Therapeutic hypothermia for head injury.

BACKGROUND: Induced hypothermia has been used in the treatment of head injury for many years. Encouraging results from small trials and laboratory studies led to renewed interest in the area and some larger trials. OBJECTIVES: To estimate the effects of mild induced hypothermia in moderate and severe head injury on mortality, long-term functional outcome, complications, and short-term control of intracranial pressure (ICP). SEARCH STRATEGY: We searched the Injuries Group Specialised register (last searched in 2001), MEDLINE, EMBASE and the Cochrane Controlled Trials Register. We handsearched conference proceedings and checked reference lists of relevant articles, including a systematic review published in 2003. SELECTION CRITERIA: Randomised controlled trials of mild hypothermia to 34-35 masculine Celsius for at least 12 hours versus control (open or normothermia) in patients with any closed head injury requiring hospitalisation. Two reviewers independently assessed all trials. DATA COLLECTION AND ANALYSIS: Data on death, Glasgow outcome scale, complications and ICP were sought and extracted, either from published material or by contacting the investigators. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial on an intention-to-treat basis. Quantitative synthesis of data on complications other than pneumonia or ICP was not attempted. Trials of immediate and deferred hypothermia were analysed separately. MAIN RESULTS: We found 14 trials with 1094 participants. Active immediate hypothermia was associated with an OR for death of 0.80, (1061 patients, OR 0.80, 95% CI 0.61 to 1.04), and 0.75 for odds of being dead or severely disabled, (746 patients, OR 0.75, 95% CI 0.56 to 1.00). Hypothermia treatment was associated with a statistically significant increase in odds of pneumonia (281 patients, OR 1.95, 95% CI 1.18 to 3.23). The trial of deferred hypothermia (33 patients) reported a huge but not statistically significant reduction in the odds of death at six months, (OR 0.21, 95% CI 0.04 to 1.05). For death or severe disability, deferred hypothermia was associated with an OR of 0.10 (95% CI 0.01 to 1.00). REVIEWERS' CONCLUSIONS: There is no evidence that hypothermia is beneficial in the treatment of head injury. The earlier, encouraging, trial results have not been repeated in larger trials. The reasons for this are unclear. Hypothermia increases the risk of pneumonia and has other potentially harmful side-effects. Therefore, it would seem inappropriate to use this intervention outside of controlled trials in subgroups of patients for whom there is good reason to think the treatment would be beneficial.

Therapeutic hypothermia for head injury.

BACKGROUND: Induced hypothermia has been used in the treatment of head injury for many years. Encouraging results from small trials and laboratory studies led to renewed interest in the area and some larger trials. OBJECTIVES: To estimate the effects of mild induced hypothermia in moderate and severe head injury on mortality, long-term functional outcome, complications, and short-term control of intracranial pressure (ICP). SEARCH STRATEGY: We searched the Injuries Group Specialised register (last searched in 2001), Medline, EMBASE and the Cochrane Controlled Trials Register. We handsearched conference proceedings and checked reference lists of relevant articles. SELECTION CRITERIA: Randomised controlled trials of mild hypothermia to 34-35 Celsius for a t least 12 hours versus control (open or normothermia) in patients with any closed head injury requiring hospitalisation. Two reviewers independently assessed all trials. DATA COLLECTION AND ANALYSIS: Data on death, Glasgow Outcome Scale, complications and ICP were sought and extracted, either from published material or by contacting the investigators. Odds ratios and 95% confidence intervals were calculated for each trial on an intention-to-treat basis. Quantitative synthesis of data on complications other than pneumonia or ICP was not attempted. Trials of immediate and deferred hypothermia were analysed separately. MAIN RESULTS: We found 12 trials with 812 participants. Active immediate hypothermia was associated with an odds ratio for death of 0.88, (771 patients, OR 0.88, 95% CI 0.63 to 1.21), and 0.75 for odds of being dead or severely disabled, (746 patients, OR 0.75, 95% CI 0.56 to 1.00). Hypothermia treatment was associated with a statistically significant increase in odds of pneumonia (281 patients, OR 1.95, 95% CI 1.18 to 3.23). The trial of deferred hypothermia (33 patients) reported a huge but not statistically significant reduction in the odds of death at 6 months, (OR 0.21, 95% CI 0.04 to 1.05). For death or severe disability deferred hypothermia was associated with an odds ratio of 0.10 (95% CI 0.01 to 1.00). REVIEWER'S CONCLUSIONS: There is no evidence that hypothermia is beneficial in the treatment of head injury. The earlier, encouraging, trial results have not been repeated in larger trials. The reasons for this are unclear. Hypothermia increases the risk of pneumonia and has other potentially harmful side effects. Therefore, it would seem inappropriate to use this intervention outside of controlled trials in subgroups of patients for whom there is good reason to think the treatment would be beneficial.

