Gordon D. Murray

Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993.Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups.Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure.Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method.Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p<O.001). For all five trials the ACE inhibitor group had lower rates of death than the placebo group (1,467/6,391 [23.0%] vs 1,710/6,372 [26.8%]; 0.80 [0.74-0.87]) and lower rates of reinfarction (571 [8.9%] vs 703 [11.0%]; 0.79 [0.70-0.89]), readmission for heart failure (876 [13.7%] vs 1202 [18.9%]; 0.67 [0.61-0.74]), and the composite of these events (2161 [33.8%] vs 2610 [41.0%]; 0.72 [0.67-0.78]; all p<0.0001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined.

This prospective, multicenter study was performed to determine the frequency of symptomatic complications up to 30 months after stroke using prespecified definitions of complications.We recruited 311 consecutive stroke patients admitted to hospital. Research nurses reviewed their progress on a weekly basis until hospital discharge and again at 6, 18, and 30 months after stroke.Complications during hospital admission were recorded in 265 (85%) of stroke patients. Specific complications were as follows: neurological-recurrent stroke (9% of patients), epileptic seizure (3%); infections-urinary tract infection (24%), chest infection (22%), others (19%); mobility related-falls (25%), falls with serious injury (5%), pressure sores (21%); thromboembolism-deep venous thrombosis (2%), pulmonary embolism (1%); pain-shoulder pain (9%), other pain (34%); and psychological-depression (16%), anxiety (14%), emotionalism (12%), and confusion (56%). During follow-up, infections, falls, "blackouts, " pain, and symptoms of depression and anxiety remained common. Complications were observed across all 3 hospital sites, and their frequency was related to patient dependency and duration after stroke.Our prospective cohort study has confirmed that poststroke complications, particularly infections and falls, are common. However, we have also identified complications relating to pain and cognitive or affective symptoms that are potentially preventable and may previously have been underestimated.

Background Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors. Methods and Findings Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial. Conclusions Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.

<h2>Summary</h2><h3>Background</h3> The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10–100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. <h3>Methods</h3> In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. <h3>Findings</h3> 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI −4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). <h3>Interpretation</h3> The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. <h3>Funding</h3> UK Medical Research Council.

To determine the efficacy of oral nimodipine in reducing cerebral infarction and poor outcomes (death and severe disability) after subarachnoid haemorrhage.Double blind, placebo controlled, randomised trial with three months of follow up and intention to treat analysis. To have an 80% chance with a significance level of 0.05 of detecting a 50% reduction in an incidence of cerebral infarction of 15% a minimum of 540 patients was required.Four regional neurosurgical units in the United Kingdom.In all 554 patients were recruited between June 1985 and September 1987 out of a population of 1115 patients admitted with subarachnoid haemorrhage proved by the results of lumbar puncture or computed tomography, or both. The main exclusion criterion was admission to the neurosurgical units more than 96 hours after subarachnoid haemorrhage. There were four breaks of code and no exclusions after entry. One patient was withdrawn and in 130 treatment was discontinued early. All patients were followed up for three months and were included in the analysis, except the patient who had been withdrawn.Placebo or nimodipine 60 mg was given orally every four hours for 21 days to 276 and 278 patients, respectively. Treatment was started within 96 hours after subarachnoid haemorrhage.Incidence of cerebral infarction and ischaemic neurological deficits and outcome three months after entry.Demographic and clinical data, including age, sex, history of hypertension and subarachnoid haemorrhage, severity of haemorrhage according to an adaptation of the Glasgow coma scale, number and site of aneurysms on angiography, and initial findings on computed tomography were measured at entry. Deterioration, defined as development of a focal sign or fall of more than one point on the Glasgow coma scale for more than six hours, was investigated by using clinical criteria and by computed tomography, by lumbar puncture, or at necropsy when appropriate. All episodes of deterioration and all patients with a three month outcome other than a good recovery were assessed by a review committee.Demographic and clinical data at entry were similar in the two groups. In patients given nimodipine the incidence of cerebral infarction was 22% (61/278) compared with 33% (92/276) in those given placebo, a significant reduction of 34% (95% confidence interval 13 to 50%). Poor outcomes were also significantly reduced by 40% (95% confidence interval 20 to 55%) with nimodipine (20% (55/278) in patients given nimodipine v 33% (91/278) in those given placebo).Oral nimodipine 60 mg four hourly is well tolerated and reduces cerebral infarction snd improves outcome after subarachnoid haemorrhage.

Objective The aim of this study was to determine the reproducibility of pulse wave velocity (PWV) and augmentation index (AIx) measured using pulse wave analysis (PWA), prior to its use in large-scale clinical trials. Methods Arterial pressure waveforms were recorded and analysed using an established technique (Sphygmocor). Subjects with and without a range of recognized cardiovascular risk factors were studied to provide a wide range of values. Measurements were made after a brief introduction to the technique in a clinical setting. Two observers recorded aortic and brachial PWV in 24 subjects, each on two occasions, in a random order. In a separate study, two different observers used PWA to determine AIx in 33 subjects, each on two occasions, in a random order. Data were analysed using Bland-Altman plots and presented as mean ± SD. Results Brachial PWV was 8.65 ± 1.58 m/s (range 6.16–10.95 m/s) and aortic PWV was 8.15 ± 3.01 m/s (5.01–17.97 m/s). Within-observer variability was 0.14 ± 0.82 m/s for brachial PWV and 0.07 ± 1.17 m/s for aortic PWV. Corresponding between-observer values were −0.44 ± 1.09 m/s and −0.30 ± 1.25 m/s. AIx ranged from −15.0 to + 45.0%, with a group mean of + 19.6 ± 12.0%. The within-observer difference was 0.49 ± 5.37% and between-observer difference 0.23 ± 3.80%. Conclusion PWA is a simple and reproducible technique with which to measure PWV and AIx. Reproducibility accords with that reported by other workers using different methodologies. PWA may, therefore, be suitable for large-scale population and intervention studies investigating the clinical relevance of vascular stiffness.

Spontaneous supratentorial intracerebral haemorrhage accounts for 20% of all stroke-related sudden neurological deficits, has the highest morbidity and mortality of all stroke, and the role of surgery remains controversial. We undertook a prospective randomised trial to compare early surgery with initial conservative treatment for patients with intracerebral haemorrhage.A parallel-group trial design was used. Early surgery combined haematoma evacuation (within 24 h of randomisation) with medical treatment. Initial conservative treatment used medical treatment, although later evacuation was allowed if necessary. We used the eight-point Glasgow outcome scale obtained by postal questionnaires sent directly to patients at 6 months follow-up as the primary outcome measure. We divided the patients into good and poor prognosis groups on the basis of their clinical status at randomisation. For the good prognosis group, a favourable outcome was defined as good recovery or moderate disability on the Glasgow outcome scale. For the poor prognosis group, a favourable outcome also included the upper level of severe disability. Analysis was by intention to treat.1033 patients from 83 centres in 27 countries were randomised to early surgery (503) or initial conservative treatment (530). At 6 months, 51 patients were lost to follow-up, and 17 were alive with unknown status. Of 468 patients randomised to early surgery, 122 (26%) had a favourable outcome compared with 118 (24%) of 496 randomised to initial conservative treatment (odds ratio 0.89 [95% CI 0.66-1.19], p=0.414); absolute benefit 2.3% (-3.2 to 7.7), relative benefit 10% (-13 to 33).Patients with spontaneous supratentorial intracerebral haemorrhage in neurosurgical units show no overall benefit from early surgery when compared with initial conservative treatment.

Background Variation in outcome after head injury is not fully explained by known prognostic features. Polymorphism of the apolipoprotein E gene (APOE) influences neuropathological findings in patients who die from head injuries. More people who die from head injuries than non-head-injured controls have deposits of amyloid β-protein in the cerebral cortex, with amyloid β-protein deposits present predominantly in patients with the APOE ε4 allele. We report a prospective clinical study to test the hypothesis that patients with APOE ε4 have a worse clinical outcome 6 months after head injury than those without APOE ε4. Methods We studied a prospectively recruited series of patients admitted after a head injury to a neurosurgical unit (n=93). Assessment of severity of the initial injury was by means of the Glasgow Coma Score (GCS). Outcome 6 months after injury was assessed by means of the Glasgow Outcome Scale. APOE genotypes were determined from blood samples by standard methods. Findings Detailed information on outcome was available for 89 patients. 17 (57%) of 30 patients with APOE ε4 had an unfavourable outcome (dead, vegetative state, or severe disability) compared with 16 (27%) of the 59 patients without APOE ε4 (p=0·006). The association remained significant when adjustment was made to control for age, GCS, and computed tomography scan findings (p=0·024). Interpretation Our findings show a significant genetic association of APOE polymorphism with outcome after head injury supporting the hypothesis of a genetically determined influence. Patients with APOE ε4 are more than twice as likely as those without APOE ε4 to have an unfavourable outcome 6 months after head injury. Further studies are under way to confirm and further evaluate this association.

Since 1974, the Glasgow Coma Scale has provided a practical method for bedside assessment of impairment of conscious level, the clinical hallmark of acute brain injury. The scale was designed to be easy to use in clinical practice in general and specialist units and to replace previous ill-defined and inconsistent methods. 40 years later, the Glasgow Coma Scale has become an integral part of clinical practice and research worldwide. Findings using the scale have shown strong associations with those obtained by use of other early indices of severity and outcome. However, predictive statements should only be made in combination with other variables in a multivariate model. Individual patients are best described by the three components of the coma scale; whereas the derived total coma score should be used to characterise groups. Adherence to this principle and enhancement of the reliable practical use of the scale through continuing education of health professionals, standardisation across different settings, and consensus on methods to address confounders will maintain its role in clinical practice and research in the future.

Guidelines for the management of severe head injury in adults as evolved by the European Brain Injury Consortium are presented and discussed. The importance of preventing and treating secondary insults is emphasized and the principles on which treatment is based are reviewed. Guidelines presented are of a pragmatic nature, based on consensus and expert opinion, covering the treatment from accident site to intensive care unit. Specific aspects pertaining to the conduct of clinical trials in head injury are highlighted. The adopted approach is further discussed in relation to other approaches to the development of guidelines, such as evidence based analysis.

Increasing age is associated with poorer outcome in patients with closed traumatic brain injury (TBI). It is uncertain whether critical age thresholds exist, however, and the strength of the association has yet to be investigated across large series. The authors studied the shape and strength of the relationship between age and outcome, that is, the 6-month mortality rate and unfavorable outcome based on the Glasgow Outcome Scale.The shape of the association was examined in four prospective series with individual patient data (2664 cases). All patients had a closed TBI and were of adult age (96% < 65 years of age). The strength of the association was investigated in a metaanalysis of the aforementioned individual patient data (2664 cases) and aggregate data (2948 cases) from TBI studies published between 1980 and 2001 (total 5612 cases). Analyses were performed with univariable and multivariable logistic regression. Proportions of mortality and unfavorable outcome increased with age: 21 and 39%, respectively, for patients younger than 35 years and 52 and 74%, respectively, for patients older than 55 years. The association between age and both mortality and unfavorable outcome was continuous and could be adequately described by a linear term and expressed even better statistically by a linear and a quadratic term. The use of age thresholds (best fitting threshold 39 years) in the analysis resulted in a considerable loss of information. The strength of the association, expressed as an odds ratio per 10 years of age, was 1.47 (95% confidence interval [CI] 1.34-1.63) for death and 1.49 (95% CI 1.43-1.56) for unfavorable outcome in univariable analyses, and 1.39 (95% CI 1.3-1.5) and 1.46 (95% CI 1.36-1.56), respectively, in multivariable analyses. Thus, the odds for a poor outcome increased by 40 to 50% per 10 years of age.An older age is continuously associated with a worsening outcome after TBI; hence, it is disadvantageous to define the effect of age on outcome in a discrete manner when we aim to estimate prognosis or adjust for confounding variables.

We studied the prognostic value of a wide range of conventional and novel prognostic factors on admission after traumatic brain injury (TBI) using both univariate and multivariable analysis. The outcome measure was Glasgow Outcome Scale at 6 months after injury. Individual patient data were available on a cohort of 8686 patients drawn from eight randomized controlled trials and three observational studies. The most powerful independent prognostic variables were age, Glasgow Coma Scale (GCS) motor score, pupil response, and computerized tomography (CT) characteristics, including the Marshall CT classification and traumatic subarachnoid hemorrhage. Prothrombin time was also identified as a powerful independent prognostic factor, but it was only available for a limited number of patients coming from three of the relevant studies. Other important prognostic factors included hypotension, hypoxia, the eye and verbal components of the GCS, glucose, platelets, and hemoglobin. These results on prognostic factors will underpin future work on the IMPACT project, which is focused on the development of novel approaches to the design and analysis of clinical trials in TBI. In addition, the results provide pointers to future research, including further analysis of the prognostic value of prothrombin time, and the evaluation of the clinical impact of intervening aggressively to correct abnormalities in hemoglobin, glucose, and coagulation.

The Glasgow Outcome Scale (GOS), two decades after its description, remains the most widely used method of analyzing outcome in series of severely head-injured patients. This review considers limitations recognized in the use of the GOS and discusses a new approach to assessment, using a structured questionnaire-based interview. Assignments can be made to an extended eight-point scale (GOSE) as well as the original five-point approach—in each case, with a high degree of interobserver consistency. The assignments are coherent with the principles of the World Health Organization classification of impairments, disabilities, and handicaps, and their validity is supported by strong associations with the results of neuropsychological testing and assessment of general health status. The need to allow for disability existing before injury, issues concerning the time of assessment after injury, and subdivisions of the scale into "favorable" and "unfavorable" categories are discussed. It is concluded that, in its improved structured format, the Glasgow Outcome Scale should remain the primary method of assessing outcome in trials of the management of severe head injury.

Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure.Participants in this randomised, placebo-controlled, double-blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included within 30 h of symptom onset. Patients were randomly allocated to candesartan or placebo (1:1) for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7. Randomisation was stratified by centre, with blocks of six packs of candesartan or placebo. Patients and investigators were masked to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered, number NCT00120003 (ClinicalTrials.gov), and ISRCTN13643354.2029 patients were randomly allocated to treatment groups (1017 candesartan, 1012 placebo), and data for status at 6 months were available for 2004 patients (99%; 1000 candesartan, 1004 placebo). During the 7-day treatment period, blood pressures were significantly lower in patients allocated candesartan than in those on placebo (mean 147/82 mm Hg [SD 23/14] in the candesartan group on day 7 vs 152/84 mm Hg [22/14] in the placebo group; p<0·0001). During 6 months' follow-up, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio 1·09, 95% CI 0·84-1·41; p=0·52). Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1·17, 95% CI 1·00-1·38; p=0·048 [not significant at p≤0·025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (<1%) on placebo had symptomatic hypotension, and renal failure was reported for 18 (2%) patients taking candesartan and 13 (1%) allocated placebo.There was no indication that careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. If anything, the evidence suggested a harmful effect.South-Eastern Norway Regional Health Authority; Oslo University Hospital Ullevål; AstraZeneca; Takeda.

To determine whether raised plasma glucose concentration independently influences outcome after acute stroke or is a stress response reflecting increased stroke severity.Long-term follow up study of patients admitted to an acute stroke unit.Western Infirmary, Glasgow.811 patients with acute stroke confirmed by computed tomography. Analysis was restricted to the 750 non-diabetic patients.Survival time and placement three months after stroke.645 patients (86%) had ischaemic stroke and 105 patients (14%) haemorrhagic stroke. Cox's proportional hazards modelling with stratification according to Oxfordshire Community Stroke Project categories identified increased age (relative hazard 1.36 per decade; 95% confidence interval 1.21 to 1.53), haemorrhagic stroke (relative hazard 1.67; 1.22 to 2.28), time to resolution of symptoms > 72 hours (relative hazard 2.15; 1.15 to 4.05), and hyperglycaemia (relative hazard 1.87; 1.43 to 2.45) as predictors of mortality. The effect of glucose concentration on survival was greatest in the first month.Plasma glucose concentration above 8 mmol/l after acute stroke predicts a poor prognosis after correcting for age, stroke severity, and stroke subtype. Raised plasma glucose concentration is therefore unlikely to be solely a stress response and should arguably be treated actively. A randomised trial is warranted.

