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Paul M. Brennan, Gordon D. Murray and Graham M. Teasdale

OBJECTIVE

Glasgow Coma Scale (GCS) scores and pupil responses are key indicators of the severity of traumatic brain damage. The aim of this study was to determine what information would be gained by combining these indicators into a single index and to explore the merits of different ways of achieving this.

METHODS

Information about early GCS scores, pupil responses, late outcomes on the Glasgow Outcome Scale, and mortality were obtained at the individual patient level by reviewing data from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9,045) study and the IMPACT (International Mission for Prognosis and Clinical Trials in TBI; n = 6855) database. These data were combined into a pooled data set for the main analysis.

Methods of combining the Glasgow Coma Scale and pupil response data varied in complexity from using a simple arithmetic score (GCS score [range 3–15] minus the number of nonreacting pupils [0, 1, or 2]), which we call the GCS-Pupils score (GCS-P; range 1–15), to treating each factor as a separate categorical variable. The content of information about patient outcome in each of these models was evaluated using Nagelkerke’s R2.

RESULTS

Separately, the GCS score and pupil response were each related to outcome. Adding information about the pupil response to the GCS score increased the information yield. The performance of the simple GCS-P was similar to the performance of more complex methods of evaluating traumatic brain damage. The relationship between decreases in the GCS-P and deteriorating outcome was seen across the complete range of possible scores. The additional 2 lowest points offered by the GCS-Pupils scale (GCS-P 1 and 2) extended the information about injury severity from a mortality rate of 51% and an unfavorable outcome rate of 70% at GCS score 3 to a mortality rate of 74% and an unfavorable outcome rate of 90% at GCS-P 1. The paradoxical finding that GCS score 4 was associated with a worse outcome than GCS score 3 was not seen when using the GCS-P.

CONCLUSIONS

A simple arithmetic combination of the GCS score and pupillary response, the GCS-P, extends the information provided about patient outcome to an extent comparable to that obtained using more complex methods. The greater range of injury severities that are identified and the smoothness of the stepwise pattern of outcomes across the range of scores may be useful in evaluating individual patients and identifying patient subgroups. The GCS-P may be a useful platform onto which information about other key prognostic features can be added in a simple format likely to be useful in clinical practice.

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Gordon D. Murray, Paul M. Brennan and Graham M. Teasdale

OBJECTIVE

Clinical features such as those included in the Glasgow Coma Scale (GCS) score, pupil reactivity, and patient age, as well as CT findings, have clear established relationships with patient outcomes due to neurotrauma. Nevertheless, predictions made from combining these features in probabilistic models have not found a role in clinical practice. In this study, the authors aimed to develop a method of displaying probabilities graphically that would be simple and easy to use, thus improving the usefulness of prognostic information in neurotrauma. This work builds on a companion paper describing the GCS-Pupils score (GCS-P) as a tool for assessing the clinical severity of neurotrauma.

METHODS

Information about early GCS score, pupil response, patient age, CT findings, late outcome according to the Glasgow Outcome Scale, and mortality were obtained at the individual adult patient level from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9045) and IMPACT (International Mission for Prognosis and Clinical Trials in TBI; n = 6855) databases. These data were combined into a pooled data set for the main analysis. Logistic regression was first used to model the combined association between the GCS-P and patient age and outcome, following which CT findings were added to the models. The proportion of variability in outcomes “explained” by each model was assessed using Nagelkerke’s R2.

RESULTS

The authors observed that patient age and GCS-P have an additive effect on outcome. The probability of mortality 6 months after neurotrauma is greater with increasing age, and for all age groups the probability of death is greater with decreasing GCS-P. Conversely, the probability of favorable recovery becomes lower with increasing age and lessens with decreasing GCS-P. The effect of combining the GCS-P with patient age was substantially more informative than the GCS-P, age, GCS score, or pupil reactivity alone. Two-dimensional charts were produced displaying outcome probabilities, as percentages, for 5-year increments in age between 15 and 85 years, and for GCS-Ps ranging from 1 to 15; it is readily seen that the movement toward combinations at the top right of the charts reflects a decreasing likelihood of mortality and an increasing likelihood of favorable outcome.

Analysis of CT findings showed that differences in outcome are very similar between patients with or without a hematoma, absent cisterns, or subarachnoid hemorrhage. Taken in combination, there is a gradation in risk that aligns with increasing numbers of any of these abnormalities. This information provides added value over age and GCS-P alone, supporting a simple extension of the earlier prognostic charts by stratifying the original charts in the following 3 CT groupings: none, only 1, and 2 or more CT abnormalities.