Variations between countries in outcome after stroke in the International Stroke Trial (IST).

BACKGROUND AND PURPOSE: This study describes the large variations in outcome after stroke between countries that participated in the International Stroke Trial and seeks to define whether they could be explained by variations in case mix or by other factors. METHODS: We analyzed data from the 15 116 patients recruited in Argentina, Australia, Italy, the Netherlands, Norway, Poland, Sweden, Switzerland, and the United Kingdom: We compared crude case fatality and the proportion of patients dead or dependent at 6 months; we used logistic regression to adjust for age, sex, atrial fibrillation, systolic blood pressure, level of consciousness, and number of neurological deficits. We used the frequency of prerandomization head CT scan and prescription of aspirin at discharge to indicate quality of care. RESULTS: The differences in outcome (all treatment groups combined) between the "best" and "worst" countries were very large for death (171 cases per 1000 patients) and for death or dependency (375 cases per 1000 patients). The differences were somewhat smaller after adjustment for case mix (160 and 311 cases per 1000 patients, respectively). Process of care may have accounted for some but not all of the residual variation in outcome. CONCLUSIONS: Adjustment for case mix explained only some of the variation in outcome between countries. The residual differences in outcome were too large to be explained by variations in care and most likely reflect differences in unmeasured baseline factors. These findings demonstrate the need to achieve balance of treatment and control within each country in multinational randomized controlled stroke trials and the need for caution in the interpretation of nonrandomized comparisons of outcome after stroke between countries.

Reliability of the relative's questionnaire for assessment of outcome after brain injury.

PURPOSE: The relative's questionnaire (RQ) was developed to assess outcome after brain injury. The present study investigated its test-retest reliability when used in a postal survey. METHOD: Hospital records were used to identify and contact 288 surviving patients treated for brain injury five to seven years earlier. Patients were sent a copy of the RQ (RQ1) and one month later a second copy (RQ2) was sent to those who returned RQ1. RESULT: Two hundred and eleven patients were successfully contacted, of whom 128 (61%) returned RQ1, and 94 of these (73%) returned RQ2. The reliability of items was variable, with most having a kappa value of > 0.6 suggesting 'substantial agreement' or better. CONCLUSION: The data presented suggest that the RQ is a reliable instrument in collecting outcome information in brain-injured patients by postal survey. Further research is recommended to test the suitability of the RQ for the use as a telephone interview.

Therapeutic hypothermia for head injury.