In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear.

The relationship between levels of circulating inflammatory markers and risk of progressive atherosclerosis is relatively undetermined. We therefore studied inflammatory markers as predictors of peripheral atherosclerotic progression, measured by the ankle-brachial index (ABI) at 3 consecutive time points over 12 years.The Edinburgh Artery Study is a population cohort study of 1592 men and women aged 55 to 74 years. C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin were measured at baseline. Valid ABI measurements were obtained on 1582, 1081, and 813 participants at baseline and 5-year and 12-year follow-up examinations, respectively. At baseline, a significant trend was found between higher plasma levels of CRP (P< or =0.05) and increasing severity of peripheral arterial disease (PAD), after adjustment for baseline cardiovascular risk factors. IL-6 at baseline (P< or =0.001) was associated with progressive atherosclerosis at 5 years (ABI change from baseline), and CRP (P< or =0.01), IL-6 (P< or =0.001), and ICAM-1 (P< or =0.01) were associated with changes at 12 years, independently of baseline ABI, cardiovascular risk factors, and baseline cardiovascular disease. Only IL-6 independently predicted ABI change at 5 years (P< or =0.01) and 12 years (P< or =0.05) in analyses of all inflammatory markers simultaneously and adjusted for baseline ABI, cardiovascular risk factors, and cardiovascular disease at baseline.These findings suggest that CRP, IL-6, and ICAM-1 are molecular markers associated with atherosclerosis and its progression. IL-6 showed more consistent results and stronger independent predictive value than other inflammatory markers.

To determine the strength and consistency with which a low ankle brachial pressure index (ABI), measured in the general population, is associated with an increased risk of subsequent death and/or cardiovascular events.Systematic review.Medline, Embase, reference lists and grey literature were searched; studies known to experts were also retrieved.All cause mortality, fatal and non-fatal coronary heart disease and stroke.Longitudinal studies in which participants were representative of the general population (all ages, either sex) and which used any standard method for measurement and calculation of the ABI. Studies in which participants were selected according to presence of pre-existing disease or were post intervention (e.g. angioplasty or peripheral arterial grafting) were excluded.11 studies comprising 44,590 subjects from six different countries were included. Despite clinical heterogeneity between studies, the findings were remarkably consistent in demonstrating an increased risk of clinical cardiovascular disease associated with a low ABI. A low ABI (<0.9) was associated with an increased risk of subsequent all cause mortality (pooled RR 1.60, 95% CI 1.32-1.95), cardiovascular mortality (pooled RR 1.96, 95% CI 1.46-2.64), coronary heart disease (pooled RR 1.45, 95% CI 1.08-1.93) and stroke (pooled RR 1.35, 95% CI 1.10-1.65) after adjustment for age, sex, conventional cardiovascular risk factors and prevalent cardiovascular disease.The ABI may help to identify asymptomatic individuals in the general population who are at increased risk of subsequent cardiovascular events. Evaluation is now required of the potential of incorporating ABI measurement into cardiovascular prevention programmes.

Information on the nature and relative frequency of diagnoses made in referrals to neurology outpatient clinics is an important guide to priorities in services, teaching and research. Previous studies of this topic have been limited by being of only single centres or lacking in detail. We aimed to describe the neurological diagnoses made in a large series of referrals to neurology outpatient clinics.Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded the initial diagnosis they made. An additional rating of the degree to which the neurologist considered the patient's symptoms to be explained by disease was used to categorise those diagnoses that simply described a symptom such as 'fatigue'.Three thousand seven hundred and eighty-one patients participated (91% of those eligible). The commonest categories of diagnosis made were: headache (19%), functional and psychological symptoms (16%), epilepsy (14%), peripheral nerve disorders (11%), miscellaneous neurological disorders (10%), demyelination (7%), spinal disorders (6%), Parkinson's disease/movement disorders (6%), and syncope (4%). Detailed breakdowns of each category are provided.Headache, functional/psychological disorders and epilepsy are the most common diagnoses in new patient referral to neurological services. This information should be used to shape priorities for services, teaching and research.

Traumatic brain injury (TBI) is a heterogeneous condition that encompasses a broad spectrum of disorders. Outcome can be highly variable, particularly in more severely injured patients. Despite the association of many variables with outcome, prognostic predictions are notoriously difficult to make. Multivariable analysis has identified age, clinical severity, CT abnormalities, systemic insults (hypoxia and hypotension), and laboratory variables as relevant factors to include in models to predict outcome in individual patients. Advances in statistical modelling and the availability of large datasets have facilitated the development of prognostic models that have greater performance and generalisability. Two prediction models are currently available, both of which have been developed on large datasets with state-of-the-art methods, and offer new opportunities. We see great potential for their use in clinical practice, research, and policy making, as well as for assessment of the quality of health-care delivery. Continued development, refinement, and validation is advocated, together with assessment of the clinical impact of prediction models, including treatment response.

To provide a picture of contemporary practice, a survey was carried out of severely and moderately head injured patients admitted to 67 `neuro' centres in 12 European countries. 1,005 adult head injuries were recruited over a three month period. Sixty items of information on demography, clinical features, investigations, management and early complications were captured on a simple, two-page questionnaire and, information on outcome at six months on a third page. The median age of the subjects was 38 years, 74% were male and 51% injured in road traffic accidents; 57% of patients were transferred to the `neuro' centre from another hospital. Assessment of clinical responsiveness was limited by the use of sedation and intubation and information from four early time points (pre-hospital, arrival at the Accident and Emergency department, post-resuscitation, and arrival at the `neuro' unit) was combined to stratify the subjects as severe (58%), moderate (17%) or intermediate (19%). In 48% of patients classified the CT scan showed features of a `mass lesion' and in 40% showed a subarachnoid haemorrhage. Fifty-five centres provided the data on outcome for 94% of the cases recruited in these centres six months after injury. 31% died, 3% were vegetative, 16% severely disabled, 20% moderately disabled and 31% had made a good recovery. Comparison of the data from different parts of Europe showed differences in the frequency of secondary transfer, cause of injury, occurrence of major extracranial injury, CT scan findings, intracranial operation, clinical severity of injury and utilisation of the components of intensive care and the occurrence of a favourable outcome, although the latter difference was not statistically significant when variations in the initial severity of injury were taken into account. The findings in the present survey are compared with newly analysed information for three previous large series: the International Data Bank involving the UK, the Netherlands and the USA, the North American Traumatic Coma Data Bank, and data from four centres in the UK. The comparisons showed substantial similarities and also differences that may reflect variations in policy for admission of the head injury to `neuro' units, and evolution in methods of assessment, investigation and management. The effects of these differences on outcome requires further, rigorous prospective study.

We determined the relationship between secondary insults (hypoxia, hypotension, and hypothermia) occurring prior to or on admission to hospital and 6-month outcome after traumatic brain injury (TBI). A meta-analysis of individual patient data, from seven Phase III randomized clinical trials (RCT) in moderate or severe TBI and three TBI population-based series, was performed to model outcome as measured by the Glasgow Outcome Scale (GOS). Proportional odds modeling was used to relate the probability of a poor outcome to hypoxia (N = 5661), hypotension ( N = 6629), and hypothermia ( N = 4195) separately. We additionally analyzed the combined effects of hypoxia and hypotension and performed exploratory analysis of associations with computerized tomography (CT) classification and month of injury. Having a pre-enrollment insult of hypoxia, hypotension or hypothermia is strongly associated with a poorer outcome (odds ratios of 2.1 95% CI [1.7-2.6], 2.7 95% CI [2.1-3.4], and 2.2 95% CI [1.6-3.2], respectively). Patients with both hypoxia and hypotension had poorer outcomes than those with either insult alone. Radiological signs of raised intracranial pressure (CT class III or IV) were more frequent in patients who had sustained hypoxia or hypotension. A significant association was observed between month of injury and hypothermia. The occurrence of secondary insults prior to or on admission to hospital in TBI patients is strongly related to poorer outcome and should therefore be a priority for emergency department personnel.

Clinical trials routinely use stroke scales to compare baseline characteristics of treatment groups. It is unclear which stroke scale provides the most prognostic information. This often leads to collection of multiple scales in clinical trials. We aimed to determine which of several commonly used scales best predicted outcome.A single observer scored consecutive admissions to an acute stroke unit on the National Institutes of Health Stroke Scale (NIHSS), the Canadian Neurological Scale, and the Middle Cerebral Artery Neurological Score. Guy's prognostic score was determined from clinical data. Outcome at 2, 3, 6, and 12 months was categorized as good (alive at home) or poor (alive in care or dead). Predictive accuracy of the variables was compared by receiver operating characteristic curves and stepwise logistic regression.Of the 408 patients studied, 373 had confirmed acute stroke and completed follow-up. The three stroke rating scales each predicted 3-month outcome with an accuracy of .79 or greater. The NIHSS provided the most prognostic information: sensitivity to poor outcome, .71 (95% confidence interval [CI], .64 to .79); specificity, .90 (95% CI, .86 to .94); and overall accuracy, .83 (95% CI, .79 to .87). Logistic regression showed that the NIHSS added significantly to the predictive value of all other scores. No score added useful information to the NIHSS. A cut point of 13 on the NIHSS best predicted 3-month outcome.Baseline NIHSS best predicts 3-month outcome. The Canadian Neurological Scale and Middle Cerebral Artery Neurological Score also perform well. Baseline assessments in clinical trials only need to include a single stroke rating scale.

Traumatic brain injury (TBI) is a major health and socio-economic problem throughout the world. Many randomized controlled trials (RCTs) have been performed to investigate the effectiveness of new therapies, but none have convincingly demonstrated benefit. Clinical trials in TBI pose complex methodological challenges and meeting these requires new approaches. The challenges are related to the heterogeneity of head injuries, to optimum analysis of outcome and to aspects of the design of trials. To address these, we have created the IMPACT database on TBI through merging individual patient data from eight RCTs and three observational surveys. This database forms a culture medium in which innovative approaches to improving trial design and analysis are being explored. We hypothesize that the statistical power of TBI trials may be increased by adjusting for heterogeneity with covariate adjustment and/or prognostic targeting, by exploiting the ordinal nature of the Glasgow Outcome Scale and by relating the outcome obtained in individual patients to their baseline prognostic risk. Extensive prognostic analysis was required as a first step towards our aim of optimizing the chance of demonstrating benefit of new therapies in future trials. The fruits of this analysis are reported in detail in the subsequent reports in this issue of the Journal of Neurotrauma. The results will lead to the development and validation of new prognostic models, which will be applied to deal with heterogeneity. The findings will be synthesized into recommendations for the design and analysis of future RCTs, with the expectation of increasing the likelihood of demonstrating the benefit of a truly effective new therapy or therapeutic agent in victims of a head injury.

Major depressive disorder severely impairs the quality of life of patients with medical disorders such as cancer, but evidence to guide its management is scarce. We aimed to assess the efficacy and cost of a nurse-delivered complex intervention that was designed to treat major depressive disorder in patients who have cancer.We did a randomised trial in a regional cancer centre in Scotland, UK. 200 outpatients who had cancer with a prognosis of greater than 6 months and major depressive disorder (identified by screening) were eligible and agreed to take part. Their mean age was 56.6 (SD 11.9) years, and 141 (71%) were women. We randomly assigned 99 of these participants to usual care, and 101 to usual care plus the intervention, with minimisation for sex, age, diagnosis, and extent of disease. The intervention was delivered by a cancer nurse at the centre over an average of seven sessions. The primary outcome was the difference in mean score on the self-reported Symptom Checklist-20 depression scale (range 0 to 4) at 3 months after randomisation. Analysis was by intention to treat. This trial is registered as ISRCTN84767225.Primary outcome data were missing for four patients. For 196 patients for whom we had data at 3 months, the adjusted difference in mean Symptom Checklist-20 depression score, between those who received the intervention and those who did not, was 0.34 (95% CI 0.13-0.55). This treatment effect was sustained at 6 and 12 months. The intervention also improved anxiety and fatigue but not pain or physical functioning. It cost an additional pound sterling 5278 (US$10 556) per quality-adjusted life-year gained.The intervention-Depression Care for People with Cancer-offers a model for the management of major depressive disorder in patients with cancer and other medical disorders who are attending specialist medical services that is feasible, acceptable, and potentially cost effective.

We studied the prognostic strength of the individual components of the Glasgow Coma Scale (GCS) and pupil reactivity to Glasgow Outcome Score (GOS) at 6 months post-injury. A total of 8721 moderate or severe traumatic brain injury (TBI) patient data from the IMPACT database on traumatic brain injury comprised the study cohort. The associations between motor score and pupil reactivity and 6-month GOS were analyzed by binary logistic regression and proportional odds methodology. The strength of prognostic effects were expressed as the unadjusted odds ratios presented for all individual studies as well as in meta-analysis. We found a consistent strong association between motor score and 6-month GOS across all studies (OR 1.74–7.48). The Eye and Verbal components were also strongly associated with GOS. In the pooled population, one or both un-reactive pupils and lower motor scores were significantly associated with unfavorable outcome (range 2.71–7.31). We also found a significant change in motor score from pre-hospital direct to study hospital enrollment ( p < 0.0001) and from the first in-hospital to study enrollment scores (p < 0.0001). Pupil reactivity was more robust between these time points. It is recommended that the study hospital enrollment GCS and pupil reactivity be used for prognostic analysis.

It has been previously reported that a substantial proportion of newly referred neurology out-patients have symptoms that are considered by the assessing neurologist as unexplained by ‘organic disease’. There has however been much controversy about how often such patients subsequently develop a disease diagnosis that, with hindsight, would have explained the symptoms. We aimed to determine in a large sample of new neurology out-patients: (i) what proportion are assessed as having symptoms unexplained by disease and the diagnoses given to them; and (ii) how often a neurological disorder emerged which, with hindsight, explained the original symptoms. We carried out a prospective cohort study of patients referred from primary care to National Health Service neurology clinics in Scotland, UK. Measures were: (i) the proportion of patients with symptoms rated by the assessing neurologist as ‘not at all’ or only ‘somewhat explained’ by ‘organic disease’ and the neurological diagnoses recorded at initial assessment; and (ii) the frequency of unexpected new diagnoses made over the following 18 months (according to the primary-care physician). One thousand four hundred and forty-four patients (30% of all new patients) were rated as having symptoms ‘not at all’ or only ‘somewhat explained’ by ‘organic disease’. The most common categories of diagnosis were: (i) organic neurological disease but with symptoms unexplained by it (26%); (ii) headache disorders (26%); and (iii) conversion symptoms (motor, sensory or non-epileptic attacks) (18%). At follow-up only 4 out of 1030 patients (0.4%) had acquired an organic disease diagnosis that was unexpected at initial assessment and plausibly the cause of the patients’ original symptoms. Eight patients had died at follow-up; five of whom had initial diagnoses of non-epileptic attacks. Seven other types of diagnostic change with very different implications to a ‘missed diagnosis’ were found and a new classification of diagnostic revision is presented. One-third of new neurology out-patients are assessed as having symptoms ‘unexplained by organic disease’. A new diagnosis, which with hindsight explained the original symptoms, rarely became apparent to the patient's primary care doctor in the 18 months following the initial hospital consultation.

Several techniques for discriminant analysis are applied to a set of data from patients with severe head injuries, for the purpose of prognosis. The data are such that multidimensionality, continuous, binary and ordered categorical variables and missing data must be coped with. The various methods are compared using criteria of prognostic success and reliability. In general, performance varies more with choice of the set of predictor variables than with that of the discriminant rule.

Cerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location.We undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM.139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0-5·7 vs 29·5%, 4·1-55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1-15·4 vs 42·4%, 26·8-58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1-33·4) in year 1 to 5·0% (0·0-14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17).The risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men.UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

The International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation After Significant Head injury prognostic models predict outcome after traumatic brain injury but have not been compared in large datasets. The objective of this is study is to validate externally and compare the International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation after Significant Head injury prognostic models for prediction of outcome after moderate or severe traumatic brain injury.External validation study.We considered five new datasets with a total of 9,036 patients, comprising three randomized trials and two observational series, containing prospectively collected individual traumatic brain injury patient data.Outcomes were mortality and unfavorable outcome, based on the Glasgow Outcome Score at 6 months after injury. To assess performance, we studied the discrimination of the models (by area under the receiver operating characteristic curves), and calibration (by comparison of the mean observed to predicted outcomes and calibration slopes). The highest discrimination was found in the Trauma Audit and Research Network trauma registry (area under the receiver operating characteristic curves between 0.83 and 0.87), and the lowest discrimination in the Pharmos trial (area under the receiver operating characteristic curves between 0.65 and 0.71). Although differences in predictor effects between development and validation populations were found (calibration slopes varying between 0.58 and 1.53), the differences in discrimination were largely explained by differences in case mix in the validation studies. Calibration was good, the fraction of observed outcomes generally agreed well with the mean predicted outcome. No meaningful differences were noted in performance between the International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation After Significant Head injury models. More complex models discriminated slightly better than simpler variants.Since both the International Mission on Prognosis and Analysis of Clinical Trials and the Corticoid Randomisation After Significant Head injury prognostic models show good generalizability to more recent data, they are valid instruments to quantify prognosis in traumatic brain injury.

BackgroundDepression has substantial effects on cancer patients' quality of life. Estimates of its prevalence vary widely. We aimed to systematically review published studies to obtain the best estimate of the prevalence of depression in clinically meaningful subgroups of cancer patients.DesignSystematic review that addressed the limitations of previous reviews by (i) including only studies that used diagnostic interviews; (ii) including only studies that met basic quality criteria (random or consecutive sampling, ≥70% response rate, clear definition of depression caseness, sample size ≥100); (iii) grouping studies into clinically meaningful subgroups; (iv) describing the effect on prevalence estimates of different methods of diagnosing depression.ResultsOf 66 relevant studies, only 15 (23%) met quality criteria. The estimated prevalence of depression in the defined subgroups was as follows: 5% to 16% in outpatients, 4% to 14% in inpatients, 4% to 11% in mixed outpatient and inpatient samples and 7% to 49% in palliative care. Studies which used expert interviewers (psychiatrists or clinical psychologists) reported lower prevalence estimates.ConclusionsOf the large number of relevant studies, few met our inclusion criteria, and prevalence estimates are consequently imprecise. We propose that future studies should be designed to meet basic quality criteria and employ expert interviewers.

The benefit of statins in patients with acute aneurysmal subarachnoid haemorrhage is unclear. We aimed to determine whether simvastatin 40 mg could improve the long-term outcome in patients with this disorder.In this international, multicentre, randomised, double-blind trial, we enrolled patients aged 18-65 years with confirmatory evidence of an aneurysmal subarachnoid haemorrhage and presenting less than 96 h from ictus from 35 acute neurosurgical centres in nine countries. Patients were randomly allocated (1:1) to receive either simvastatin 40 mg or placebo once a day for up to 21 days. We used a computer-generated randomisation code to randomise patients in every centre by blocks of ten (five simvastatin, five placebo). Participants and investigators were masked to treatment assignment. The primary outcome was the distribution of modified Rankin Scale (mRS) score obtained by questionnaire at 6 months. Analyses were done on the intention-to-treat population. This trial has been completed and is registered with Current Controlled Trials, number ISRCTN75948817.Between Jan 6, 2007, and Feb 1, 2013, apart from the period between May 15, 2009, and Feb 8, 2011, when recruitment was on hold, 803 patients were randomly assigned to receive either simvastatin 40 mg (n=391) or placebo (n=412). All patients were included in the intention-to-treat population. 782 (97%) patients had outcome data recorded at 6 months, of whom 560 (72%) were classed as having a favourable outcome, mRS 0-2 (271 patients in the simvastatin group vs 289 in the placebo group). The primary ordinal analysis of the mRS, adjusted for age and World Federation of Neurological Surgeons grade on admission, gave a common odds ratio (OR) of 0·97, 95% CI 0·75-1·25; p=0·803. At 6 months, we recorded 37 (10%) deaths in the simvastatin group compared with 35 (9%) in the placebo group (log-rank p=0·592). 70 (18%) serious adverse events were reported in the simvastatin group compared with 74 (18%) in the placebo group. No suspected unexpected serious adverse reactions were reported.The STASH trial did not detect any benefit in the use of simvastatin for long-term or short-term outcome in patients with aneurysmal subarachnoid haemorrhage. Despite demonstrating no safety concerns, we conclude that patients with subarachnoid haemorrhage should not be treated routinely with simvastatin during the acute stages.British Heart Foundation.

The improvement in left-ventricular ejection fraction (LVEF) in response to beta blockers is heterogeneous in patients with heart failure due to ischaemic heart disease, possibly indicating variations in the myocardial substrate underlying left-ventricular dysfunction. We investigated whether improvement in LVEF was associated with the volume of hibernating myocardium (viable myocardium with contractile failure).We did a double-blind, randomised trial to compare placebo and carvedilol for 6 months in individuals with stable, chronic heart failure due to ischaemic left-ventricular systolic dysfunction. We enrolled 489 patients, of whom 387 were randomised. Patients were designated hibernators or non-hibernators according to the volume of hibernating myocardium. The primary endpoint was change in LVEF, measured by radionuclide ventriculography, in hibernators versus non-hibernators, on carvedilol compared with placebo. Analysis was by intention to treat.82 patients dropped out of the study because of adverse events, withdrawal of consent, or failure to complete the investigation. Thus, 305 (79%) were analysed. LVEF was unchanged with placebo (mean change -0.4 [SE 0.9] and -0.4 [0.8] for non-hibernators and hibernators, respectively) but increased with carvedilol (2.5 [0.9] and 3.2 [0.8], respectively; p<0.0001 compared with baseline). Mean placebo-subtracted change in LVEF was 3.2% (95% CI 1.8-4.7; p=0.0001) overall, and 2.9% (0.7-5.1; p=0.011) and 3.6% (1.7-5.4; p=0.0002) in non-hibernators and hibernators, respectively. Effect of hibernator status on response of LVEF to carvedilol was not significant (0.7 [-2.2 to 3.5]; p=0.644). However, patients with more myocardium affected by hibernation or by hibernation and ischaemia had a greater increase in LVEF on carvedilol (p=0.0002 and p=0.009, respectively).Some of the effect of carvedilol on LVEF might be mediated by improved function of hibernating or ischaemic myocardium, or both. Medical treatment might be an important adjunct or alternative to revascularisation for patients with hibernating myocardium.

The early prediction of outcome after traumatic brain injury (TBI) is important for several purposes, but no prognostic models have yet been developed with proven generalizability across different settings. The objective of this study was to develop and validate prognostic models that use information available at admission to estimate 6-month outcome after severe or moderate TBI. To this end, this study evaluated mortality and unfavorable outcome, that is, death, and vegetative or severe disability on the Glasgow Outcome Scale (GOS), at 6 months post-injury. Prospectively collected data on 2269 patients from two multi-center clinical trials were used to develop prognostic models for each outcome with logistic regression analysis. We included seven predictive characteristics-age, motor score, pupillary reactivity, hypoxia, hypotension, computed tomography classification, and traumatic subarachnoid hemorrhage. The models were validated internally with bootstrapping techniques. External validity was determined in prospectively collected data from two relatively unselected surveys in Europe (n = 796) and in North America (n = 746). We evaluated the discriminative ability, that is, the ability to distinguish patients with different outcomes, with the area under the receiver operating characteristic curve (AUC). Further, we determined calibration, that is, agreement between predicted and observed outcome, with the Hosmer-Lemeshow goodness-of-fit test. The models discriminated well in the development population (AUC 0.78-0.80). External validity was even better (AUC 0.83-0.89). Calibration was less satisfactory, with poor external validity in the North American survey (p < 0.001). Especially, observed risks were higher than predicted for poor prognosis patients. A score chart was derived from the regression models to facilitate clinical application. Relatively simple prognostic models using baseline characteristics can accurately predict 6-month outcome in patients with severe or moderate TBI. The high discriminative ability indicates the potential of this model for classifying patients according to prognostic risk.

Purpose Eicosapentaenoic acid (EPA) has been proposed to have specific anticachectic effects. This trial compared EPA diethyl ester with placebo in cachectic cancer patients for effects on weight and lean body mass. Patients and Methods Five hundred eighteen weight-losing patients with advanced gastrointestinal or lung cancer were studied in a multicenter, double-blind, placebo controlled trial. Patients were randomly assigned to receive a novel preparation of pure EPA at a dose of 2 g or 4 g daily or placebo (2g EPA, n = 175; 4 g EPA, n = 172; placebo, n = 171). Patients were assessed at 4 weeks and 8 weeks. Results The groups were well balanced at baseline. Mean weight loss at baseline was 18% (n = 518). Over the 8-week treatment period, both intention-to-treat analysis and per protocol analysis revealed no statistically significant improvements in survival, weight, or other nutritional variables. There was, however, a trend in favor of EPA with analysis of the primary end point, weight, at 8 weeks showing a borderline, nonsignificant treatment effect (P = .066). Relative to placebo, mean weight increased by 1.2 kg with 2 g EPA (95% CI, 0 kg to 2.3 kg) and by 0.3 kg with 4g EPA (−0.9 kg to 1.5 kg). Conclusion The results indicate no statistically significant benefit from single agent EPA in the treatment of cancer cachexia. Future studies should concentrate on other agents or combination regimens.

Outcome following traumatic brain injury (TBI) is not only dependent on the nature and severity of injury and subsequent treatment, but also on constituent characteristics of injured individuals. We aimed to describe and quantify the relationship between demographic characteristics and six month outcome assessed by the Glasgow Outcome Scale (GOS) after TBI. Individual patient data on age (n = 8719), gender (n = 8720), race (n = 5320), and education (n = 2201) were extracted from eight therapeutic Phase III randomized clinical trials and three surveys in moderate or severe TBI, contained in the IMPACT database. The strength of prognostic effects was analyzed with binary and proportional odds regression analysis and expressed as an odds ratio. Age was analyzed as a continuous variable with spline functions, and the odds ratio calculated over the difference between the 75 th and 25 th percentiles. Associations with other predictors were explored. Increasing age was strongly related to poorer outcome (OR 2.14; 95% CI 2.00–2.28) in a continuous fashion that could be approximated by a linear function. No gender differences in outcome were found (OR: 1.01; CI 0.92–1.11), and exploratory analysis failed to show any gender/age interaction. The studies included predominantly Caucasians (83%); outcome in black patients was poorer relative to this group (OR 1.30; CI 1.09–1.56). This relationship was sustained on adjusted analyses, and requires further study into mediating factors. Higher levels of education were weakly related to a better outcome (OR: 0.70; CI 0.52–0.94). On multivariable analysis adjusting for age, motor score, and pupils, the prognostic effect of race and education were sustained. We conclude that outcome following TBI is dependent on age, race, to a lesser extent on education, but not on gender.

Traumatic brain injury is a major cause of death and disability. We sought to assess the safety and efficacy of dexanabinol, a synthetic cannabinoid analogue devoid of psychotropic activity, in severe traumatic brain injury.861 patients with severe traumatic brain injury admitted to 86 specialist centres from 15 countries were included in a multi-centre, placebo-controlled, phase III trial. Patients were randomised to receive a single intravenous 150 mg dose of dexanabinol or placebo within 6 h of injury. The primary outcome was the extended Glasgow outcome scale assessed at 6 months, with the point of dichotomisation into unfavourable versus favourable outcome differentiated by baseline prognostic risk. Prespecified subgroup analyses were defined by injury severity, recruitment rate, and time to dosing. Secondary analysis included control of intracranial pressure and quality of life. Analysis were prespecified in the protocol and the statistical analysis plan. This study is registered with ClinicalTrials.gov, number NCT00129857.846 patients were included in the efficacy analysis. The extended Glasgow outcome scale at 6 months did not differ between groups; 215 (50%) patients in the dexanabinol group and 214 (51%) patients in the placebo group had an unfavourable outcome (odds ratio for a favourable response 1.04; 95% CI 0.79-1.36). Improvements in the control of intracranial pressure or quality of life were not recorded and subgroup analysis showed no indication of differential treatment effects. Dexanabinol was not associated with hepatic, renal, or cardiac toxic effects.Dexanabinol is safe, but is not efficacious in the treatment of traumatic brain injury.

Computerized tomography (CT) scanning provides an objective assessment of the structural damage to the brain following traumatic brain injury (TBI). We aimed to describe and quantify the relationship between CT characteristics and 6-month outcome, assessed by the Glasgow Outcome Scale (GOS). Individual patient data from the IMPACT database were available on CT classification (N = 5209), status of basal cisterns ( N = 3861), shift ( N = 4698), traumatic subarachnoid hemorrhage (tSAH) ( N = 7407), and intracranial lesions ( N = 7613). We used binary logistic and proportional odds regression for prognostic analyses. The CT classification was strongly related to outcome, with worst outcome for patients with diffuse injuries in CT class III (swelling; OR 2.50; CI 2.09–3.0) or CT class IV (shift; OR 3.03; CI 2.12–4.35). The prognosis in patients with mass lesions was better for patients with an epidural hematoma (OR 0.64; CI 0.56–0.72) and poorer for an acute subdural hematoma (OR 2.14; CI 1.87–2.45). Partial obliteration of the basal cisterns (OR 2.45; CI 1.88–3.20), tSAH (OR 2.64; CI 2.42–2.89), or midline shift (1–5 mm—OR 1.36; CI 1.09–1.68); >5 mm—OR 2.20; CI 1.64–2.96) were strongly related to poorer outcome. Discrepancies were found between the scoring of basal cisterns/shift and the CT classification, indicating observer variation. These were less marked in studies that had used a central review process. Multivariable analysis indicated that individual CT characteristics added substantially to the prognostic value of the CT classification alone. We conclude that both the CT classification and individual CT characteristics are important predictors of outcome in TBI. For clinical trials, a central review process is advocated to minimize observer variability in CT assessment.

The authors compared both the initial and the long-term outcomes of patients undergoing stapled and sutured colorectal anastomoses.Sutured and stapled large bowel anastomoses are perceived to be equally safe, but concern has been raised about increased rates of tumor recurrence with the use of stapling instruments.The outcome of patients with sutured and stapled colorectal anastomoses were compared in a prospective, multicenter, randomized study. Factors affecting long-term outcomes were assessed by both univariate and multivariate analysis.Seven hundred thirty-two patients were recruited. There was a significant increase in radiologic leakage in the sutured group (14.4% vs. 5.2%, p < 0.05), but there was no difference in clinical anastomotic leak rates, morbidity, or postoperative mortality. Tumor recurrence and cancer-specific mortality were higher in the sutured patients (7.5% and 6.7%, respectively) and in patients with anastomotic leaks.This study shows that suturing or stapling are equally safe in large bowel surgery. However, it also shows a long-term benefit of stapling in colorectal cancer patients.

To determine the factors influencing the risk of an acute traumatic intracranial haematoma in children and adults with a recent head injury.Prospective study of incidence of risk factors in samples of patients attending accident and emergency departments and in all patients having an acute traumatic intracranial haematoma evacuated in one regional neurosurgical unit during 11 years.Accident and emergency departments in Scotland or Teesside and regional neurosurgical centre in Glasgow.8406 Adults and children (less than or equal to 14 years) who attended accident and emergency departments and 1007 consecutive patients who had an operation for an acute traumatic intracranial haematoma. Data were complete in 8366 and 960 patients respectively.Overall, children were less at risk than adults (one in 2100 v one in 348 respectively). In both age groups the presence of a skull fracture and changes in conscious level permitted identification of subgroups of patients with widely differing degrees of risk. In children the absolute risk ranged from one in almost 13,000 without a fracture or altered conscious level to one in 12 for a child in a coma and with a fracture; the pattern was similar in adults, the risks in corresponding groups ranging from one in almost 7900 to one in four.Although children attending hospital after a head injury have a lower overall risk of a traumatic haematoma, the main indicators of risk, a skull fracture and conscious level, are the same as in adults, and the pattern of their combined effect is similar. Guidelines for managing adults with recent head injury may therefore be applied safely to children; with the increasing provision of facilities for computed tomography they should be revised to ensure early scanning of more patients with head injury.

