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Biomedical subjects

David K Menon

Publications and source records attributed to David K Menon.

At least 19 recordsLinked to original sources
PubMed2004

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↗
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↗
PubMed2004

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↗
PubMed2004

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

Responses of posttraumatic pericontusional cerebral blood flow and blood volume to an increase in cerebral perfusion pressure.

In and around traumatic contusions, cerebral blood flow (CBF) is often near or below the threshold for ischemia. Increasing cerebral perfusion pressure (CPP) in patients with head injuries may improve CBF in these regions. However, the pericontusional response to this intervention has not been studied. Using positron emission tomography (PET), we have quantified the response to an increase in CPP in and around contusions in 18 contusions in 18 patients. Regional CBF and cerebral blood volume (CBV) were measured with PET at CPPs of 70 and 90 mmHg using norepinephrine to control CPP. Based upon computed tomography, regions of interest (ROIs) were placed as two concentric ellipsoids, each of 1-cm width, around the core of the contusions. Measurements were compared with a control ROI in tissue with normal anatomic appearance. Baseline CBF and CBV increased significantly with increasing distance from the core of the lesion. The increase in CPP led to small increases in CBF in all ROIs except the core. The largest absolute CBF increase was found in the control ROI. Relative CBF increases did not differ between ROIs so that ischemic areas remained ischemic. Pericontusional oedema on computed tomography was associated with lower absolute values of CBF and CBV but did not differ from nonoedematous tissue in the relative response to CPP elevation.

Adolescent↗
PubMed2003

The effects of large-dose propofol on cerebrovascular pressure autoregulation in head-injured patients.

UNLABELLED: In healthy individuals, cerebrovascular pressure autoregulation is preserved or even improved when propofol is infused. We examined the effect of an increase in propofol plasma concentration on pressure autoregulation in 10 head-injured patients. Using target-controlled infusions, the static rate of autoregulation was determined at a moderate (2.3 +/- 0.4 microg/mL) and a large (4.3 +/- 0.04 microg/mL) plasma target concentration of propofol. Using norepinephrine to control cerebral perfusion pressure, transcranial Doppler measurements from the middle cerebral artery were made at a cerebral perfusion pressure of 70 and 85 mm Hg at each propofol concentration. Middle cerebral artery flow velocities at the large propofol concentration were significantly lower than at the moderate concentration, without any concurrent increase in arterio-jugular difference in oxygen content, a finding compatible with maintained flow-metabolism coupling. Despite this, static rate of autoregulation decreased significantly from 54% +/- 36% to 28% +/- 35% (P = 0.029). Our data suggest that after head injury, the cerebrovascular effects of propofol are different from those observed in healthy individuals. We propose that large doses of propofol should be used cautiously in head-injured patients, because there is the potential to increase the injured brain's vulnerability to secondary insults. IMPLICATIONS: Propofol is used for sedation and control of intracranial pressure in head-injured patients. In contrast to previous data from healthy individuals, we show a deterioration of cerebrovascular pressure autoregulation with fast propofol infusion rates after head injury. Large propofol doses may increase the injured brain's vulnerability to secondary insults.

Adult↗
PubMed2003

Positron emission tomographic cerebral perfusion disturbances and transcranial Doppler findings among patients with neurological deterioration after subarachnoid hemorrhage.

OBJECTIVE: After aneurysmal subarachnoid hemorrhage, approximately 30% of patients experience delayed neurological deficits, related in part to arterial vasospasm and dysautoregulation. Transcranial Doppler (TCD) ultrasonography is commonly used to noninvasively detect arterial vasospasm. We studied cerebral perfusion patterns and associated TCD indices for 25 patients who developed clinical signs of delayed neurological deficits. METHODS: Patients were treated in a neurosurgical intensive care unit and were studied if they exhibited delayed focal or global neurological deterioration. Positron emission tomographic cerebral blood flow (CBF) studies and TCD studies measuring the mean flow velocity (FV) of the middle cerebral artery and the middle cerebral artery FV/internal carotid artery FV ratio (with the internal carotid artery FV being measured extracranially at the cranial base) were performed. Glasgow Outcome Scale scores were assessed at 6 months. RESULTS: A markedly heterogeneous pattern of CBF distribution was observed, with hyperemia, normal CBF values, and reduced flow being observed among patients with delayed neurological deficits. TCD indices were not indicative of the cerebral perfusion findings. The mean CBF value was slightly lower for patients who did not survive (32.3 ml/100 g/min), compared with those who did survive (36.0 ml/100 g/min, P = 0.05). CONCLUSION: Among patients who developed delayed neurological deficits after aneurysmal subarachnoid hemorrhage, a wide range of cerebral perfusion disturbances was observed, calling into question the traditional concept of large-vessel vasospasm. Commonly used TCD indices do not reflect cerebral perfusion values.