BACKGROUND: Mild to moderate induced hypothermia has been used in the treatment of head injury for over 50 years, although few randomised controlled trials have been performed. Recent encouraging results from small, single-centre trials and consistent findings of a cerebral protection effect of cooling in laboratory models of global ischaemia has led to a renewed interest in the area. OBJECTIVES: To determine whether the use of mild therapeutic hypothermia in the treatment of moderate and severe head injury improves short-term control of intracranial pressure (ICP) and long-term functional outcome. SEARCH STRATEGY: Electronic searches of the Injuries Group trial registry and EMBASE for any relevant randomised trials, supplemented by hand searching of conference proceedings and reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials of mild hypothermia versus control (open or normothermia) in the treatment of patients with any closed head injury requiring hospitalisation. Mild hypothermia was defined as local or systemic cooling to a target temperature of at most 34-35 degrees Celsius for a period of at least 12 hours. Outcome was all-cause mortality and death or severe disability at the end of the scheduled follow-up period. All trials were assessed by two reviewers, and included or excluded on a consensus basis. DATA COLLECTION AND ANALYSIS: Eleven potential trials of therapeutic hypothermia for head injury were found, of which two are ongoing and one is awaiting assessment. The eight remaining trials were included in the systematic review. Data on death, GOS score at final follow-up, complications and ICP were sought and extracted, either from published material or by contact with the investigators. Mantel-Haenzel odds ratios and 95% confidence intervals were calculated for death and death and severe disability for each trial on an intention-to-treat basis. No quantitative synthesis of data on either complications or ICP was attempted. Trials of immediate and deferred hypothermia were analysed separately. MAIN RESULTS: Active immediate hypothermic treatment was associated with a 33% non-significant (p=0.16) reduction in the odds of death at the end of treatment or final follow-up, (OR 0.67, 95% confidence interval 0.38 to 1.17), and a 61% reduction (p=0.004) in the odds of being dead or severely disabled, (OR 0.39, 95% confidence interval 0.20 to 0.74). Similar effect sizes were found for delayed hypothermia. These results are, however, based on a few small trials each of less than 100 patients. A multi-centre trials of hypothermia versus control in 392 patients will be reporting results in 1999, providing substantially more evidence than is currently available. REVIEWER'S CONCLUSIONS: Although this review would suggest a strong positive effect of therapeutic hypothermia, the results are based on several small trials carried out in single, specialist centres. The results of a large multi-centre trial are expected in 1999 and will more than treble the available evidence. Until these results have been released, it would be inappropriate to make any short-term recommendations for clinical practice or research.

Simple assessment of outcome after acute brain injury using the Glasgow Outcome Scale.

To evaluate alternative methods of determining Glasgow Outcome Scale scores, a postal survey was made of 288 general practitioners and 128 relatives of patients who had sustained acute brain injuries 5-7 years previously. The Glasgow Outcome Scale score from the general practitioner and relative were compared with that calculated from questionnaire information by an experienced rater. There was poor agreement between general practitioner and rater (K = 0.17) and relative and rater (K = 0.35) scores. Both general practitioners and relatives indicated more favourable outcomes than the rater, with a higher level of agreement (K = 0.61) between them. When Glasgow Outcome Scale scores are used, the methods employed should be valid and reliable; failure to ensure this may be responsible for a considerable proportion of variability in reported studies of brain injury outcome.

What pathological components indicate carotid atheroma activity and can these be identified reliably using ultrasound?

OBJECTIVE: The aim of this project was to determine whether histological features of 'active' plaque as described in the coronary circulation following acute myocardial infarction were similar in the carotid circulation, and whether these factors could be detected ultrasonically. METHOD: Endarterectomy specimens were prospectively collected, and examined histologically and assessed by two observers for ulceration, inflammation, size of necrotic core, thickness of fibrous cap, haemorrhage and luminal thrombosis. Ultrasound of the plaque obtained preoperatively was similarly coded (blind to pathology) and compared with the pathology. RESULTS: In 42 endarterectomy specimens, there was a highly significant relationship between a thin fibrous cap and a large necrotic core (P<0.002), irregular plaque contour (P<0.05) and ulceration (P<0.01) and between a large necrotic core (P<0.002) and ulceration and inflammation (P<0.05). Increasing amounts of necrosis were associated with more surface thrombosis (P<0.02). Ultrasound detected the thickness of the fibrous cap and 'any necrosis or haemorrhage' with some reliability (kappas are 0.53 and 0.5, respectively), but not ulceration, necrosis or haemorrhage on their own. CONCLUSION: Features corresponding to active atheromatous plaque are similar in the carotid and coronary arteries, and some of these, namely lucent areas in the plaque (corresponding to necrosis or haemorrhage) and the thickness of the fibrous cap, can be determined reliably with ultrasound.

