Biomedical subjects

Anthony G Marson

Publications and source records attributed to Anthony G Marson.

12 recordsLinked to original sources

PubMed2006

The relationship between cardiac output, cerebral electrical activity, cerebral fractional oxygen extraction and peripheral blood flow in premature newborn infants.

Cardiac output is a determinant of systemic blood flow and its measurement may therefore be a useful indicator of abnormal hemodynamics and tissue oxygen delivery. The purpose of this study was to investigate in very premature newborn infants the relationships between cardiac output (left and right ventricular outputs), systemic blood pressure, peripheral blood flow (PBF) and two indicators of cerebral oxygen delivery (cerebral electrical activity and cerebral fractional oxygen extraction (CFOE)). This was a prospective observational study performed on 40 infants of less than 30 wk gestation. Digital electroencephalograms (EEGs) were recorded for one hour every day during the first four days after birth and subjected to qualitative and quantitative analysis. Left and right ventricular outputs, mean blood pressure (MBP), CFOE, PBF and arterial blood gases were measured at the same time. Within the ranges studied, there was no apparent relationship between left or right ventricular output (RVO), PBF and indicators of cerebral perfusion (cerebral electrical activity and CFOE). The EEG was normal in infants with low left and right ventricular outputs (<150 mL/kg/min) and MBP > 30 mm Hg. Infants with low cardiac output and normal MBP seem able to maintain cerebral perfusion, possibly through vasodilatation of the cerebral microvasculature.

Blood Circulation↗

PubMed2006

Prediction of risk of seizure recurrence after a single seizure and early epilepsy: further results from the MESS trial.

BACKGROUND: The MRC Multicentre trial for Early Epilepsy and Single Seizures (MESS) showed a reduced risk of further seizures in patients, for whom treatment with antiepileptic drugs was uncertain, who were randomly assigned immediate treatment compared with delayed treatment. However, there was no evidence of an effect on [corrected] long-term remission rates. This study was undertaken to assess the role of patient characteristics and treatment in the prediction of seizure recurrence. This will enable decision-making on the basis of the perceived risk of treatment compared with the benefit of reducing the risk of further seizures in the initial years after diagnosis. METHODS: A prognostic model was developed based on individual patient data from MESS to enable identification of patients at low, medium, or high risk of seizure recurrence. A split-sample approach was used in which the model was developed on a subsample of the full data and validated on the remainder of the sample. Distinction of the prognostic groups and predictive accuracy of the model were assessed. FINDINGS: Number of seizures of all types at presentation, presence of a neurological disorder, and an abnormal electroencephalogram (EEG) were significant factors in indicating future seizures. Individuals with two or three seizures, a neurological disorder, or an abnormal EEG were identified as the medium-risk group, those with two of these features or more than three seizures as the high-risk group, and those with a single seizure only as the low-risk group. INTERPRETATION: The model shows that there is little benefit to immediate treatment in patients at low risk of seizure recurrence, but potentially worthwhile benefits are seen in those at medium and high risk.

Adolescent↗

PubMed2006

Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response: a prospective cohort study.

BACKGROUND: The ABCB1 3435C-->T single-nucleotide polymorphism (SNP) or a three-SNP haplotype containing 3435C-->T has been implicated in multidrug resistance in epilepsy in three retrospective case-control studies, but a further three have failed to replicate the association. We aimed to determine the effect of the ABCB1 gene on epilepsy drug response, using a unique large cohort of epilepsy patients with prospectively measured seizure and drug response outcomes. METHODS: The ABCB1 3435C-->T polymorphism and three-SNP haplotype, plus a comprehensive set of tag SNPs across ABCB1 and adjacent ABCB4, were genotyped in a cohort of 503 epilepsy patients with prospectively measured seizure and drug response outcomes. Clinical, demographic, and genetic data were analysed. Treatment outcome was measured in terms of time to 12-month remission, time to first seizure, and time to drug withdrawal due to inadequate seizure control or side-effects. Randomly selected genome-wide HapMap SNPs (n=129) were genotyped in all patients for genomic control. FINDINGS: Number of seizures before treatment was the dominant feature predicting seizure outcome after starting antiepileptic drug therapy, measured by both time to first seizure (hazard ratio 1.34, 95% CI 1.21-1.49, p<0.0001) and time to 12-month remission (0.83, 0.73-0.94, p=0.003). There was no association of the ABCB1 3435C-->T polymorphism, the three-SNP haplotype, or any gene-wide tag SNP with time to first seizure after starting drug therapy, time to 12-month remission, or time to drug withdrawal due to unacceptable side-effects or to lack of seizure control. INTERPRETATION: We found no evidence that ABCB1 common variation influences either seizure or drug withdrawal outcomes after initiation of antiepileptic drug therapy.