Adult↗
PubMed2002

Specialist neurocritical care and outcome from head injury.

OBJECTIVES: To document the effect of neurocritical care, delivered by specialist staff and based on protocol-driven therapy aimed at intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targets, on outcome in acute head injury. DESIGN: Retrospective record review to compare presentation, therapy and outcome in patients with head injury referred to a regional neurosurgical centre, before and after establishment of protocol-driven therapy. SETTING: Neurosciences Critical Care Unit (NCCU). PARTICIPANTS: Two hundred and eighty-five patients aged 18-65 years with at least one reactive pupil, referred with a diagnosis of head injury, requiring tracheal intubation and mechanical ventilation. INTERVENTIONS: Measurement of Glasgow Outcome Scale 6 months after injury. RESULTS: Patients from the two epochs were well matched for admission Glasgow Coma Scale and extracranial injuries. When all referred patients were considered, institution of protocol-driven therapy was not associated with a statistically significant increase in favourable outcomes (56.0% vs. 66.4%). However, we observed a significant increase in favourable outcomes in the severely head injured patients studied (40.4% vs. 59.6%). The proportion of favourable outcomes was also high (66.6%) in those presenting with evidence of raised ICP in the absence of a mass lesion and (60.0%) in those that required complex interventions to optimise ICP/CPP. CONCLUSIONS: Specialist neurocritical care with protocol-driven therapy is associated with a significant improvement in outcome for all patients with severe head injury. Such management may also benefit patients requiring no surgical therapy, some of whom may need complex therapeutic interventions. We found it impossible to predict need for such interventions from clinical features at presentation. These data suggest that specialist critical care with ICP/CPP guided therapy may benefit patients with severe head injury.

Adult↗
PubMed2002

Integrated image analysis solutions for PET datasets in damaged brain.

OBJECTIVE: To identify and discuss the problems inherent in the processing of multiparametric functional imaging datasets from patients with acute brain injury, using "triple oxygen" positron emission tomography (PET) as an example. To present an integrated imaging solution for analysis of such datasets and report on its use in practice. METHODS: Structured analysis of the steps in image analysis for triple oxygen studies in patients with acute brain injury, subarachnoid haemorrhage and carotid artery disease was undertaken. Systematic identification of the drawbacks of conventional manual processing techniques, which make use of modules from different commercially available software packages was carried out. This analysis informed the construction of an image analysis gateway that addressed these issues. RESULTS: We describe an integrated image analysis gateway (PETAn) that provides for the automated integration of all processing steps, along with outputs that detail analysis stages, error logs and results. Implementation of PETAn allowed batch processing of clinical PET data sets, reduced the level of technical expertise required for analysis, improved the quality of results and achieved significant reductions in operator analysis time. CONCLUSIONS: While modules from several imaging software suites can be usefully combined to allow analysis of multiparametric PET data sets from patients with acute brain injury, sequential use of these modules for various steps in image analysis is fraught with difficulty. Careful automation and integration of these steps greatly facilitates the interrogation of information-rich data sets and increases research productivity.

Algorithms↗
PubMed2002

Arteriojugular endothelin-1 gradients in aneurysmal subarachnoid haemorrhage.