Trying to understand routine stroke outcome data: the need for adequate casemix adjustment and some practical considerations.

OBJECTIVE: To determine how far the difference in published stroke case fatality between the Western General Hospital (WGH), Edinburgh and the Falkirk and District Royal Infirmary (FDRI) for the period 1990-93 can be explained by adjusting more fully for casemix. DESIGN: The cases were ascertained and followed prospectively at the WGH and retrospectively at the FDRI; casemix correction was performed using a validated logistic regression model. SETTING: The WGH is a teaching hospital and the FDRI a district general hospital. SUBJECTS: Four hundred and thirty seven patients with a verified acute stroke at the WGH; 471 patients assigned a cerebrovascular disease discharge diagnostic code at the FDRI. OUTCOME MEASURE: Thirty day case fatality. RESULTS: About half of the difference in the two hospitals' published stroke case fatality could be accounted for by variation in measured casemix. The residual difference in adjusted case fatality might have been due to differences in the structure of stroke care or simply to remaining differences in casemix. Full investigation of the cause was prevented by the destruction of the deceased patients records. CONCLUSIONS: Comparisons of routinely collected stroke outcomes will remain difficult to interpret unless casemix is properly accounted for and deceased patients' records stored for several years.

Glasgow head injury outcome prediction program: an independent assessment.

Using an independent data set, the utility of the Glasgow Head Injury Outcome Prediction Program was investigated in terms of possible frequency of use and reliability of outcome prediction in patients with severe head injury, or haematoma requiring evacuation, or coma lasting 6 hours or more, in whom outcome had been reliably assessed at 6 to 24 months after injury. Predictions were calculated on admission, before evacuation of a haematoma, or 24 hours, 3 days, and 7 days after onset of coma lasting 6 hours or more. Three hundred and twenty four patients provided 426 predictions which were possible in 76%, 97%, 19%, 34%, and 53% of patients on admission, before operation, 24 hours, 3 days, and 7 days respectively. Major reasons for non-feasible predictions were that patients were paralysed/ventilated as part of resuscitation or management. Overall, 75.8% of predictions were correct, 14.6% were pessimistic (outcome better than predicted), and 9.6% optimistic (outcome worse than predicted). Of 197 patients (267 predictions) whose eventual outcome was good or moderate, 84.3% of predictions were correct. For death or vegetative survival (96 patients with 110 predictions), 83.6% of predictions were correct but for severe disability (31 patients with 49 predictions), only 12.2% were correctly predicted. The utility of the Glasgow Head Injury Outcome Prediction Program compares favourably with other outcome prediction algorithms for patients with head injury.

Inverse relation between Braak stage and cerebrovascular pathology in Alzheimer predominant dementia.

The most common neuropathological substrates of dementia are Alzheimer's disease, cerebrovascular disease, and dementia with Lewy bodies. A preliminary, retrospective postmortem analysis was performed of the relative burden of each pathology in 25 patients with predominantly Alzheimer's disease-type dementia. Log linear modelling was used to assess the relations between ApoE genotype, Alzheimer's disease, and cerebrovascular disease pathology scores. Sixteen of 18 cases (89%) with a Braak neuritic pathology score

Delayed intracranial hypertension: relationship to leukocyte count.

OBJECTIVE: Secondary intracranial hypertension has been linked to leukocytosis. We examined our data bank containing physiologic recordings and outcome data of severely head injured patients to investigate the relationship between delayed increases in intracranial pressure (ICP), defined as occurring after a 12-hr period of normal ICP values, and leukocytosis. DESIGN: A retrospective study of observational data. SETTING: Regional neurosurgical unit and intensive care unit. PATIENTS: Sixty-four patients suffered increased ICP >20 mm Hg. Thirty-five patients fulfilled selection criteria for delayed increases in ICP (group 1). Twenty-nine patients with increased ICP with no preceding or intervening periods of normal ICP were selected as a comparison group (group 2). MEASUREMENTS AND MAIN RESULTS: Comparison of 12-month outcome revealed that 11% of group 1 patients died, with 49% remaining severely disabled, in contrast to group 2, where 35% of patients died and 14% were left severely disabled (p = .021). The pattern of outcome was independent of monitoring time, or injury severity. Regression modeling was performed for prediction of delayed increase in ICP. Of 46 patients with an initial increase then decrease in leukocyte count in the first 48 hrs, 65% experienced delayed increases in ICP, as compared with 18% of the 11 patients without this pattern p = .01 1). CONCLUSIONS: Patients with delayed increases have a significantly different pattern of outcome. Change in leukocyte count from admission to day 2 is a significant predictor of such a delayed increase.