The aim of our present study was to compare the association of a wide range of 17 biomarkers of inflammation, hemostasis, and blood rheology with incident heart disease and stroke after accounting for an indicator of subclinical atherosclerotic disease and traditional risk factors and also to determine their incremental predictive ability.We used data from the Edinburgh Artery Study, a population cohort study started in 1987 that comprised 1592 men and women aged 55 to 74 years. Subjects were followed for a mean of 17 years, and 416 of them suffered at least 1 cardiovascular event. In analyses adjusted for cardiovascular risk factors and history of cardiovascular disease (CVD): C-reactive protein, interleukin-6, fibrinogen, fibrin D-dimer, tissue plasminogen activator (t-PA), leukocyte elastase, and lipoprotein(a) (all P<0.01), as well as von Willebrand factor and plasma viscosity (both P<0.05), had significant hazard ratios for incident CVD. Further adjustment for a measure of subclinical atherosclerosis (ankle brachial index) had little impact on these associations. The hazard ratios (95% CI) for incident CVD between top and bottom tertiles in the latter analysis were 1.78 (1.30 to 2.45) for C-reactive protein, 1.85 (1.33 to 2.58) for interleukin-6, and 1.76 (1.35 to 2.31) for fibrinogen. Single biomarkers provided little additional discrimination of incident CVD to that obtained from cardiovascular risk factors and the ankle brachial index. An incremental score of multiple markers [interleukin-6, t-PA, intercellular adhesion molecule 1, and lipoprotein(a)] provided some added discrimination.Several "novel" risk factors predicted CVD after adjustments for conventional risk factors and also for a measure of asymptomatic disease. However, their incremental predictive ability was modest and their clinical utility remains uncertain.

We enrolled 479 patients with subarachnoid hemorrhage in a multicenter, randomized, double-blind, placebo-controlled trial to determine whether treatment with the antifibrinolytic agent tranexamic acid improves outcome by preventing rebleeding. At three months there was no statistical difference between the outcomes in the tranexamic acid group and the control group. Of the 173 patients who died, 84 had received tranexamic acid and 89 placebo (95 per cent confidence interval for the difference in mortality rate, -6 to 11 per cent). Similarly, when analysis was restricted to patients with an angiographically demonstrated aneurysm, there was no significant difference between the groups. This absence of effect was not due to a lack of antifibrinolytic action, since the rate of rebleeding was reduced from 24 per cent in the control group to 9 per cent in the tranexamic acid-treated group (chi-square = 18.07, P<0.001), but resulted from a concurrent increase in the incidence of ischemic complications (15 per cent in the control group and 24 per cent in the tranexamic acid group; chi-square = 8.07, P<0.01). We conclude that until some method can be found to minimize ischemic complications, tranexamic acid is of no benefit in patients with subarachnoid hemorrhage. (N Engl J Med 1984; 311:432–7.)

A prospective study of 1969 patients with intermittent claudication receiving placebo medication for a minimum of 1 year is reported. Patients were carefully monitored and only four patients were lost to follow-up. Annual mortality was 4.3%. Thirty-six patients developed a definite myocardial infarction, 27 a major stroke, 32 required a major amputation and 111 required surgical or radiological intervention for deteriorating ischaemia of the leg. The entry characteristics of the patients were analysed as a predictor of serious cardiovascular events. The most sensitive predictors of total mortality were age, history of coronary heart disease and an ankle/arm pressure ratio below 0.5. Of the laboratory measurements performed only the initial white cell count was a significant predictor of myocardial infarction, stroke and vascular deaths.

The expression of the c-erbB-2 oncogene has been evaluated using an immunohistochemical technique with the 21N polyclonal antibody in paraffin embedded tissue from 465 patients treated between the years 1975-1981 for Stage I and II breast cancer. One hundred and four (22%) patients exhibited positive staining. This was not associated with any other variables. Expression of the oncogene was associated with significantly poorer survival which was independent of other tumour variables.

Objective Menorrhagia is defined as blood loss of >80 mL, but in routine clinical practice measurement is seldom undertaken. Our aim was to identify the features of the clinical history that best predict menorrhagic blood loss. Study design A questionnaire survey of 952 menstrual complaint referrals at 3 hospital gynecology clinics in Glasgow and Edinburgh included 226 women with putatively heavy periods who also had consented to the measurement of their blood loss. Results Only 34% (95% CI, 28%-40%) of women had blood loss volume of >80 mL, but the volume was associated with subjective heaviness of period. Logistic regression with ferritin status, clots, and changing rate during full flow correctly predicts a loss of >80 mL for 76% of women (n = 161 patients; sensitivity, 60%; specificity, 86%). Diagnosis and treatment of patients seem unrelated to the volume of blood loss. Conclusion The subjective judgment of the volume of blood loss is better than has been believed. Clinical features can be combined to predict losses of >80 mL.

The objective of this report is to describe the design and content of the International Mission for Prognosis And Clinical Trial (IMPACT) database of traumatic brain injury which contains the complete dataset from most clinical trials and organized epidemiologic studies conducted over the past 20 years. This effort, funded by the U.S. National Institutes of Health, has led to the accumulation thus far of data from 9205 patients with severe and moderate brain injuries from eight randomized placebo controlled trials and three observational studies. Data relevant to the design and analysis of pragmatic Phase III clinical trials, including pre-hospital, admission, and post-resuscitation assessments, information on the acute management, and short-and long-term outcome were merged into a top priority data set (TPDS). The major emphasis during the first phase of study is on information from time of injury to post-resuscitation and outcome at 6 months thereby providing a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of Phase III trials in traumatic brain injury.

Abnormalities in laboratory parameters are frequent following traumatic brain injury (TBI), but few studies have investigated their predictive value. We aimed to describe and quantify the relation between laboratory parameters that are routinely determined on admission and final outcome following TBI. Individual patient data were available in the IMPACT database from six Phase III randomized controlled trials and one observational study in TBI. We studied glucose (N = 4834), sodium ( N = 5270), pH ( N = 3398), hemoglobin (Hb, N = 3875), platelet count ( N = 1629), and prothrombin time (PT; N = 840) for their associations with outcome at 6 months (Glasgow Outcome Scale [GOS]). We used logistic regression models with linear, quadratic, and restricted cubic spline functions. The strength of the associations was expressed as an unadjusted odds ratio, calculated over the shift in outcome between the 25th and 75th percentiles. Proportional odds methodology was further applied to quantify the strength of the associations across the full range of the GOS. All parameters were consistently associated with outcome in a continuous relationship: glucose and prothrombin time showed a positive linear relation to outcome (i.e., increasing values associated with poorer outcome) and Hb, platelets, and pH an inverse linear relation (i.e., low values associated with poorer outcome). Sodium demonstrated a U-shaped relation to outcome, with low levels being more strongly related to poorer outcome. Effects were strongest for increasing levels of glucose (odds ratio 1.7; 95% CI 1.54–1.83) and decreasing levels of Hb (odds ratio 0.7; CI 0.60–0.78). Higher glucose values were associated with increasing age, but on adjusted analysis, the strength of the association with outcome remained. Whether treatment of abnormal values may improve outcome needs further rigorous study.

Two methods of predicting difficult laryngoscopy were compared prospectively. Mallampati class and Wilson risk-sum were determined before operation and laryngeal view graded in 675 patients. Both tests identified five of 12 difficult laryngoscopies; twice as many patients were predicted to be difficult by Mallampati classification than by Wilson risk-sum. Inter-observer variation was minimal using Wilson risk-sum, but considerable for Mallampati classification. We prefer the Wilson risk-sum for assessment of the airway, while noting that both tests have poor sensitivities.

✓ Patients with severe head injury frequently have evidence of elevated intracranial pressure (ICP) and ischemic neuronal damage at autopsy. Mannitol has been used clinically to reduce ICP with varying success, and it is possible that it is more effective in some types of head injury than in others. The aim of the present study was to determine the effect of mannitol on ICP, cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) in patients with severe head injury, and to discover if these effects differed in different types of injury. Measurements of CPP, ICP, and CBF were made in 55 patients with severe head injury. In general, the resting level of CBF was higher in patients with diffuse injury (mean 50.2 ml/100 gm/min) than in those with focal injury (mean 39.8 ml/100 gm/min). Mannitol consistently reduced ICP and increased CPP and CBF by 10 to 20 minutes after infusion. The lowest flows (31.8 ml/100 gm/min) were recorded from the most damaged hemispheres of patients with focal injuries and elevated ICP. The baseline levels of flow did not correlate with ICP, CPP, Glasgow Coma Scale score, or outcome. Only four of the 55 patients had a CBF of less than 20 ml/100 gm/min in either or both hemispheres. The few low CBF's in this and other studies may reflect the steady-state conditions under which measurements are made in intensive care units, and that these patients have entered a phase of reperfusion.

Previous preliminary studies have suggested that possession of the APOE epsilon4 allele is associated with a poor outcome after head injury. This study was designed to confirm and extend those observations in a larger study with examination of additional variables. We prospectively identified admissions to a Neurosurgical Unit for head injury, collected demographic and clinical data, determined APOE genotypes and obtained follow-up information at 6 months. A total of 1094 subjects were enrolled (age range: 0-93 years, mean 37 years). Outcome was assessed using the Glasgow Outcome Scale. There was no overall association between APOE genotype and outcome, with 36% of APOE epsilon4 carriers having an unfavourable outcome compared with 33% of non-carriers of APOE epsilon4. However, there was evidence of an interaction between age and APOE genotype on outcome (P = 0.007) such that possession of APOE epsilon4 reduced the prospect of a favourable outcome in children and young adults. The influence of APOE genotype in younger patients after head injury can be expressed as, at age <15 years, carriage of APOE epsilon4 being equivalent to ageing by 25 years. This finding is consistent with experimental data suggesting that the effect of APOE genotype on outcome after head injury may be expressed through the processes of repair and recovery.

To determine the disability, distress and employment status of new neurology outpatients with physical symptoms unexplained by organic disease and to compare them with patients with symptoms explained by organic disease.As part of a cohort study (the Scottish Neurological Symptoms Study) neurologists rated the extent to which each new patient's symptoms were explained by organic disease. Patients whose symptoms were rated as 'not at all' or only 'somewhat' explained by disease were considered cases, and those whose symptoms were 'largely' or 'completely' explained by disease were considered controls. All patients completed self-ratings of disability, health status (Medical Outcomes Study Short Form 12-Item Scale (SF-12)) and emotional distress (Hospital Anxiety and Depression Scale) and also reported their employment and state financial benefit status.3781 patients were recruited: 1144 (30%) cases and 2637 (70%) controls. Cases had worse physical health status (SF-12 score 42 vs 44; difference in means 1.7 (95% CI -2.5 to 0.9)) and worse mental health status (SF-12 score 43 vs 47; difference in means -3.5 (95% CI -4.3 to to 2.7)). Unemployment was similar in cases and controls (50% vs 50%) but cases were more likely not to be working for health reasons (54% vs 37% of the 50% not working; OR 2.0 (95% CI 1.6 to 2.4)) and also more likely to be receiving disability-related state financial benefits (27% vs 22%; (OR 1.3, 95% CI 1.1 to 1.6)).New neurology patients with symptoms unexplained by organic disease have more disability-, distress- and disability-related state financial benefits than patients with symptoms explained by disease.

Stroke patients conventionally undergo a substantial part of their rehabilitation in hospital. Services have been developed that offer patients early discharge from hospital with rehabilitation at home (early supported discharge [ESD]). We have assessed the effects and costs of such services.We did a meta-analysis of data from individual patients who took part in randomised trials that recruited patients with stroke in hospital to receive either conventional care or any ESD service intervention that provided rehabilitation and support in a community setting with the aim of shortening the duration of hospital care. The primary outcome was death or dependency at the end of scheduled follow-up.Outcome data were available for 11 trials (1597 patients). ESD services were mostly provided by specialist multidisciplinary teams to a selected group (median 41%) of stroke patients admitted to hospital. There was a reduced risk of death or dependency equivalent to six (95% CI one to ten) fewer adverse outcomes for every 100 patients receiving an ESD service (p=0.02). The hospital stay was 8 days shorter for patients assigned ESD services than for those assigned conventional care (p<0.0001). There were also significant improvements in scores on the extended activities of daily living scale and in the odds of living at home and reporting satisfaction with services. The greatest benefits were seen in the trials evaluating a coordinated multidisciplinary ESD team and in stroke patients with mild to moderate disability.Appropriately resourced ESD services provided for a selected group of stroke patients can reduce long-term dependency and admission to institutional care as well as shortening hospital stays.

Functional (psychogenic or somatoform) symptoms are common in neurology clinics. Cognitive-behavioral therapy (CBT) can be an effective treatment, but there are major obstacles to its provision in practice. We tested the hypothesis that adding CBT-based guided self-help (GSH) to the usual care (UC) received by patients improves outcomes.We conducted a randomized trial in 2 neurology services in the United Kingdom. Outpatients with functional symptoms (rated by the neurologist as "not at all" or only "somewhat" explained by organic disease) were randomly allocated to UC or UC plus GSH. GSH comprised a self-help manual and 4 half-hour guidance sessions. The primary outcome was self-rated health on a 5-point clinical global improvement scale (CGI) at 3 months. Secondary outcomes were measured at 3 and 6 months.In this trial, 127 participants were enrolled, and primary outcome data were collected for 125. Participants allocated to GSH reported greater improvement on the primary outcome (adjusted common odds ratio on the CGI 2.36 [95% confidence interval 1.17-4.74; p = 0.016]). The absolute difference in proportion "better" or "much better" was 13% (number needed to treat was 8). At 6 months the treatment effect was no longer statistically significant on the CGI but was apparent in symptom improvement and in physical functioning.CBT-based GSH is feasible to implement and efficacious. Further evaluation is indicated.This study provides Class III evidence that CBT-based GSH therapy improves self-reported general health, as measured by the CGI, in patients with functional neurologic symptoms.

In this study with randomized controls, we administered fludrocortisone acetate to 46 of 91 patients with subarachnoid hemorrhage in an attempt to prevent excessive natriuresis and plasma volume depletion. Fludrocortisone significantly reduced the frequency of a negative sodium balance during the first 6 days (from 63% to 38%, p = 0.041). A negative sodium balance was significantly correlated with decreased plasma volume during both the first 6 days (p = 0.014) and during the entire 12-day study period (p = 0.004). Although fludrocortisone treatment tended to diminish the decrease in plasma volume, the difference was not significant (p = 0.188). More patients in the control group developed cerebral ischemia (31% vs. 22%) and, consequently, more control patients were treated with plasma volume expanders (24% vs. 15%), which may have masked the effects of fludrocortisone on plasma volume. Fludrocortisone therefore reduces natriuresis and remains of possible therapeutic benefit in the prevention of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Cancer is associated with an increased risk of suicide and attempted suicide. However, we do not know how many cancer patients have thoughts that they would be better off dead or thoughts of hurting themselves. This study aimed to determine the prevalence of such thoughts in cancer outpatients and which patients are most likely to have them.A survey of consecutive patients who attended the outpatient clinics of a regional cancer center in Edinburgh, United Kingdom. Patients completed the Patient Health Questionnaire-9 (PHQ-9), which included Item 9 that asks patients if they have had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Those who reported having had such thoughts for at least several days in this period were labeled as positive responders. Patients also completed the Hospital Anxiety and Depression Scale (HADS) and a pain scale. The participating patients' cancer diagnoses and treatments were obtained from the cancer center clinical database.Data were available on 2,924 patients; 7.8% (229 of 2,924; 95% CI, 6.9% to 8.9%) were positive responders. Clinically significant emotional distress, substantial pain, and--to a lesser extent--older age, were associated with a positive response. There was strong evidence of interactions between these effects, and emotional distress played the most important role.A substantial number of cancer outpatients report thoughts that they would be better off dead or thoughts of hurting themselves. Management of emotional distress and pain should be a central aspect of cancer care.