Plasma endothelin (ET) is elevated in patients with vasospasm following subarachnoid haemorrhage (SAH). However, systemic levels provide no indication regarding local production in the brain, and late elevation may be a consequence rather than a cause of vasospasm. We measured arteriojugular (AJ) gradients of ET-1 in 17 patients over the first week after SAH, and related these to the subsequent development of vasospasm. Daily, paired arterial and jugular bulb blood samples were obtained up to seven days post SAH, and assayed for ET-1 using radioimmunoassay. Systemic levels and AJ gradients were compared in patients with and without vasospasm. Significant AJ gradients were observed for ET-1 (P<0.01). These differences remained significant in the subgroup of patients who developed vasospasm (0.12+/-0.05 pmol/l; P<0.05), in whom AJ gradients represented 25+/-7% of systemic levels (0.84+/-0.05 pmol/l). AJ gradients did not reach significance in patients who did not develop vasospasm (0.09+/-0.07 pmol/l; P=0.2). Systemic ET-1 levels and AJ gradients were unrelated to SAH grade, surgical or endovascular interventions, or extracranial complications. AJ gradients in the first week following SAH suggest early production of ET-1 in the cerebrovascular bed. However, early systemic ET-1 levels did not discriminate between patients with and without vasospasm. Larger AJ differences may predict vasospasm, but further work is needed to confirm this observation. AJ gradient measurement may provide a useful technique for investigating the role of other peptides in acute brain injury.

Adult↗
PubMed2002

Detecting residual cognitive function in persistent vegetative state.

Despite converging agreement about the definition of persistent vegetative state, recent reports have raised concerns about the accuracy of diagnosis in some patients, and the extent to which, in a selection of cases, residual cognitive functions may remain undetected. Objective assessment of residual cognitive function can be extremely difficult as motor responses may be minimal, inconsistent, and difficult to document in many patients, or may be undetectable in others because no cognitive output is possible. Here we describe strategies for using H(2)(15)O positron emission tomography activation studies to study covert cognitive processing in patients with a clinical diagnosis of persistent vegetative state. Three cases are described in detail. Of these, two exhibited clear and predicted regional cerebral blood flow responses during well-documented activation paradigms (face recognition and speech perception) which have been shown to produce specific, robust and reproducible activation patterns in normal volunteers. Some months after scanning, both patients made a significant recovery. In a third case, blood flow data were acquired during a speech perception task, although methodological difficulties precluded any systematic interpretation of the results. In spite of the multiple logistic and procedural problems involved, these results have major clinical and scientific implications and provide a strong basis for the systematic study of possible residual cognitive function in patients diagnosed as being in a persistent vegetative state.

Adult↗
PubMed2002

Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.

OBJECTIVES: To define optimal cerebral perfusion pressure (CPPOPT) in individual head-injured patients using continuous monitoring of cerebrovascular pressure reactivity. To test the hypothesis that patients with poor outcome were managed at a cerebral perfusion pressure (CPP) differing more from their CPPOPT than were patients with good outcome. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: A total of 114 head-injured patients admitted between January 1997 and August 2000 with continuous monitoring of mean arterial blood pressure (MAP) and intracranial pressure (ICP). MEASUREMENTS AND MAIN RESULTS: MAP, ICP, and CPP were continuously recorded and a pressure reactivity index (PRx) was calculated online. PRx is the moving correlation coefficient recorded over 4-min periods between averaged values (6-sec periods) of MAP and ICP representing cerebrovascular pressure reactivity. When cerebrovascular reactivity is intact, PRx has negative or zero values, otherwise PRx is positive. Outcome was assessed at 6 months using the Glasgow Outcome Scale. A total of 13,633 hrs of data were recorded. CPPOPT was defined as the CPP where PRx reaches its minimum value when plotted against CPP. Identification of CPPOPT was possible in 68 patients (60%). In 22 patients (27%), CPPOPT was not found because it presumably lay outside the studied range of CPP. Patients' outcome correlated with the difference between CPP and CPPOPT for patients who were managed on average below CPPOPT (r =.53, p <.001) and for patients whose mean CPP was above CPPOPT (r = -.40, p <.05). CONCLUSIONS: CPPOPT could be identified in a majority of patients. Patients with a mean CPP close to CPPOPT were more likely to have a favorable outcome than those whose mean CPP was more different from CPPOPT. We propose use of the criterion of minimal achievable PRx to guide future trials of CPP oriented treatment in head injured patients.

Adolescent↗