta mSOFA (P =.19). There was no difference between those patients with favorable or unfavorable neurological outcome with respect to admission mSOFA (P =.24), maximum mSOFA (P =.84), or delta mSOFA (P =.20). CONCLUSIONS: Cardiopulmonary failure, as defined by SOFA, is common in intensive care unit patients with severe head injury and subarachnoid hemorrhage. In contrast to other intensive care unit patient populations, the mortality of patients with closed head injury or subarachnoid hemorrhage was not related to the severity of organ dysfunction on admission or its development during the intensive care unit stay.
Adult↗
Procrustes, the traumatic penumbra, and perfusion pressure targets in closed head injury.
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Brain↗