To describe the modeling techniques used for early prediction of outcome in traumatic brain injury (TBI) and to identify aspects for potential improvements.We reviewed key methodological aspects of studies published between 1970 and 2005 that proposed a prognostic model for the Glasgow Outcome Scale of TBI based on admission data.We included 31 papers. Twenty-four were single-center studies, and 22 reported on fewer than 500 patients. The median of the number of initially considered predictors was eight, and on average five of these were selected for the prognostic model, generally including age, Glasgow Coma Score (or only motor score), and pupillary reactivity. The most common statistical technique was logistic regression with stepwise selection of predictors. Model performance was often quantified by accuracy rate rather than by more appropriate measures such as the area under the receiver-operating characteristic curve. Model validity was addressed in 15 studies, but mostly used a simple split-sample approach, and external validation was performed in only four studies.Although most models agree on the three most important predictors, many were developed on small sample sizes within single centers and hence lack generalizability. Modeling strategies have to be improved, and include external validation.

The primary objective was to conduct a detailed analysis of individual variation in psychological morbidity in the year following surgery for breast cancer. The salience of the patients' “illness perceptions” to morbidity was examined as a secondary objective. Psychological morbidity was assessed with the General Health Questionnaire (GHQ-28) in a prospective study of 371 women having surgery for primary breast cancer. Patients also completed the Illness Perception Questionnaire (IPQ), Mental Adjustment to Cancer Scale (MAC) and the Eysenck Personality Scales (EPS). Assessments were made postoperatively and at 3, 6 and 12 months after surgery. Whilst descriptive statistics indicated a general reduction in mean distress over the 12-month follow-up, close analysis showed that a quarter of all patients maintained clinically significant levels of distress throughout the period. Patients with chronically elevated distress were characterised by higher levels of neuroticism, greater symptom awareness, more pain and poorer self-rated general health. In the regression analysis, psychological morbidity across the 1-year follow-up was predicted principally by the immediate postoperative state of distress, IPQ symptom awareness and the perceived time line of the illness, general health and, to a more minor extent, by neuroticism. There is marked individual variation in psychological morbidity in the year following breast cancer surgery, which is reliably predicted by the patient's immediate postoperative state of distress, her perception of the impact of the symptoms and the time line of the disease. Subgroups of patients with chronically high distress are characterised by factors including personality and negative perceptions and beliefs about their illness.

To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes.A cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary-based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing.Higher IL-6 and TNF-alpha levels were associated with poorer age- and sex-adjusted scores on the majority of the individual cognitive tests. They were also associated with g using standardized regression coefficients -0.074 to -0.173 (P < 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g.In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.

Hypotension following traumatic brain injury (TBI) is recognized as an important secondary insult that is associated with adverse outcome. We aimed to describe the relationship between actual levels of admission blood pressure and Glasgow Outcome Scale (GOS) at 6 months. Individual patient data from the IMPACT database were available on systolic (N = 6801) and mean arterial (N = 6647) blood pressure. Regression models with restricted cubic spline functions were used to explore the shape of the relationships between blood pressure and outcome in unadjusted and adjusted analyses. Proportional odds methodology was applied to quantify the strength of the associations across the full range of the GOS. Analyses were performed to search for threshold values. A smooth U-shaped relationship was observed between systolic (SBP) and mean arterial (MABP) blood pressures and outcome, without any evidence of an abrupt threshold effect. Best outcomes were observed for values of SBP of the order of 135 mm Hg and for values of MABP of the order of 90 mm Hg. Both lower (OR 1.53; 95% CI: 1.31–1.80) and higher levels (OR 1.42; CI: 1.20–1.68) of SBP and lower (OR 1.30; CI 1.12–1.51) and higher levels of MABP (OR 1.45; CI 1.19–1.76) were associated with poorer outcome. These findings were consistent across studies. The relationship between high blood pressure level and poorer outcome largely disappeared on adjusted analysis. Current guidelines for the management of blood pressure in TBI focus on the avoidance of hypotension as defined by SBP < 90 mm Hg. Our finding of a smooth relationship with improving outcome as SBP increases up to 135 mm Hg, while not supporting a strong causal inference, does suggest that current guidelines need to be reconsidered.

Systematic screening for depression has been recommended for patients who have medical conditions like cancer. The 9-item Patient Health Questionnaire (PHQ-9) is becoming widely used, but its diagnostic accuracy has not yet been tested in a cancer patient population. In this article, the authors report on the performance of the PHQ-9 as a screening instrument for major depressive disorder (MDD) in patients with cancer.Data obtained from a depression screening service for patients who were attending clinics of a Regional Cancer Centre in Edinburgh, United Kingdom were used. Patients had completed both the PHQ-9 and a 2-stage procedure to identify cases of MDD. Performance of the PHQ-9 in identifying cases of MDD was determined using receiver operating characteristic (ROC) analysis.Data were available on 4264 patients. When scored as a continuous measure, the PHQ-9 performed well with an area under the ROC curve of 0.94 (95% confidence interval [CI], 0.93-0.95). A cutoff score of ≥ 8 provided a sensitivity of 93% (95% CI, 89%-95%), a specificity of 81% (95% CI, 80%-82%), a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 99% and could be considered optimum in a screening context. The PHQ-9 did not perform as well when it was scored using an algorithm with a sensitivity of 56% (95% CI, 55%-57%), a specificity of 96% (95% CI, 95%-97%), a PPV of 52%, and an NPV of 97%.The PHQ-9 scored as a continuous measure with a cutoff score of ≥ 8 performed well in identifying MDD in cancer patients and should be considered as a screening instrument in this population.

Research in traumatic brain injury (TBI) is challenging for several reasons; in particular, the heterogeneity between patients regarding causes, pathophysiology, treatment, and outcome. Advances in basic science have failed to translate into successful clinical treatments, and the evidence underpinning guideline recommendations is weak. Because clinical research has been hampered by non-standardised data collection, restricted multidisciplinary collaboration, and the lack of sensitivity of classification and efficacy analyses, multidisciplinary collaborations are now being fostered. Approaches to deal with heterogeneity have been developed by the IMPACT study group. These approaches can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid haemorrhage. Rather than trying to limit heterogeneity, we might also be able to exploit it by analysing differences in treatment and outcome between countries and centres in comparative effectiveness research. This approach has great potential to advance care in patients with TBI.

Clinical trials in traumatic brain injury (TBI) pose complex methodological challenges, largely related to the heterogeneity of the population. The International Mission on Prognosis and Clinical Trial Design in TBI study group has explored approaches for dealing with this heterogeneity with the aim to optimize clinical trials in TBI. Extensive prognostic analyses and simulation studies were conducted on individual patient data from eight trials and three observational studies. Here, we integrate the results of these studies into the International Mission on Prognosis and Clinical Trial Design in TBI recommendations for design and analysis of trials in TBI: Broad inclusion criteria, prespecified covariate adjustment, and an ordinal analysis will promote an efficient trial, yielding gains in statistical efficiency of more than 40%. This corresponds to being able to detect a 7% treatment effect with the same number of patients needed to demonstrate a 10% difference with an unadjusted analysis based on the dichotomized Glasgow outcome scale.

In clinical trials, ordinal outcome measures are often dichotomized into two categories. In traumatic brain injury (TBI) the 5-point Glasgow outcome scale (GOS) is collapsed into unfavourable versus favourable outcome. Simulation studies have shown that exploiting the ordinal nature of the GOS increases chances of detecting treatment effects. The objective of this study is to quantify the benefits of ordinal analysis in the real-life situation of a large TBI trial.We used data from the CRASH trial that investigated the efficacy of corticosteroids in TBI patients (n = 9,554). We applied two techniques for ordinal analysis: proportional odds analysis and the sliding dichotomy approach, where the GOS is dichotomized at different cut-offs according to baseline prognostic risk. These approaches were compared to dichotomous analysis. The information density in each analysis was indicated by a Wald statistic. All analyses were adjusted for baseline characteristics.Dichotomous analysis of the six-month GOS showed a non-significant treatment effect (OR = 1.09, 95% CI 0.98 to 1.21, P = 0.096). Ordinal analysis with proportional odds regression or sliding dichotomy showed highly statistically significant treatment effects (OR 1.15, 95% CI 1.06 to 1.25, P = 0.0007 and 1.19, 95% CI 1.08 to 1.30, P = 0.0002), with 2.05-fold and 2.56-fold higher information density compared to the dichotomous approach respectively.Analysis of the CRASH trial data confirmed that ordinal analysis of outcome substantially increases statistical power. We expect these results to hold for other fields of critical care medicine that use ordinal outcome measures and recommend that future trials adopt ordinal analyses. This will permit detection of smaller treatment effects.

ContextPain, depression, and fatigue are common symptoms in cancer populations. They often coexist and have been suggested as a specific symptom cluster. Systemic inflammation (SI) may be a possible common mechanism.ObjectiveThis study examined whether pain, depression, and fatigue exist as a symptom cluster in advanced cancer patients with cachexia and might be related to the presence of SI.MethodsSecondary data analysis was undertaken of two clinical trials in patients with cancer cachexia (n=654). Pain, depression, and fatigue were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Plasma C-reactive protein (CRP) was measured as a marker of SI in a subgroup (n=436). Multivariate analysis and a series of regression analyses were undertaken relating pain, depression, fatigue, and CRP.ResultsPain, depression, and fatigue clustered, with between two and four times as many patients having all three symptoms as would be expected if the symptoms only coexist by chance (P<0.001). CRP was not related to the symptom cluster. There was a strong relationship between the pattern of symptoms and physical functioning (P<0.001).ConclusionPain, depression, and fatigue is an identifiable symptom cluster in a cohort of cachexic cancer patients and is associated with reduced physical functioning.

The Glasgow Outcome Scale (GOS) is firmly established as the primary outcome measure for use in Phase III trials of interventions in traumatic brain injury (TBI). However, the GOS has been criticized for its lack of sensitivity to detect small but clinically relevant changes in outcome. The Glasgow Outcome Scale-Extended (GOSE) potentially addresses this criticism, and in this study we estimate the efficiency gain associated with using the GOSE in place of the GOS in ordinal analysis of 6-month outcome. The study uses both simulation and the reanalysis of existing data from two completed TBI studies, one an observational cohort study and the other a randomized controlled trial. As expected, the results show that using an ordinal technique to analyze the GOS gives a substantial gain in efficiency relative to the conventional analysis, which collapses the GOS onto a binary scale (favorable versus unfavorable outcome). We also found that using the GOSE gave a modest but consistent increase in efficiency relative to the GOS in both studies, corresponding to a reduction in the required sample size of the order of 3–5%. We recommend that the GOSE be used in place of the GOS as the primary outcome measure in trials of TBI, with an appropriate ordinal approach being taken to the statistical analysis.

The susceptibility to type 2 diabetes of people of south Asian descent is established, but there is little trial-based evidence for interventions to tackle this problem. We assessed a weight control and physical activity intervention in south Asian individuals in the UK.We did this non-blinded trial in two National Health Service (NHS) regions in Scotland (UK). Between July 1, 2007, and Oct 31, 2009, we recruited men and women of Indian and Pakistani origin, aged 35 years or older, with waist circumference 90 cm or greater in men or 80 cm or greater in women, and with impaired glucose tolerance or impaired fasting glucose determined by oral glucose tolerance test. Families were randomised (using a random number generator program, with permuted blocks of random size, stratified by location [Edinburgh or Glasgow], ethnic group [Indian or Pakistani], and number of participants in the family [one vs more than one]) to intervention or control. Participants in the same family were not randomised separately. The intervention group received 15 visits from a dietitian over 3 years and the control group received four visits in the same period. The primary outcome was weight change at 3 years. Analysis was by modified intention to treat, excluding participants who died or were lost to follow-up. We used linear regression models to provide mean differences in baseline-adjusted weight at 3 years. This trial is registered, number ISRCTN25729565.Of 1319 people who were screened with an oral glucose tolerance test, 196 (15%) had impaired glucose tolerance or impaired fasting glucose and 171 entered the trial. Participants were in 156 family clusters that were randomised (78 families with 85 participants were allocated to intervention; 78 families with 86 participants were allocated to control). 167 (98%) participants in 152 families completed the trial. Mean weight loss in the intervention group was 1.13 kg (SD 4.12), compared with a mean weight gain of 0.51 kg (3.65) in the control group, an adjusted mean difference of -1.64 kg (95% CI -2.83 to -0.44).Modest, medium-term changes in weight are achievable as a component of lifestyle-change strategies, which might control or prevent adiposity-related diseases.National Prevention Research Initiative, NHS Research and Development; NHS National Services Scotland; NHS Health Scotland.

Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome "dead or dependent" in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59-0·67) and for haemorrhagic events was 0·60 (0·55-0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.MRC.

In the Acute Infarction Ramipril Efficacy (AIRE) Study, the effect of angiotensin-converting-enzyme (ACE) inhibition on the survival of patients with clinical heart failure after acute myocardial infarction (AMI), was assessed. At an average follow-up time of 15 months after randomisation, all-cause mortality was reduced from 22.6% (placebo group) to 16.9% (ramipril group) representing an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI 11-40%; p = 0.002). Our aim in this study was to assess the long-term (3 years after the AIRE Study closed) magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril (target dose 5 mg twice a day) when compared with placebo.We investigated the mortality status of all 603 patients recruited from the 30 UK centres involved in the AIRE Study. Through government records we were able to confirm the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment with masked trial medication was 13.4 months for placebo and 12.4 months for ramipril.By 0000 h March 1, 1996, death from all causes had occurred in 117 (38.9%) of 301 patients randomly assigned placebo and 83 (27.5%) of 302 patients randomly assigned ramipril, representing a relative risk reduction of 36% (95% CI 15-52%; p = 0.002) and an absolute reduction in mortality of 11.4% (114 additional 5-year survivors per 1000 patients treated for an average of 12.4 months).Our data provide robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years.

The conventional approach to the analysis of a Phase III trial in head injury or stroke takes an ordered scale measuring functional outcome and collapses the scale to a binary outcome of favorable versus unfavorable. This discards potentially relevant information which limits statistical power and moreover is not in accord with clinical practice. We propose an alternative approach where a favorable outcome is defined as better than would be expected, taking account of each individual patient's baseline prognosis. This is illustrated through a worked example based on data from a Phase III trial in head injury. The approach is also compared with the proportional odds model, which is another statistical approach that can exploit an ordered outcome scale. The approach raises issues of clinical, statistical, and regulatory importance, and we initiate what we believe needs to become a widespread debate amongst the community involved in clinical research in head injury and stroke.

Background: Existing evidence suggests that some patients who sustain a head injury suffer cognitive decline many years later, and that head injury and possession of the APOE e4 allele are each risk factors for Alzheimer's disease.Objective: To determine whether late cognitive decline after head injury is more prevalent among carriers of APOE e4.Methods: A database of head injured patients was used.Initial assessment was at the time of their injury, between 1968 and 1985, and outcome data at six months were available.Their ages at the time of injury ranged between 2 and 70 years.A cohort of 396 subjects was reassessed at a mean of 18 years later, with determination of APOE genotype and detailed neuropyschological testing.Results: Judging by the Glasgow outcome scale, twice as many patients had deteriorated as improved between six months after injury and the late assessment; 22.2% of APOE e4 carriers had a good late outcome compared with 30.5% of non-carriers (95% confidence interval for the difference, -0.7% to 17.2%; p = 0.084).There were no clear differences between e4 carriers and non-carriers in detailed neuropsychological assessments.Conclusions: Although this study provides additional evidence that a late decline may occur after head injury, there was no clear relation to APOE genotype.Despite the follow up interval of 15 to 25 years, the cohort is still too young (mean age 42.1 years) to assess the risk of Alzheimer's disease. . . . . . . . . . .

Aims Recently, markers of inflammation, haemostasis, and blood rheology have received much attention as risk factors for coronary heart disease and stroke. However, their role in peripheral arterial disease (PAD) is not well established and some of them, including the pro-inflammatory cytokine interleukin-6 (IL-6), have not been examined before in prospective epidemiological studies.