Predicting survival using simple clinical variables: a case study in traumatic brain injury.

OBJECTIVES: Prediction of patient outcome can be useful as an aid to clinical decision making, to explore possible biological mechanisms, and as part of the clinical audit process. Many studies have constructed predictive models for survival after traumatic brain injury, but these have often used expensive, time consuming, or highly specialised measurements. The aim of this study was to develop a simple easy to use model involving only variables which are rapidly and easily clinically achievable in routine practice. METHODS: All consecutive patients admitted to a regional trauma centre with moderate or severe head injury were enrolled in the study. Basic demographic, injury, and CT characteristics were recorded. Patient survival at 1 year was used to construct a simple predictive model which was then validated on a very similar patient group. RESULTS: 372 patients were included in the study, of whom 365 (98%) were followed up for survival at 1 year. Multiple logistic regression resulted in a model containing age (p<0.001), Glasgow coma scale score (p<0.001), injury severity score (p<0.001), pupil reactivity (p=0.004), and presence of haematoma on CT (p=0.004) as independently significant predictors of survival. The model was validated on an independent set of 520 patients, showing good discrimination and adequate calibration, but with a tendency to be pessimistic about very severely injured patients. It is presented as an easy to use nomogram. CONCLUSIONS: All five variables have previously been shown to be related to survival. All variables in the model are clinically simple and easy to measure rapidly in a centre with access to 24 hour CT, resulting in a model that is both well validated and clinically useful.

Adding insult to injury: the prognostic value of early secondary insults for survival after traumatic brain injury.

OBJECTIVES: To assess the prognostic value of summary measures of secondary physiological insult in addition to baseline clinical variables for patients with traumatic brain injury. METHODS: A series of 110 patients with traumatic brain injury had data on intracranial pressure (ICP), arterial blood pressure (ABP), cerebral perfusion pressure (CPP), arterial O2 saturation (SaO2), temperature in degrees C (Temp), and heart rate in beats/min (HRT) monitored and recorded every minute. Secondary insults were defined according to the Edinburgh University secondary insult grading system. The prognostic value of summary measures of these secondary insults was assessed by adding them to a prognostic model for survival at 1 year after controlling for baseline clinical variables using a previously validated model. RESULTS: Of the eight secondary insults measured, only ICP added significantly to the prediction of survival in the first 72 hours after injury. The particular type of summary measure did not seem to influence the results. After the addition of ICP to the model, none of the other secondary insult measures could improve the predictive power of the model significantly. CONCLUSIONS: Early intracranial hypertension is confirmed as a sign of poor prognosis in patients with traumatic brain injury, even after controlling for baseline clinical variables. The value or otherwise of treating such secondary insults, however, can only be definitively established in the context of prospective randomised controlled trials. The specific pathophysiological evolution of secondary insults is still the subject of much research, and a clear understanding will be necessary before the development of specific treatments is feasible.

The influence of baseline prognostic variables on outcome after thrombolysis. MAST-Italy Collaborative Group.