ATP-Binding Cassette Transporters↗

PubMed2006

Relationship between blood pressure, cerebral electrical activity, cerebral fractional oxygen extraction, and peripheral blood flow in very low birth weight newborn infants.

There is uncertainty about the level of systemic blood pressure required to maintain adequate cerebral oxygen delivery and organ integrity. This prospective, observational study on 35 very low birth weight infants aimed to determine the mean blood pressure (MBP) below which cerebral electrical activity, peripheral blood flow (PBF), and cerebral fractional oxygen extraction (CFOE) are abnormal. Digital EEG, recorded every day on the first 4 d after birth, were analyzed a) by automatic spectral analysis, b) by manual measurement of interburst interval, and c) qualitatively. CFOE and PBF measurements were performed using near-infrared spectroscopy and venous occlusion. MBP was measured using arterial catheters. The median (range) of MBP recorded was 32 mm Hg (16-46). The EEG became abnormal at MBP levels below 23 mm Hg: a) the relative power of the delta (0.5-3.5 Hz) frequency band was decreased, b) interburst intervals were prolonged, and c) all four qualitatively abnormal EEG (low amplitude and prolonged interburst intervals) from four different patients were recorded below this MBP level. The only abnormally high CFOE was measured at MBP of 20 mm Hg. PBF decreased at MBP levels between 23 and 33 mm Hg. None of the infants in this study developed cystic periventricular leukomalacia. One infant (MBP, 22 mm Hg) developed ventricular dilatation after intraventricular hemorrhage. The EEG and CFOE remained normal at MBP levels above 23 mm Hg. It would appear that cerebral perfusion is probably maintained at MBP levels above 23 mm Hg.

Blood Pressure↗

PubMed2005

Investigating heterogeneity in an individual patient data meta-analysis of time to event outcomes.

Differences across studies in terms of design features and methodology, clinical procedures, and patient characteristics, are factors that can contribute to variability in the treatment effect between studies in a meta-analysis (statistical heterogeneity). Regression modelling can be used to examine relationships between treatment effect and covariates with the aim of explaining the variability in terms of clinical, methodological, or other factors. Such an investigation can be undertaken using aggregate data or individual patient data. An aggregate data approach can be problematic as sufficient data are rarely available and translating aggregate effects to individual patients can often be misleading. An individual patient data approach, although usually more resource demanding, allows a more thorough investigation of potential sources of heterogeneity and enables a fuller analysis of time to event outcomes in meta-analysis. Hierarchical Cox regression models are used to identify and explore the evidence for heterogeneity in meta-analysis and examine the relationship between covariates and censored failure time data in this context. Alternative formulations of the model are possible and illustrated using individual patient data from a meta-analysis of five randomized controlled trials which compare two drugs for the treatment of epilepsy. The models are further applied to simulated data examples in which the degree of heterogeneity and magnitude of treatment effect are varied. The behaviour of each model in each situation is explored and compared.

Anticonvulsants↗

PubMed2005

Spectral analysis of electroencephalography in premature newborn infants: normal ranges.