Objective Menorrhagia is defined in terms of statistical“abnormality”as blood loss of >80 mL. We examined the usefulness of this definition in women who were referred to gynecology clinics with heavy periods. Study design A questionnaire survey of 952 menstrual complaint referrals at 3 hospital gynaecology clinics in Glasgow and Edinburgh included 226 women with heavy periods who had also consented to the measurement of their blood loss. Results Women reported a range of problems with their periods, but absolute volume (31.2%) was less prevalent than period pain (37.5%), mood change (35.7%), and change in the amount (volume) of the period (33.8%). Although there were associations with volume, these associations were due to the heaviest and lightest of the loss groups, whereas the 2 groups with loss either side of 80 mL were virtually indistinguishable. Conclusion The 80-mL criterion for menorrhagia is of limited clinical usefulness because it is prognostic neither for problems nor iron status and apparently does not guide management.

Treatment decisions in clinical cardiology are directed by results from randomized clinical trials (RCTs). We studied the appropriateness of the use and interpretation of subgroup analysis in current therapeutic cardiovascular RCTs. We reviewed main reports of phase 3 cardiovascular RCTs with at least 100 patients, published in 2002 and 2004, and from major journals (Circulation, J Am Coll Cardiol, Am Heart J, Am J Cardiol, N Engl J Med, Lancet, JAMA, BMJ, Ann Intern Med). Information on subgroups included prespecification, number, interaction test use, significant subgroups found, and emphasis on findings. We examined appropriateness of reporting and differences according to sample size, overall trial result, and CONSORT adoption. We selected 63 RCTs, with a median of 496 (range 100-15 245) patients. Thirty-nine RCTs were reported with subgroup analyses and 26 with >5 subgroups. No trial was specifically powered to detect subgroup effects, and only 14 RCTs were reported with fully prespecified subgroups. Only 11 RCTs were reported with interaction tests. Furthermore, 21 RCTs were reported with claims of significant subgroups and 15 with equal or more emphasis to subgroups than to the overall results. Subgroup analyses in large RCTs (>500 patients) were reported more often than in small ones (24/30 vs 15/33, P = .005). No differences were found according to overall result (positive/negative) or CONSORT adoption. Subgroup analyses in recent cardiovascular RCTs were reported with several shortcomings, including a lack of prespecification and testing of a large number of subgroups without the use of the statistically appropriate test for interaction. Reporting of subgroup analysis needs to be substantially improved because emphasis on these secondary results may mislead treatment decisions.

Abstract OBJECTIVE: Controversy exists about the indications and timing for surgery in head injured patients with an intradural mass lesion. The aim of this study was to survey contemporary approaches to the treatment of head injured patients with an intradural lesion, placing a particular focus on the utilization of decompressive craniectomy. METHODS: A prospective international survey was conducted over a 3-month period in 67 centers from 24 countries on the neurosurgical management of head injured patients with an intradural mass lesion and/or radiological signs of raised intracranial pressure. Information was obtained about demographic, clinical, and radiological features; surgical management, and mortality at discharge. RESULTS: Over the period of the study, data were collected about 729 patients consecutively admitted to one of the participating centers. The survey included 397 patients with a severe head injury (Glasgow Coma Scale [GCS] 3–8), 155 with a moderate head injury (GCS 9–12) and 143 patients with a mild head injury (GCS 13–15). An operation was performed on 502 patients (69%). Emergency surgery (&amp;lt;24 h) was most frequently performed for patients with an extracerebral mass lesions (subdural hematomas) whereas delayed surgery was most frequently performed for an intracerebral hematoma or contusion. Decompressive craniectomy was performed in a substantial number of patients, either during an emergency procedure (n = 134, 33%) or a delayed procedure (n = 47, 31%). The decompressive procedure was nearly always combined with evacuation of a mass lesion. The size of the decompression was however considered too small in 25% of cases. CONCLUSION: The results provide a contemporary picture of neurosurgical surgical approaches to the management of head injured patients with an intradural mass lesion and/or signs of raised intracranial pressure in some Neurosurgical Units across the world. The relative benefits of early versus delayed surgery in patients with intraparenchymal lesions and on the indications, technique and benefits of decompressive craniectomy could be topics for future head injury research.

The differentiation of cerebral infarction and cerebral haemorrhage is the most important first step in the management of acute stroke, because clinical management of the two disorders differs substantially. The Guy's Hospital and Siriraj stroke diagnostic scores were developed to aid clinicians in this decision. We have tested the performance of the two scores on a group of 1059 patients admitted to the acute stroke unit (ASU) at the Western Infirmary, Glasgow, with suspected stroke between May, 1990, and December, 1993. The diagnosis was confirmed as stroke by computed tomography (CT) scanning or necropsy (n = 10) in 991 patients. For each clinical score we subjectively identified the cut-off point that maximised sensitivity to cerebral haemorrhage with the smallest loss of specificity. At its optimum cut-off point the Guy's Hospital score had a sensitivity for the diagnosis of haemorrhage of 70% and specificity of 64%. The corresponding figures for the Siriraj score at its optimum cut-off point were 68% sensitivity and 64% specificity. The overall predictive accuracy of both scores was 64%. The greater complexity of the Guy's Hospital score (thirteen variables included) did not result in substantially superior performance to the Siriraj score (five variables). This validation study suggests that neither score is useful for exclusion of haemorrhage before anticoagulant treatment is initiated or as a diagnostic screening procedure for trials of low-risk treatments such as aspirin. Our findings emphasise the need for routine CT scanning in this setting, since this method remains the most accurate for differentiating between haemorrhage and infarction.

A double-blind controlled study of long-acting propranolol in the secondary prevention of variceal hemorrhage was conducted in 81 cirrhotic patients. After the index hemorrhage, all patients were treated with injection sclerotherapy on one occasion to secure hemostasis and then randomized within 72 h to propranolol or placebo therapy which was continued for 2 yr. Study endpoints were severe recurrence of variceal hemorrhage or death. Forty-two patients did not fulfill the entry criteria for the study. Thirty-eight patients received propranolol of whom 18 (47%) had further hemorrhage, 14 died, eight had side-effects (2 withdrawals), and 3 did not complete follow-up. Forty-three patients received placebo of whom 33 (77%) had further hemorrhage, 19 died, 5 had side-effects (2 withdrawals), and 5 failed to complete follow-up. The median time from onset of hemorrhage to starting drug therapy was 6 days for both groups. Life table analysis showed an equivalent incidence of further hemorrhage in both groups over the first 60 days, following which the propranolol group did consistently better than the placebo group. There was a significantly lower incidence of rebleeding in modified Child's C patients receiving propranolol (39%) than those on placebo (90%). No statistically significant effect on mortality was seen. In this study, propranolol reduced the incidence of late recurrence of variceal hemorrhage in patients with cirrhosis.

BACKGROUND: Differences between centers in patient outcome after traumatic brain injury are of importance for multicenter studies and have seldom been studied. OBJECTIVE: To quantify the differences in centers enrolling patients in randomized clinical trials (RCTs) and surveys. METHODS: We analyzed individual patient data from 9578 patients with moderate and severe traumatic brain injury enrolled in 10 RCTs and 3 observational studies. We used random-effects logistic regression models to estimate the between-center differences in unfavorable outcome (dead, vegetative state, or severe disability measured with the Glasgow Outcome Scale) at 6 months adjusted for differences in patient characteristics. We calculated the difference in odds of unfavorable outcome between the centers at the higher end vs those at the lower end of the outcome distribution. We analyzed the total database, Europe and the United States separately, and 4 larger RCTs. RESULTS: The 9578 patients were enrolled at 265 centers, and 4629 (48%) had an unfavorable outcome. After adjustment for patient characteristics, there was a 3.3-fold difference in the odds of unfavorable outcome between the centers at the lower end of the outcome distribution (2.5th percentile) vs those at the higher end of the outcome distribution (97.5th percentile; P < .001). In the 4 larger RCTs, the differences between centers were similar. However, differences were smaller between centers in the United States (2.4-fold) than between centers in Europe (3.8-fold). CONCLUSION: Outcome after traumatic brain injury differs substantially between centers, particularly in Europe. Further research is needed to study explanations for these differences to suggest where quality of care might be improved.

Traumatic brain injury is a major cause of death and severe disability worldwide with 1,000,000 hospital admissions per annum throughout the European Union. Therapeutic hypothermia to reduce intracranial hypertension may improve patient outcome but key issues are length of hypothermia treatment and speed of re-warming. A recent meta-analysis showed improved outcome when hypothermia was continued for between 48 hours and 5 days and patients were re-warmed slowly (1°C/4 hours). Previous experience with cooling also appears to be important if complications, which may outweigh the benefits of hypothermia, are to be avoided. This is a pragmatic, multi-centre randomised controlled trial examining the effects of hypothermia 32-35°C, titrated to reduce intracranial pressure <20 mmHg, on morbidity and mortality 6 months after traumatic brain injury. The study aims to recruit 1800 patients over 41 months. Enrolment started in April 2010. Participants are randomised to either standard care or standard care with titrated therapeutic hypothermia. Hypothermia is initiated with 20-30 ml/kg of intravenous, refrigerated 0.9% saline and maintained using each centre's usual cooling technique. There is a guideline for detection and treatment of shivering in the intervention group. Hypothermia is maintained for at least 48 hours in the treatment group and continued for as long as is necessary to maintain intracranial pressure <20 mmHg. Intracranial hypertension is defined as an intracranial pressure >20 mmHg in accordance with the Brain Trauma Foundation Guidelines, 2007. The Eurotherm3235Trial is the most important clinical trial in critical care ever conceived by European intensive care medicine, because it was launched and funded by the European Society of Intensive Care Medicine and will be the largest non-commercial randomised controlled trial due to the substantial number of centres required to deliver the target number of patients. It represents a new and fundamental step for intensive care medicine in Europe. Recruitment will continue until January 2013 and interested clinicians from intensive care units worldwide can still join this important collaboration by contacting the Trial Coordinating Team via the trial website http://www.eurotherm3235trial.eu . Current Controlled Trials ISRCTN34555414

Patients whose symptoms are 'unexplained by disease' often have a poor symptomatic outcome after specialist consultation, but we know little about which patient factors predict this. We therefore aimed to determine predictors of poor subjective outcome for new neurology out-patients with symptoms unexplained by disease 1 year after the initial consultation.The Scottish Neurological Symptom Study was a 1-year prospective cohort study of patients referred to secondary care National Health Service neurology clinics in Scotland (UK). Patients were included if the neurologist rated their symptoms as 'not at all' or only 'somewhat explained' by organic disease. Patient-rated change in health was rated on a five-point Clinical Global Improvement (CGI) scale ('much better' to 'much worse') 1 year later.The 12-month outcome data were available on 716 of 1144 patients (63%). Poor outcome on the CGI ('unchanged', 'worse' or 'much worse') was reported by 482 (67%) out of 716 patients. The only strong independent baseline predictors were patients' beliefs [expectation of non-recovery (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.40-2.96), non-attribution of symptoms to psychological factors (OR 2.22, 95% CI 1.51-3.26)] and the receipt of illness-related financial benefits (OR 2.30, 95% CI 1.37-3.86). Together, these factors predicted 13% of the variance in outcome.Of the patients, two-thirds had a poor outcome at 1 year. Illness beliefs and financial benefits are more useful in predicting poor outcome than the number of symptoms, disability and distress.

Background Clinical trials in traumatic brain injury have a disappointing track record, with a long history of ‘negative’ Phase III trials. One contributor to this lack of success is almost certainly the low efficiency of the conventional approach to the analysis, which discards information by dichotomizing an ordinal outcome scale. Purpose Our goal was to evaluate the potential efficiency gains, which can be achieved by using techniques, which extract additional information from ordinal outcome data — the proportional odds model and the sliding dichotomy. In addition, we evaluated the additional efficiency gains, which can be achieved through covariate adjustment. Methods The study was based on simulations, which were built around a database of patient-level data extracted from eight Phase III trials and three observational studies in traumatic brain injury. Two different putative treatment effects were explored, one which followed the proportional odds model, and the other which assumed that the effect of the intervention was to reduce the risk of death without changing the distribution of outcomes within survivors. The results are expressed as efficiency gains, reported as the percentage reduction in sample size that can be used with the ordinal analyses without loss of statistical power relative to the conventional binary analysis. Results The simulation results show substantial efficiency gains. Use of the sliding dichotomy allows sample sizes to be reduced by up to 40% without loss of statistical power. The proportional odds model gives modest additional gains over and above the gains achieved by use of the sliding dichotomy. Limitations As with any simulation study, it is difficult to know how far the findings may be extrapolated beyond the actual situations that were modeled. Conclusions Both ordinal techniques offer substantial efficiency gains relative to the conventional binary analysis. The choice between the two techniques involves subtle value judgments. In the situations examined, the proportional odds model gave efficiency gains over and above the sliding dichotomy, but arguably, the sliding dichotomy is more intuitive and clinically appealing. Clinical Trials 2010; 7: 44—57. http://ctj.sagepub.com

Although it is increasingly recognized that cancer patients often have sleep problems, we lack data on their prevalence and associations in representative clinical populations. We aimed to determine (i) the prevalence of sleep problems amongst outpatients of a cancer centre and (ii) the association with medical variables, emotional distress and pain.Secondary analysis of self-report and medical data on 2862 cancer centre outpatients. Sleep problems were identified using the sleep item from the Patient Health Questionnaire-9: 'Over the last two weeks, how often have you been bothered by trouble falling or staying asleep or sleeping too much?' scored on a four-point frequency scale. Emotional distress was measured using the Hospital Anxiety and Depression Scale and pain using the subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Core 30 questionnaire. Medical data were obtained from the cancer centre clinical database.Sleep problems (bothered more than half the days during the previous 2 weeks) were reported by 30.2% (865/2862, 95% CI = 28.5 to 31.9) of the patients. They were common in both patients with active cancer (34.5%) and in cancer survivors (28.0%). There was only a modest association with cancer site and treatment status, but there was a strong association with pain (odds ratio = 2.7, 95% CI = 2.2 to 3.4) and emotional distress (odds ratio = 4.5, 95% CI = 3.7 to 5.6).Sleep problems are common in cancer outpatients and are strongly associated with pain and emotional distress. A combined approach to the management of sleep, pain and emotional distress is indicated. Copyright © 2011 John Wiley & Sons, Ltd.

Patients with serious medical illnesses, such as cancer, are at increased risk of suicide but are also often facing death. The Patient Health Questionnaire-9 (PHQ-9) is widely used to screen patients for depression. It includes an item that asks about thoughts of death and hurting yourself (Item-9). To describe the nature of thoughts of death and suicide reported in clinical interviews carried out to further assess suicidal ideation of cancer outpatients who had endorsed the “suicidal thoughts item” (Item-9) of the PHQ-9 during routine depression screening. Secondary analysis of anonymized service data (with ethical approval) derived from the routine clinical administration of self-report questionnaires and telephone interviews to outpatients attending a Cancer Centre in the UK. Complete data were available on 330/463 (71%) of patients who had endorsed Item-9. In a subsequent structured telephone interview, approximately one-third of these patients denied any thoughts that they would be better off dead, another third acknowledged having thoughts that they would be better off dead, but not of suicide, and the remaining third reported clear thoughts of committing suicide. Only one-third of cancer outpatients who endorse the “suicidal thoughts item” of the PHQ-9 report suicidal thoughts at a subsequent interview. Services planning to set up depression screening with the PHQ-9 need to carefully consider the relative benefits and burden to their service and patients of including Item-9 and interviewing all those who endorse it.