CONCLUSIONS

The important prognostic features in neurotrauma can be brought together to display graphically their combined effects on risks of death or on prospects for independent recovery. This approach can support decision making and improve communication of risk among health care professionals, patients, and their relatives. These charts will not replace clinical judgment, but they will reduce the risk of influences from biases.

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A. David Mendelow, Graham M. Teasdale, Thomas Russell, John Flood, James Patterson and Gordon D. Murray

✓ 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.

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Malcolm D. M. Shaw, Marinus Vermeulen, Gordon D. Murray, John D. Pickard, B. Anthony Bell and Graham M. Teasdale

Object. 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 ETA/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.

Methods. 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.

Conclusions. 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.

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Davi J. Fontoura Solla, Manoel Jacobsen Teixeira and Wellingson Silva Paiva

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Don Ilodigwe, M. Stat., Gordon D. Murray, Neal F. Kassell, James Torner, Richard S. C. Kerr, Andrew J. Molyneux and R. Loch Macdonald

Object

In randomized clinical trials of subarachnoid hemorrhage (SAH) in which the primary clinical outcomes are ordinal, it has been common practice to dichotomize the ordinal outcome scale into favorable versus unfavorable outcome. Using this strategy may increase sample sizes by reducing statistical power. Authors of the present study used SAH clinical trial data to determine if a sliding dichotomy would improve statistical power.

Methods

Available individual patient data from tirilazad (3552 patients), clazosentan (the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage trial [CONSCIOUS-1], 413 patients), and subarachnoid aneurysm trials (the International Subarachnoid Aneurysm Trial [ISAT], 2089 patients) were analyzed. Treatment effect sizes were examined using conventional fixed dichotomy, sliding dichotomy (logical or median split methods), or proportional odds modeling. Whether sliding dichotomy affected the difference in outcomes between the several age and neurological grade groups was also evaluated.

Results

In the tirilazad data, there was no significant effect of treatment on outcome (fixed dichotomy: OR = 0.92, 95% CI 0.80–1.07; and sliding dichotomy: OR = 1.02, 95% CI 0.87–1.19). Sliding dichotomy reversed and increased the difference in outcome in favor of the placebo over clazosentan (fixed dichotomy: OR = 1.06, 95% CI 0.65–1.74; and sliding dichotomy: OR = 0.85, 95% CI 0.52–1.39). In the ISAT data, sliding dichotomy produced identical odds ratios compared with fixed dichotomy (fixed dichotomy vs sliding dichotomy, respectively: OR = 0.67, 95% CI 0.55–0.82 vs OR = 0.67, 95% CI 0.53–0.85). When considering the tirilazad and CONSCIOUS-1 groups based on age or World Federation of Neurosurgical Societies grade, no consistent effects of sliding dichotomy compared with fixed dichotomy were observed.

Conclusions

There were differences among fixed dichotomy, sliding dichotomy, and proportional odds models in the magnitude and precision of odds ratios, but these differences were not as substantial as those seen when these methods were used in other conditions such as head injury. This finding suggests the need for different outcome scales for SAH.

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Chantal W. P. M. Hukkelhoven, Ewout W. Steyerberg, Anneke J. J. Rampen, Elana Farace, J. Dik F. Habbema, Lawrence F. Marshall, Gordon D. Murray and Andrew I. R. Maas

Object. 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.

Methods. 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.

Conclusions. 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.

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Haiyan Wang, Shanbao Cai, Barbara J. Bailey, M. Reza Saadatzadeh, Jixin Ding, Eva Tonsing-Carter, Taxiarchis M. Georgiadis, T. Zachary Gunter, Eric C. Long, Robert E. Minto, Kevin R. Gordon, Stephanie E. Sen, Wenjing Cai, Jacob A. Eitel, David L. Waning, Lauren R. Bringman, Clark D. Wells, Mary E. Murray, Jann N. Sarkaria, Lawrence M. Gelbert, David R. Jones, Aaron A. Cohen-Gadol, Lindsey D. Mayo, Harlan E. Shannon and Karen E. Pollok

OBJECTIVE

Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM.

METHODS

The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM.

RESULTS

In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy.

CONCLUSIONS

Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.