Continuous EEG monitoring has not been used widely in neonatal intensive care, especially in the care of extremely premature infants, probably in part because of a lack of a reliable quantitative method. The purpose of this study was to quantify the EEG of the very premature infants just after birth by using spectral analysis and to describe the characteristics of the spectral signal when infants were clinically stable. Digital EEG recordings were performed on 53 infants who were < or =30 wk gestation for 75 min each day during the first 4 d after birth. Artefact was rejected manually after visual inspection of trace. The EEG was analyzed by manual measurement of interburst interval and automatically by spectral analysis using Fast Fourier Transformation. Spectral analysis generated the normal ranges of the relative power of the delta (0.5-3.5 Hz), theta (4-7.5 Hz), alpha (8-12.5 Hz), and beta (13-30 Hz) frequency bands, spectral edge frequency, and symmetry. The median (range) relative power of the delta band increased significantly from 68% (62-76%) on day 1 to 81% (72-89%) on day 4 (p=0.001). The interburst intervals became progressively shorter between days 1 [14s (10-25)] and 3 [8s (6-12)]; there were no significant differences between days 3 and 4. The relative power of the delta band seemed to be the most useful and repeatable spectral measurement for continuous long-term monitoring. However, automatic artefact rejection software needs to be developed before continuous quantitative EEG monitoring can be used in the neonatal intensive care environment.

Age Factors↗

PubMed2005

A systematic review of treatment of typical absence seizures in children and adolescents with ethosuximide, sodium valproate or lamotrigine.

PURPOSE: To evaluate the role of ethosuximide, sodium valproate and lamotrigine in children and adolescents with typical absence seizures (AS). METHODS: A systematic review of randomized controlled trials that included children or adolescents with typical absence seizures who received treatment with ethosuximide, sodium valproate or lamotrigine. RESULTS: Four RCTs fulfilled the inclusion criteria. Due to the heterogeneity of the studies the results could not be pooled in a meta-analysis. CONCLUSIONS: We found no reliable evidence to inform clinical practice. The design of further trials should be pragmatic and compare one drug with another.

Anticonvulsants↗

PubMed2005

An overview of methods and empirical comparison of aggregate data and individual patient data results for investigating heterogeneity in meta-analysis of time-to-event outcomes.

Combining the results of individual studies using meta-analysis may be undertaken using either aggregate data (AD) or individual patient data (IPD). In any meta-analysis it is important to consider statistical heterogeneity between studies. Potential sources of heterogeneity can be explored using regression models with either AD or IPD. An overview of approaches and empirical assessment of how the results and conclusions differ from these analyses is undertaken using a meta-analysis of five randomized controlled trials comparing two antiepileptic drugs with time-to-event outcomes. Alternative meta-regression models using AD are compared to stratified Cox regression models using IPD. Age as a potential cause of heterogeneity is detected by both AD and IPD regression models. Time from first ever seizure to randomization is only identified by some AD models. A more thorough explanation of heterogeneity is obtained from the model using IPD but further empirical evidence comparing IPD and AD results are needed.

Clinical Trials as Topic↗

PubMed2005

Effect of carbon dioxide on background cerebral electrical activity and fractional oxygen extraction in very low birth weight infants just after birth.

Decreased arterial carbon dioxide tension (PaCO2) results in decreased cerebral blood flow, which is associated with diminished cerebral electrical activity. In such a situation, cerebral fractional oxygen extraction (CFOE) would be expected to increase to preserve cerebral oxygen delivery. This study aimed to determine whether changes in blood gases in infants less than 30 wk' gestation were associated with changes in background electroencephalograms (EEG) and CFOE. Thirty-two very low birth weight infants were studied daily for the first three days after birth. Digital EEG recordings were performed for 75 min each day. CFOE, mean blood pressure and arterial blood gases were measured midway through each recording. EEG was analysed by (a) spectral analysis and (b) manual calculation of interburst interval. Blood pressure, pH and PaCO2 did not have any effect on the EEG. On day one, only PaCO2 showed a relationship with the relative power of the delta frequency band (0.5-3.5 Hz) and the interburst interval. The relative power of the delta band remained within normal limits when PaCO2 was between 24 and 55 mmHg on day one. There was a negative association between PaCO2 and CFOE. The associations between PaCO2 and EEG measurements were strongest on day one, weaker on day two, and absent on day three. The slowing of EEG and increased CFOE at lower levels of PaCO2 are likely to be due to decreased cerebral oxygen delivery induced by hypocarbia. When PaCO2 was higher, there was suppression of the EEG.