Within the spectrum of spontaneous intracerebral haemorrhage there are some patients with large or space occupying haemorrhage who require surgery for neurological deterioration and others with small haematomas who should be managed conservatively. There is equipoise about the management of patients between these two extremes. In particular there is some evidence that patients with lobar haematomas and no intraventricular haemorrhage might benefit from haematoma evacuation. The STICH II study will establish whether a policy of earlier surgical evacuation of the haematoma in selected patients will improve outcome compared to a policy of initial conservative treatment. an international multicentre randomised parallel group trial. Only patients for whom the treating neurosurgeon is in equipoise about the benefits of early craniotomy compared to initial conservative treatment are eligible. All patients must have a CT scan confirming spontaneous lobar intracerebral haemorrhage (≤1 cm from the cortex surface of the brain and 10-100 ml in volume). Any clotting or coagulation problems must be corrected and randomisation must take place within 48 hours of ictus. With 600 patients, the study will be able to demonstrate a 12% benefit from surgery (2p < 0.05) with 80% power. Stratified randomisation is undertaken using a central 24 hour randomisation service accessed by telephone or web. Patients randomised to early surgery should have the operation within 12 hours. Information about the status (Glasgow Coma Score and focal signs) of all patients through the first five days of their trial progress is also collected in addition to another CT scan at about five days (+/- 2 days). Outcome is measured at six months via a postal questionnaire to the patient. Primary outcome is death or severe disability defined using a prognosis based 8 point Glasgow Outcome Scale. Secondary outcomes include: Mortality, Rankin, Barthel, EuroQol, and Survival. ISRCTN: ISRCTN22153967

The UK Cystic Fibrosis Gene Therapy Consortium has been working towards clinical gene therapy for patients with cystic fibrosis for several years. We have recently embarked on a large, multi-dose clinical trial of a non-viral, liposome-based formulation powered for the first time to detect clinical benefit. The article describes the details of the protocol.

There have been few comparative studies of microsurgical excision vs conservative management of cerebral cavernous malformations (CCM) and none of them has reliably demonstrated a statistically and clinically significant difference.We conducted a prospective, population-based study to identify and independently validate definite CCM diagnoses first made in 1999-2003 in Scottish adult residents. We used multiple sources of prospective follow-up to assess adults' dependence and to identify and independently validate outcome events. We used univariate and multivariable survival analyses to test the influence of CCM excision on outcome, adjusted for prognostic factors and baseline imbalances.Of 134 adults, 25 underwent CCM excision; these adults were younger (34 vs 43 years at diagnosis, p = 0.004) and more likely to present with symptomatic intracranial hemorrhage or focal neurologic deficit than adults managed conservatively (48% vs 26%; odds ratio 2.7, 95% confidence interval [CI] 1.1-6.5). During 5 years of follow-up, CCM excision was associated with a deterioration to an Oxford Handicap Scale score 2-6 sustained over at least 2 successive years (adjusted hazard ratio [HR] 2.2, 95% CI 1.1-4.3) and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (adjusted HR 3.6, 95% CI 1.3-10.0).CCM excision was associated with worse outcomes over 5 years compared to conservative management. Long-term follow-up will determine whether this difference is sustained over patients' lifetimes. Meanwhile, a randomized controlled trial appears justified.This study provides Class III evidence that CCM excision worsens short-term disability scores and increases the risk of symptomatic intracranial hemorrhage and new focal neurologic deficits.

The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women.An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Background and Purpose— Intravenous recombinant tissue-type plasminogen activator (r-tPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit. Methods— We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg r-tPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with r-tPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome. Results— Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risks in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH ( P for difference &gt;0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58–0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77–0.82) similarly to complex models. There was no evidence that the effect of r-tPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk. Conclusions— There is a clinically relevant net positive effect of r-tPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN25765518.

Conventional methodology to investigate cognitive impairment after coronary artery bypass graft (CABG) surgery leaves unclear the potential for pre-existing cognitive deficits to influence outcome. Individuals with pre-existing deficits may be more vulnerable to the effects of CABG, hence biasing the results of a typical prospective trial if account is not taken of their state. The present study examined the effect of pre-existing cognitive impairment upon cognitive outcome in 81 patients undergoing CABG. Patients performed the Stroop Neuropsychological Screening Test and other psychometric assessments prior to and at 6 days and 6 months after CABG. Those with pre-existing cognitive deficits were significantly more likely to display impairment at 6-day and 6-month follow-ups than were those without pre-existing deficits. Greater age and lower pre-morbid intelligence were also significant predictors of post-CABG deficit, confirming earlier findings. The results imply both that pre-existing cognitive impairments may render patients more vulnerable to post-operative deficits and that, in the absence of such pre-existing impairments, CABG surgery does not inevitably lead to later deficits. The study also replicated previous findings showing a similar influence of pre-existing depression upon emotional state after CABG. Overall, the results confirm the importance both of a patient's pre-existing cognitive and emotional states, and the methodology to assess them, in influencing outcome after cardiac surgery and the conclusions to be drawn as to the supposed adverse effects of the procedure. Conventional methodology to investigate cognitive impairment after coronary artery bypass graft (CABG) surgery leaves unclear the potential for pre-existing cognitive deficits to influence outcome. Individuals with pre-existing deficits may be more vulnerable to the effects of CABG, hence biasing the results of a typical prospective trial if account is not taken of their state. The present study examined the effect of pre-existing cognitive impairment upon cognitive outcome in 81 patients undergoing CABG. Patients performed the Stroop Neuropsychological Screening Test and other psychometric assessments prior to and at 6 days and 6 months after CABG. Those with pre-existing cognitive deficits were significantly more likely to display impairment at 6-day and 6-month follow-ups than were those without pre-existing deficits. Greater age and lower pre-morbid intelligence were also significant predictors of post-CABG deficit, confirming earlier findings. The results imply both that pre-existing cognitive impairments may render patients more vulnerable to post-operative deficits and that, in the absence of such pre-existing impairments, CABG surgery does not inevitably lead to later deficits. The study also replicated previous findings showing a similar influence of pre-existing depression upon emotional state after CABG. Overall, the results confirm the importance both of a patient's pre-existing cognitive and emotional states, and the methodology to assess them, in influencing outcome after cardiac surgery and the conclusions to be drawn as to the supposed adverse effects of the procedure. The recent review by Arrowsmith and colleagues1Arrowsmith JE Grocott HP Reves JG Newman MF Central nervous system complications of cardiac surgery.Br J Anaesth. 2000; 84: 378-393Abstract Full Text PDF PubMed Scopus (243) Google Scholar follows earlier authors in addressing the significant issues concerning the assessment of cognitive deficits following cardiac surgery and anaesthesia.2Newman SP The incidence and nature of neuropsychological morbidity following cardiac surgery.Perfusion. 1989; 4: 93-100Crossref Scopus (65) Google Scholar, 3Newman SP Neuropsychological and psychological changes.in: Smith P Taylor K Brain and Cardiac Surgery. Edward Arnold, London1990: 43-54Google Scholar, 4Blumenthal JA Mahanna EP Madden DJ White WD Croughwell ND Newman MF Methodological issues in the assessment of neuropsychologic function after cardiac surgery.Ann Thorac Surg. 1995; 59: 1345-1350Abstract Full Text PDF PubMed Scopus (112) Google Scholar The present research illustrates the importance of detecting cognitive deficits which may exist prior to coronary artery bypass graft (CABG) surgery in order to understand more fully the effects of the procedure upon outcome. Central to the method is the use of tasks that can define absolute, rather than relative, cognitive impairment. The assessment of intellectual deficits after CABG frequently employs performance tests which lack performance norms and hence cannot establish in absolute terms whether a patient is ‘impaired’. Impairment can only be established in relative terms from differences in performance before and after surgery (either statistically different or some arbitrary difference between pre- and post-scores such as 1 sd, or 20% decline, etc.). As the approach neglects whether a patient may have been cognitively impaired prior to the procedure, two difficulties arise. First, as patients with pre-existing impairments may be more vulnerable to the adverse effects of CABG, their inclusion in a sample may then inflate the apparent risk attached to the procedure. Conversely, patients who are already impaired may be performing so poorly that a ‘floor effect’ occurs whereby there is little scope for their performance to become worse; hence giving the misleading impression that the procedure has little adverse effect. Such difficulties may be addressed by using tests that have norms to establish absolute impairment and thus detect pre-existing deficits. The present study makes such an assessment by using the Stroop Neuropsychological Screening Test5Trenerry MR Crosson B DeBoe J Leber WR Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources, Odessa, Florida1989Google Scholar which has age-related impairment norms to define absolute impairment. The Stroop assesses attention and the ability to resist distraction, and is sensitive to impairment as a result of mild brain damage and to the subtle changes seen in mild to moderate dementia.6Lezak MD Neuropsychological Assessment. 3rd edition. Oxford University Press, Oxford1995: 373-375Google Scholar Performance on the Stroop prior to CABG has already been shown to be predictive of post-operative outcome.7Sotaniemi KA Juolasmaa A Hokkanen ET Neuropsychologic outcome after open-heart surgery.Arch Neurol. 1981; 38: 2-8Crossref PubMed Scopus (77) Google Scholar However, critically, the investigators did not take account of whether the pre-operative performance was indicative of absolute impairment. Other studies which have employed the Stroop to investigate both CABG-related impairment8Vingerhoets G Van Nooten G Jannes C Effect of asymptomatic carotid artery disease on cognitive outcome after cardiopulmonary bypass.J Int Neuropsych Soc. 1996; 2: 236-239Crossref PubMed Google Scholar, 9McKhann GM Goldsborough MA Borowicz LM et al.Cognitive outcome after coronary artery bypass: a one-year prospective study.Ann Thorac Surg. 1997; 63: 510-515Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 10McDaid CM Lewis SA McMurray T Phillips SA Heart surgery: what are the neuropsychological consequences?.Irish J Psychol. 1994; 15: 110-125Crossref Scopus (2) Google Scholar and post-anaesthetic recovery11Dijkstra JB Houx PJ Jolles J Cognition after major surgery in the elderly: test performance and complaints.Br J Anaesth. 1999; 82: 867-874Abstract Full Text PDF PubMed Scopus (100) Google Scholar have confirmed the sensitivity of the task to change from pre- to post-operative state but, again, without accounting for pre-operative impairment. The potential importance of accounting for the patient's pre-existing cognitive state in interpreting post-CABG deficits is not speculative but is confirmed by parallel research concerning the effects of CABG upon emotional state. Whilst the reported significant increases in depression after CABG have commonly been assumed to be a direct consequence of the procedure, research has shown that the presence of pre-existing depression is a significant determinant of the post-CABG state: patients who are not depressed beforehand are at substantially lower risk.12Channer KS O'Connor S Britton S Walbridge D Russell Rees J Psychological factors influence the success of coronary artery surgery.J R Soc Med. 1988; 81: 629-632Crossref PubMed Scopus (16) Google Scholar, 13Timberlake N Klinger L Smith P Venn G Treasure T Harrison M Newman SP Incidence and patterns of depression following coronary artery bypass graft surgery.J Psychosom Res. 1997; 43: 197-207Abstract Full Text PDF PubMed Scopus (85) Google Scholar, 14McKhann GM Borowicz LM Goldsborough MA Enger C Selnes OA Depression and cognitive decline after coronary artery bypass grafting.Lancet. 1997; 349: 1282-1284Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 15Arrowsmith JE Stygall J Timberlake N Pugsley WB Harrison MJG Newman SP New depression following coronary artery bypass surgery.Anesth Analg. 1999; 88: SCA68Crossref Google Scholar The methodology of the present study involves assessment of both absolute cognitive impairment and presence of depression prior to CABG, hence clarifying whether pre-existing impairments predict post-operative outcome, and replicating the existing results concerning depression and CABG outcome. Following approval of the study by the Ethics Committee of the Western Infirmary, Glasgow, 120 patients (92 men, 28 women; 77:23%) undergoing coronary artery bypass graft (CABG) surgery gave informed consent to participate. The standard anaesthetic regimen was adapted as necessary according to the patient's physical state and cardiac drug therapy. Patients were premedicated with temazepam or lorazepam orally the night before, and on the morning of surgery. After pre-oxygenation and establishing venous and arterial access, anaesthesia was induced with propofol and fentanyl. Tracheal intubation was facilitated, and neuromuscular blockade maintained by bolus doses of pancuronium. The lungs were inflated with at least 30% oxygen in nitrous oxide with varying doses of isoflurane. During cardiopulmonary bypass, additional fentanyl was given and a propofol infusion used. The bypass system, using a membrane oxygenator, was regularly adjusted according to measurements of pH and Pco2. The patients were cooled to core temperatures between 28 and 32°C, and the heart arrested using St Thomas's cardioplegia solution. Infusions of nitroglycerine and dopamine were used to support the heart and circulation as required. The patients were transferred to a cardiac intensive care unit for recovery, the majority being returned to the ward the next day. Patients were assessed 3 days before, and 6 days and 6 months after CABG. The Stroop Neuropsychological Screening Test5Trenerry MR Crosson B DeBoe J Leber WR Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources, Odessa, Florida1989Google Scholar consists of a sheet presenting a list of 112 colour names printed in incongruous colours (e.g. the word ‘blue’ printed in green ink). The subject was required to read through the list as quickly as possible, reading out the name of the colour in which the word is printed. The interference effect produced by the incongruity of the word name and the colour of its presentation renders the task very demanding of attention and concentration. The score is the number of words read correctly in 2 min. The task norms allow an individual's score to be categorized as indicative of likely brain damage as a function of their age. Depression was assessed with the self-report Beck Depression Inventory16Beck AT Steer RA Beck Depression Inventory Manual. Psychological Corporation (Harcourt Brace Jovanovich), New York1987Google Scholar using the conventional criterion of a score ≥9 as indicative of depression. Years of education are known to have a protective function from the adverse effects of CABG, 17Newman MF Croughwell ND Blumenthal JA et al.Predictors of cognitive decline after cardiac operation.Ann Thorac Surg. 1995; 59: 1326-1330Abstract Full Text PDF PubMed Scopus (199) Google Scholar hence pre-morbid intellectual status was assessed prior to CABG with the National Adult Reading Test (NART).18Nelson HE National Adult Reading Test (NART): Test Manual. NFER-Nelson, Windsor1982Google Scholar Personality characteristics of extroversion and neuroticism can predict post-surgical outcome19Thorp JM Kennedy BW Millar K Fitch W Personality traits as predictors of anxiety prior to Caesarean section under regional anaesthesia.Anaesthesia. 1993; 48: 946-950Crossref PubMed Scopus (17) Google Scholar and were assessed prior to CABG by the Eysenck Personality Questionnaire.20Eysenck HJ Eysenck SB The Eysenck Personality Inventory. Hodder and Stoughton, London1992Google Scholar Statistical analysis was conducted with Minitab version 12 via Windows 95 on a Viglen Contender PC. Eighty-one of the 120 patients completed the assessments at all three periods (64 men, 17 women; 79:21%, the proportions being almost identical to the original full sample hence indicating equivalent attrition as a function of gender). The mean ages for men and women (sd; range) were 59.4 (8.7; 38–76) and 62.4 (10.0; 37–73) yr respectively. Because of the very small proportion of women participating in the study, the factor of gender is not considered further in the analysis. The mean NART error score of 15.2 (sd 6.85) corresponded to an average IQ of 111.5Trenerry MR Crosson B DeBoe J Leber WR Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources, Odessa, Florida1989Google Scholar Table 1 shows the number and percentage of patients suffering cognitive impairment at 6 days or 6 months follow-up, or at both follow-ups, as a function of their pre-CABG state. Prior to CABG, 13 (16%) patients had pre-existing impairment. Postoperatively, 11 (85%) of the latter patients were impaired at 6 days, a total comprising six (46%) who were impaired only at 6 days and five (39%) who were impaired at 6 days and remained so at 6 months. In contrast, of the 68 (84%) who were not impaired prior to the procedure, a total of nine (14%) became impaired at 6 days, these being eight (12%) who were impaired only at 6 days and one (2%) who was impaired at both follow-ups. By contrasting the proportion of patients who were impaired with those unimpaired before CABG and at follow-up, the presence of pre-CABG impairment was found to be a significant predictor of the post-procedure state (Fisher's exact test, both P<0.001). There was no evidence of late-onset impairment: no patient was impaired at 6 months without having previously been impaired.Table 1The number and percentage of patients suffering cognitive impairment and depression as assessed by Stroop Neuropsychological Screening Test and Beck Depression Inventory before and after coronary artery bypass graft surgery. Mean Stroop performance before and after surgery is shown in the lower panel of the table (sd in parentheses)ImpairmentPre-operative statusPost-operative statusImpaired at 6 days onlyImpaired at 6 days and 6 monthsImpaired at 6 months onlyImpaired13 (16%)6 (46%)5 (39%)0Unimpaired68 (84%)8 (12%)1 (2%)0DepressionPre-operative statusPost-operative statusDepressed at 6 days onlyDepressed at 6 days and 6 monthsDepressed at 6 months onlyDepressed23 (28%)9 (39%)9 (39%)3 (13%)Not Depressed58 (72%)6 (10%)2 (4%)3 (5%)Mean Stroop performancePre-operative6 days6 months85.5 (19.6)80.4 (22.0)93.3 (17.8) Open table in a new tab Table 1 also shows that depression as a function of the pre-CABG state follows an identical pattern to that for impairment. Of the 23 (28%) patients who reported pre-operative depression, a total of 18 (78%) continued to be depressed at 6 days follow-up, nine (39%) of these being depressed only at 6 days and nine (39%) being depressed at both follow-up periods. Of the 58 (72%) who were not depressed prior to CABG, a total of eight (14%) reported depression at 6 days follow-up, six (10%) of these being depressed only at 6 days and two (4%) being depressed at both follow-ups. By contrasting the proportions of patients who were depressed with those who were not depressed before CABG and at the subsequent two follow-ups, the presence of pre-CABG depression was found to be a significant predictor of the post-procedure state (chi-squared, both P<0.001). Late-onset depression at 6 months was evident in 6 patients, three of whom had reported no previous depression at baseline or 6-day follow-up, and three of whom had been depressed only prior to CABG. Whilst depression has been associated with cognitive impairment, the two variables were not correlated and thus impairment is not explained by a depressed state. The prediction of post-CABG impairment on the Stroop task was assessed further by multiple linear regression with the independent continuous variables of age, NART error score, and scores of extroversion and neuroticism. The regression showed the variables of age and NART to be significant predictors, together accounting for 34% of variance in Stroop performance at 6 days (P<0.001) and 24% at 6 months (P<0.01). Thus, patients who were older, and those of lower pre-morbid intellectual capacity, were more likely to suffer post-CABG deficit. The personality factors were not predictive. Table 1 also shows mean Stroop performance at each time point as in a conventional analysis to describe impairment as a change from baseline. The performance profile shows an immediate post-operative deterioration in performance, which is then followed by a marked recovery at 6 months to a level substantially above that of the pre-operative baseline. The significant main effect of time (ANOVA: F2,240=8.70, P<0.001) is located in significant differences between performance at 6 months and that at 6 days and baseline (Tukey post-hoc comparisons). The outcome of this mean-based analysis suggests an overall recovery of function at 6 months and is in contrast to the preceding analysis, based on assessment of absolute impairment, which shows some 40% of patients to be impaired at the second follow-up. The results confirm that pre-existing cognitive impairment is a significant determinant of whether deficits are observed after anaesthesia and surgery associated with CABG. Patients with a pre-existing attentional deficit as assessed by the Stroop task were significantly more likely to show post-CABG attentional impairment than those without such a deficit. MRI studies21Toner I Hamid SK Peden CJ Taylor KM Smith PLC Newman SP Magnetic resonance imaging and P300 (event-related auditory evoked potentials) in the assessment of postoperative cerebral injury following coronary artery bypass surgery.Perfusion. 1993; 8: 321-329Crossref PubMed Scopus (11) Google Scholar indicate that CNS abnormalities resulting from the patients’ chronic cardiac disease may underlie such pre-existing intellectual impairments.22Benedict RHB Cognitive function after open-heart surgery: are postoperative neuropsychological deficits caused by cardiopulmonary bypass?.Neuropsych Rev. 1994; 4: 223-255Crossref PubMed Scopus (52) Google Scholar 23Deshields TL McDonough EM Mannen RK Miller LW Psychological and cognitive status before and after heart transplantation.Gen Hosp Psychiat. 1996; 18: 62S-69SAbstract Full Text PDF PubMed Google Scholar The results also fully replicate earlier findings12Channer KS O'Connor S Britton S Walbridge D Russell Rees J Psychological factors influence the success of coronary artery surgery.J R Soc Med. 1988; 81: 629-632Crossref PubMed Scopus (16) Google Scholar−15Trenerry MR Crosson B DeBoe J Leber WR Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources, Odessa, Florida1989Google Scholar showing that post-CABG depression, too, is significantly determined by the patient's state prior to the procedure. More generally, the results support previous findings that CABG outcome is predicted by age and pre-morbid intellectual status.16Beck AT Steer RA Beck Depression Inventory Manual. Psychological Corporation (Harcourt Brace Jovanovich), New York1987Google Scholar 24Roach GW Kanchuger M Mora Mangano C et al.Adverse cerebral outcomes after coronary artery bypass surgery.New Engl J Med. 1996; 335: 1857-1863Crossref PubMed Scopus (1664) Google Scholar Older patients, and those with lower pre-morbid intellectual function, were more likely to suffer post-CABG impairment. Caution is required in extrapolating from the present study where only one cognitive assessment has been employed. Nonetheless, the obvious corollary of the results is that, unless allowance is made for pre-existing impairments, there is the risk of erroneously ascribing some adverse outcomes to a procedure and hence over-estimating its potential risks. Furthermore, where a procedure does exacerbate a pre-existing deficit, the full impact may be missed when using purely relative measures. For example, even a slight decline in the performance of an individual with a pre-existing impairment may be of considerable clinical consequence when compared with that of an individual without such impairment. The latter issue of individual variation is also critical to full understanding of CABG-related impairment. It has been widely observed, both in the case of CABG and recovery from general anaesthesia, that individual variation is often masked when results are expressed in terms of group means and that this may lead to failure to detect both decline and improvement in a subgroup of patients.2Newman SP The incidence and nature of neuropsychological morbidity following cardiac surgery.Perfusion. 1989; 4: 93-100Crossref Scopus (65) Google Scholar 22Benedict RHB Cognitive function after open-heart surgery: are postoperative neuropsychological deficits caused by cardiopulmonary bypass?.Neuropsych Rev. 1994; 4: 223-255Crossref PubMed Scopus (52) Google Scholar 25Murkin JM Newman SP Stump DA Blumenthal JA Statement of consensus on assessment of neurobehavioural outcomes after cardiac surgery.Ann Thorac Surg. 1995; 59: 1289-1295Abstract Full Text PDF PubMed Scopus (533) Google Scholar, 26Millar K Effects of anaesthetic and analgesic drugs.in: Smith AP Jones DM Handbook of Human Performance. Volume 2. Academic Press, London1992: 337-385Google Scholar, 27Hickey S Asbury AJ Millar K Psychomotor recovery after outpatient anaesthesia: individual impairment may be masked by group analysis.Br J Anaesth. 1991; 66: 345-352Crossref PubMed Scopus (10) Google Scholar The present analysis demonstrates that simply comparing average pre- and post-CABG performance does not accurately describe the adverse impact of CABG upon Stroop performance and the recovery of function. The mean-based analysis gives the impression of overall recovery of function at 6 months whereas the assessment of absolute impairment shows a substantial proportion of the patients still to be impaired. Whilst the detection of impairment is a principal concern in studying outcome after CABG, it is important also to be aware of potential improvements in function because of the procedure. Eight of the present patients who were impaired prior to CABG improved significantly to unimpaired status 6 months after surgery. Their mean change in Stroop score of 18.5 (sd 9.47) corresponds to a 28% improvement from their baseline (t7=4.55, P=0.003) and contrasts markedly with the 5% improvement due to practice typically seen in ‘normal’ subjects.5Trenerry MR Crosson B DeBoe J Leber WR Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources, Odessa, Florida1989Google Scholar Whilst speculative given the present small sample, it has been proposed that such improvement reflects both practice and the beneficial effects of improved perfusion upon cognition.23Deshields TL McDonough EM Mannen RK Miller LW Psychological and cognitive status before and after heart transplantation.Gen Hosp Psychiat. 1996; 18: 62S-69SAbstract Full Text PDF PubMed Google Scholar The present attrition rate of 32% is virtually identical to that of a very recent study of pre-existing depression and CABG14McKhann GM Borowicz LM Goldsborough MA Enger C Selnes OA Depression and cognitive decline after coronary artery bypass grafting.Lancet. 1997; 349: 1282-1284Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar but it is higher than that of others.12Channer KS O'Connor S Britton S Walbridge D Russell Rees J Psychological factors influence the success of coronary artery surgery.J R Soc Med. 1988; 81: 629-632Crossref PubMed Scopus (16) Google Scholar 13Timberlake N Klinger L Smith P Venn G Treasure T Harrison M Newman SP Incidence and patterns of depression following coronary artery bypass graft surgery.J Psychosom Res. 1997; 43: 197-207Abstract Full Text PDF PubMed Scopus (85) Google Scholar 15Arrowsmith JE Stygall J Timberlake N Pugsley WB Harrison MJG Newman SP New depression following coronary artery bypass surgery.Anesth Analg. 1999; 88: SCA68Crossref Google Scholar Attrition commonly affects studies involving long-term follow-up and may result in fundamental differences between those who continue with a study and those who ‘drop out’. Benedict22Benedict RHB Cognitive function after open-heart surgery: are postoperative neuropsychological deficits caused by cardiopulmonary bypass?.Neuropsych Rev. 1994; 4: 223-255Crossref PubMed Scopus (52) Google Scholar has observed that when a group of particularly impaired individuals drop out of a CABG data set there is then the potential for the procedure to appear to exert a less adverse effect. Further analysis of the present data confirms that, pre-operatively, the proportions of those impaired and depressed were considerably higher amongst the drop-outs than those who continued with the study (36 vs 16%, and 44 vs 28%, for impairment and depression, respectively). Whilst the differences are not statistically reliable because of the small numbers involved, they show that attrition has the potential to distort the results of such a study (P=0.21 and P=0.10, for impairment and depression, respectively). A similar effect of attrition is seen in the results of Vingerhoets and colleagues.8Vingerhoets G Van Nooten G Jannes C Effect of asymptomatic carotid artery disease on cognitive outcome after cardiopulmonary bypass.J Int Neuropsych Soc. 1996; 2: 236-239Crossref PubMed Google Scholar Some 48% of one of their CABG study groups dropped out between baseline and follow-up, the consequence being that the baseline Stroop performance of those who continued with the study (and against which long-term follow-up was evaluated) was some 23% better than that of the original sample. Extensive studies of CABG-related cognitive deficits have led to detailed ‘Consensus Statements’ by Murkin and his colleagues regarding the tasks and methodology for such research.4Blumenthal JA Mahanna EP Madden DJ White WD Croughwell ND Newman MF Methodological issues in the assessment of neuropsychologic function after cardiac surgery.Ann Thorac Surg. 1995; 59: 1345-1350Abstract Full Text PDF PubMed Scopus (112) Google Scholar 25Murkin JM Newman SP Stump DA Blumenthal JA Statement of consensus on assessment of neurobehavioural outcomes after cardiac surgery.Ann Thorac Surg. 1995; 59: 1289-1295Abstract Full Text PDF PubMed Scopus (533) Google Scholar 28Murkin JM Stump DA Blumenthal JA McKhann G Defining dysfunction: group means versus incidence analysis – a statement of consensus.Ann Thorac Surg. 1997; 64: 904-905Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar 29Newman SP Analysis and interpretation of neuropsychological tests in cardiac surgery.Ann Thorac Surg. 1995; 59: 1351-1355Abstract Full Text PDF PubMed Scopus (79) Google Scholar The present results confirm the specific consensus regarding pre-operative assessment: ‘A number of patients presenting [for CABG] may have pre-existing CNS abnormalities. [The] neuropsychologic state needs to be assessed[…] prior to operation to provide accurate baseline information.’ (p. 1289).25Murkin JM Newman SP Stump DA Blumenthal JA Statement of consensus on assessment of neurobehavioural outcomes after cardiac surgery.Ann Thorac Surg. 1995; 59: 1289-1295Abstract Full Text PDF PubMed Scopus (533) Google Scholar The present results suggest that baseline information would be obtained more accurately with tasks that provide evidence of absolute functional status than the commonly used relative measures. They have the further virtue of being predictive of outcome. The present results do not call into question the general principles outlined in the Consensus Statement for research into CABG impairment.25Murkin JM Newman SP Stump DA Blumenthal JA Statement of consensus on assessment of neurobehavioural outcomes after cardiac surgery.Ann Thorac Surg. 1995; 59: 1289-1295Abstract Full Text PDF PubMed Scopus (533) Google Scholar There would seem merit, however, in a series of studies to contrast absolute and relative measures of cognition in their ability both to detect pre-existing deficits and to predict subsequent CABG-related impairment. Indeed, retrospective analysis of some published data sets might be capable of addressing this question where those studies have involved tasks with absolute performance norms which were not employed in the original analysis. The research was funded by grant no. K/MRS/50/C2238 from the Chief Scientist Office of the Scottish Office Department of Health.