Thrombolysis increases case fatality but reduces the proportion of disabled survivors in recent trials in acute ischaemic stroke, although some trials show much higher mortality rates than others. One possible explanation for the different outcomes between trials is that the treatment effect with thrombolysis varies with baseline prognostic factors such as stroke severity. We examined the interaction between baseline risk and thrombolysis on outcome using individual patient data from the Multicentre Acute Stroke Trial-Italy (MAST-I). A multiple logistic regression of the MAST-I data was performed to identify which factors, identifiable at randomisation, most strongly predict a poor functional outcome. We then stratified the patients into those with severe strokes and those with mild strokes and examined the effect of thrombolysis on (a) case fatality and (b) dependency at 6 months after the stroke in the 157 patients who received streptokinase alone and the 156 controls. Streptokinase was found to cause an absolute increase of about 3% in case fatality in both "severe" and "mild" strokes; however, there was a 12% reduction in the number of dead or dependent "mild" strokes but a 6% increase in "severe" strokes. The number of patients was small, and therefore neither finding was statistically significant. In this exploratory analysis, the hazard with streptokinase appears similar in "severe" and "mild" strokes, but the benefit may be greater in "mild" strokes. Thrombolysis may be more effective in patients with "mild" strokes, but more information is required to confirm this hypothesis.

Bilateral ICP monitoring: its importance in detecting the severity of secondary insults.

The aim of head injury management is to prevent secondary insults to the damaged brain. Raised intracranial pressure and low cerebral perfusion pressure are two secondary insults which are important determinants of outcome following severe head injury (SHI). Traditionally ICP is measured in the right frontal region in an attempt to minimise the effects and complications of transducer placement. This assumes that the brain acts like a fluid and that ICP is transmitted equally throughout the intracranial space. Experimental studies suggest that this is not the case: expanding mass lesions are associated with the development of ICP gradients. Ten patients with SHI who had an unilateral mass lesion confirmed on CT were studied. All had bilateral placement of intraparenchymal Camino ICP transducers in the frontal regions. Data from both transducers were recorded every two minutes and stored electronically. The volume of the mass lesion was calculated from the CT scan. Significant and lasting ICP gradients between hemispheres were found in all patients with an acute subdural haematoma (greater than 10 mmHg for longer than 10 minutes). Such differences were not found in patients with intracerebral haematoma or contusions. We would advocate that ICP is recorded IPSILATERAL to the lesion in patients with SHI due to acute subdural haematoma.

Treatment by a specialist surgical neuro-oncologist does not provide any survival advantage for patients with a malignant glioma.

To determine whether patients with malignant glioma (glioblastoma and anaplastic astrocytoma) had longer survival times, and lower morbidity and mortality if operated on by a surgical neuro-oncologist rather than a general neurosurgeon the outcomes of 236 patients managed within a university surgical neurology department were analysed. Although both surgical morbidity (8.9 versus 11.8%) and mortality (3.6 versus 8.8%) were lower following surgery by the specialist neuro-oncologist neither difference was statistically significant. Crude outcome data suggested patients operated upon by a specialist surgical neuro-oncologist survived longer (p = 0.067). However, after adjustment for case mix (type of tumour, year of treatment, MRC prognostic index) using multiple logistic regression and a hazards model, there was no difference in outcome (p = 0.46, HR 0.884, 95% CI 0.639-1.22). This retrospective study (i) suggests that other outcome measures are required to validate specialist surgical neuro-oncologist treatment of patients with malignant glioma; and (ii) confirms the importance of adjustment for case mix when comparing non-randomized treatment outcomes.

A clinical evaluation of the Codman MicroSensor for intracranial pressure monitoring.

The strain-gauge Codman MicroSensor intracranial pressure (ICP) transducer has shown consistently good laboratory performance. To assess the practical performance of the system in patients following acute brain injury, 10 patients were fitted with a MicroSensor and a second ICP monitor. In five cases this was a fibre-optic transducer and in five cases an intraventricular fluid-filled device. Paired ICP values were recorded every 5 min. ICP values ranged from 0 to 31 mmHg. Altman-Bland plots showed that individual readings could differ by as much as 9 mmHg. Further analysis showed that much of this disagreement could be explained by a constant offset on each occasion. Comparison traces of ICP in individual patients show high agreement in timing and size of changes. The unexplained constant offset leads to uncertainty about the true ICP. Treatment decisions are often based upon absolute levels of ICP and patient care may therefore differ depending upon the monitor used.