Blood Gas Analysis↗

PubMed2002

Aggregate data meta-analysis with time-to-event outcomes.

In a meta-analysis of randomized controlled trials with time-to-event outcomes, an aggregate data approach may be required for some or all included studies. Variation in the reporting of survival analyses in journals suggests that no single method for extracting the log(hazard ratio) estimate will suffice. Methods are described which improve upon a previously proposed method for estimating the log(HR) from survival curves. These methods extend to life-tables. In the situation where the treatment effect varies over time and the trials in the meta-analysis have different lengths of follow-up, heterogeneity may be evident. In order to assess whether the hazard ratio changes with time, several tests are proposed and compared. A cohort study comparing life expectancy of males and females with cerebral palsy and a systematic review of five trials comparing two anti-epileptic drugs, carbamazepine and sodium valproate, are used for illustration.

Anticonvulsants↗

PubMed2002

Statistical issues in the assessment of the evidence for an interaction between factors in epilepsy trials.

We examine the common clinical belief that there is an interaction between epilepsy type and the two standard anti-epileptic drugs, valproate and carbamazepine, using data from several randomized clinical trials. Epilepsy type is not always easy to define, and three possible reclassifications are investigated to see whether misclassification of epilepsy type within the trials has potentially masked such an interaction. Regression modelling is employed to investigate whether heterogeneity between trial results can be explained by patient factors. Our work suggests that uncertainty in epilepsy type classification should be recognized in future studies. We also generate the hypothesis that the interaction of drug effect with age may reflect the perceived interaction with epilepsy type. We suggest that in any context where misclassification is likely, it is worth considering the use of an explicit 'unclassified' group, and investigating whether additional covariates can answer the substantive question.

Adolescent↗

PubMed2002

Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis.

PURPOSE: To provide an overview of the evidence comparing carbamazepine (CBZ) and valproate (VPA) monotherapy for epilepsy, investigating whether existing data support the current practice of preferring CBZ for partial-onset and VPA for generalized-onset seizures. METHODS: We performed meta-analysis of randomized controlled trials by using individual patient data. Our strategy included searches of (a) Medline, 1966-2000; (b) The Cochrane Library 2000, issue 4; and (c) the pharmaceutical industry. Outcome measures were time to discontinuation of allocated treatment, time to 12-month remission, and time to first seizure after randomization. Results are expressed as hazard ratios (HRs; 95% CI), where HR>1 indicates that an event is more likely with VPA. A test for an interaction between treatment and seizure type (partial vs. generalized onset) also was undertaken. RESULTS: Data were available for 1,265 patients from five trials. Overall results (HR, 95% CI) were Time to treatment discontinuation, 0.97 (0.79-1.18); 12-Month remission, 0.87 (0.74-1.02); and First seizure, 1.09 (0.96-1.25), suggesting no overall difference for these outcomes. The test for an interaction between Treatment and Seizure type was significant for time to first seizure, but for no other outcome. The age distribution of adults classified as having generalized seizures indicated that significant numbers of patients may have had their seizures misclassified. CONCLUSIONS: We found some evidence to support the preference of CBZ for partial-onset seizures, but no evidence to support the preference of VPA for generalized-onset seizures. Confidence intervals are too wide to infer equivalence. Misclassification of patients may have confounded our results and has important implications for future trials.

Adolescent↗