Women undergoing surgery for primary breast cancer routinely have suction drains inserted deep to the wounds, which are removed approximately 6-8 days after operation, requiring a period of stay of that duration in hospital. The aim of this study was to perform a prospective randomized clinical trial to evaluate a new surgical technique of suturing flaps without wound drainage, combined with early discharge, in women undergoing surgery for breast cancer.A total of 375 patients undergoing surgery for breast cancer were randomized to conventional surgery or suturing of flaps with no drain. The main outcome measures were length of hospital stay, surgical morbidity, psychological morbidity and health economics.Suturing of flaps and avoiding wound drainage in women undergoing surgery for breast cancer resulted in a significantly shorter hospital stay. Adopting this surgical technique with early discharge did not lead to any difference in surgical or psychological morbidity. Health economic benefits to the National Health Service resulted from saved bed days with no impact on community costs.Wound drainage following surgery for breast cancer can be avoided, thereby facilitating early discharge with no associated increase in surgical or psychological morbidity.

Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ET(A/B) receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients.Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events. There was a lower incidence of delayed ischemic events at 3 months in the TAK-044-treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo-treated and TAK-044-treated groups.The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache--side effects compatible with the drug's vasodilatory properties--occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.

This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy.Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis.A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events.GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.

Background The importance of the effects of ACE inhibitors on sudden death, progressive heart failure and recurrent infarction to the reduction in overall mortality in heart failure and after myocardial infarction is disputed. Methods The AIRE study randomized 2006 patients with clinical or radiological evidence of heart failure within 2–9 days of a myocardtal infarction to receive ramipril 5 mg b.d. or matching placebo. Outcomes were assessed independently by members of an end-points committee blinded to treatment allocation. Results Fewer patients developed severe resistant heart failure as their first validated end-point on ramipril, despite the greater number of at-risk survivors, compared to placebo (n=143 vs 178; risk reduction 23%; CI 5 to 39%; P=0.017). Ramipril did not alter the rate of reinfarction or stroke. Irrespective of treatment allocation 182 (46%) patients developed resistant heart failure prior to death. A validated acute or remote myocardial reinfarction occurred in 76 (19%) patients prior to death and chest pain occurred in 90 (23%) patients around the time of death suggesting an ischaemic element to these deaths. Eighty deaths occurred on the index admission, 167 during re-admission and 145 out-of-hospital. Sudden death accounted for 54% of all deaths and 93% of out-of-hospital deaths. Ramipril reduced the risk of sudden death by 30% (95% CI; 8-47%; P=0.011). However, overall, 45% of those patients who died suddenly had severe or worsening heart failure prior to their death. Only 39% of sudden deaths were considered to be due to arrhythmias. Ramipril reduced the risk of death from circulatory failure by 18%, but this did not reach statistical significance (95% CI; 41 to −14%; P=0.237). The magnitude of the effects on sudden death and death due to circulatory failure were not significantly different. However, 38% of the reduction in overall mortality was from the subgroup with sudden death who had developed prior severe resistant heart failure (placebo n=35, ramipril n=15), again emphasizing the marked benefit in preventing failure. Ramipril did not selectively alter the proportion of in- to out-of-hospital deaths. Conclusion Ramipril reduces mortality and progression to resistant heart failure among patients with evidence of heart failure early after myocardial infarction. Retarding the progression of heart failure appears to be a major factor contributing to the reduction in mortality both by reducing circulatory failure and by reducing sudden death. (Eur Heart J 1997; 18: 41–51)