Sanne M. Dorhout Mees

Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial

Summary Background Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage. Methods We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome—defined as a score of 4–5 on the modified Rankin Scale—3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36). Findings 1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85–1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86–1·08). Interpretation Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. Funding Netherlands Heart Foundation, UK Medical Research Council.

Comparison of Telephone and Face-to-Face Assessment of the Modified Rankin Scale

Background: A structured interview improves the reliability of the modified Rankin Scale (mRS), a commonly used functional outcome scale in stroke trials. Telephone interview is a fast and convenient way to assess the mRS grade, but its validity is unknown. We assessed the validity of a telephone interview in patients who had had an aneurysmal subarachnoid haemorrhage (SAH) by comparing it with a face-to-face assessment. Methods: Eighty-three SAH patients were interviewed twice, once face-to-face and once by telephone, by 2 of 5 observers who used a structured interview to assess the mRS grade. Intermodality agreement was measured using weighted kappa statistics. To check for systematic differences between face-to-face and telephone assessment the Wilcoxon test for matched pairs was used. Results: Agreement between telephone and face-to-face assessment was perfect in 47 (57%) patients. A difference of 1 level occurred in 31 (37%) patients and this was almost equally distributed over the grades of the mRS. Weighted kappa was 0.71 (95% CI 0.59–0.82). Telephone assessment did not result in a consistently more or less favourable grade than face-to-face assessment (Wilcoxon test for matched pairs, p = 0.33). Conclusions: Telephone assessment of the mRS with a structured interview has a good agreement with face-to-face assessment and can thus be used reliably in the setting of a clinical trial.

Validation of a Prognostic Subarachnoid Hemorrhage Grading Scale Derived Directly From the Glasgow Coma Scale

Background and Purpose— A new Glasgow Coma Scale-based scale has been developed to predict patient outcome in subarachnoid hemorrhage by calculating cut-off points by which 2 consecutive categories corresponded to a statistically significant different outcome. We assessed the external validity of this Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage (PAASH) scale and compared it to the commonly used World Federation of Neurological Surgeons scale. Methods— From our database of subarachnoid hemorrhage patients we retrieved data on all patients admitted between November 2000 and March 2006. By means of logistic regression, we calculated OR with corresponding 95% CI for poor outcome at 3 months for each category in comparison with the lowest category of both scales. Areas under the curve of the corresponding receiver operator characteristic curve were calculated. Results— We included 537 patients. For the PAASH scale, OR ranged from 3.9 (95% CI, 2.4 to 6.2) to 84 (95% CI, 25 to 287) and increased more evenly than for the World Federation of Neurological Surgeons (WFNS) scale, with OR ranging from 2.3 (95% CI, 1.3 to 4.1) to 69 (95% CI, 31 to 157). Areas under the curve were 0.81 (95% CI, 0.77 to 0.84) for the PAASH and 0.82 (95% CI, 0.79 to 0.86) for the WFNS scale. Conclusion— Both PAASH and WFNS scales have a good discriminatory ability for patient prognosis. Because the OR of the PAASH increase more gradually, it is slightly preferable to the WFNS scale.

Antiplatelet Therapy in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review

BACKGROUND AND PURPOSE Observational studies suggest that platelet inhibitors reduce the risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage and thereby have a beneficial effect on clinical outcome. Robust evidence, however, is lacking. We performed a systematic meta-analysis to determine whether antiplatelet therapy has a beneficial effect after SAH. METHODS We searched Medline and the Cochrane Library to identify all randomized controlled trials of antiplatelet drugs versus control and calculated relative risks with corresponding 95% confidence intervals (CIs) for poor outcome (dependence or death), the occurrence of DCI, and the occurrence of any intracranial hemorrhage. RESULTS We included 5 trials totaling 699 patients. The overall relative risk for poor outcome was 0.87 (95% CI, 0.65 to 1.17); for the occurrence of DCI (reported in 3 of the 5 studies), 0.65 (95% CI, 0.47 to 0.89); and for the occurrence of intracranial hemorrhage, 1.19 (reported in 4 of the 5 studies) (95% CI, 0.76 to 1.85). CONCLUSIONS Our data indicate that antiplatelet drugs reduce the risk of DCI in patients with subarachnoid hemorrhage. A randomized clinical trial is warranted to assess the effect on overall outcome.

Magnesium in aneurysmal subarachnoid hemorrhage (MASH II) phase III clinical trial MASH‐II study group

RATIONALE Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Magnesium is a neuroprotective agent that acts as an NMDA-receptor antagonist and a calcium channel blocker. In a phase II randomized clinical trial of 283 patients, magnesium treatment reduced the risk of DCI by 34% and of poor outcome by 23%. AIMS To determine whether magnesium improves clinical outcome in patients with aneurysmal SAH. DESIGN The MASH-II study is a phase III randomized, clinical international multicenter trial. Magnesium sulfate 64 mmol/day (equals 16 g/day) or placebo is started intravenously within 4 days after the SAH and is continued until 20 days after the hemorrhage. The primary outcome measure is poor outcome, defined as death or dependence (Rankin score >3) after 3 months. We aim to include 1200 patients in 5 years. STUDY OUTCOMES Primary outcome will be poor clinical outcome as measured by the modified Rankin scale at 3 months.Rationale Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Magnesium is a neuroprotective agent that acts as an NMDA-receptor antagonist and a calcium channel blocker. In a phase II randomized clinical trial of 283 patients, magnesium treatment reduced the risk of DCI by 34% and of poor outcome by 23%. Aims To determine whether magnesium improves clinical outcome in patients with aneurysmal SAH. Design The MASH-II study is a phase III randomized, clinical international multicenter trial. Magnesium sulfate 64 mmol/ day (equals 16 g/day) or placebo is started intravenously within 4 days after the SAH and is continued until 20 days after the hemorrhage. The primary outcome measure is poor outcome, defined as death or dependence (Rankin score > 3) after 3 months. We aim to include 1200 patients in 5 years. Study outcomes Primary outcome will be poor clinical outcome as measured by the modified Rankin scale at 3 months. Sponsor MASH-II is sponsored by the Netherlands Heart Foundation (grant number: 2005BO16). It is registered with IRCTN number: 68742385, EudraCT: 2006-003523-36. Introduction Subarachnoid hemorrhage (SAH) from a ruptured aneurysm is a subset of stroke. The young age (median 55 years) and poor outcome (50% of patients die; 30% of those who survive the initial weeks after the hemorrhage remain dependent) explain why in the population the loss of productive life years from SAH is as large as that from brain infarcts, the most common type of stroke (1). Summary The MASH-II study is a phase III randomized, clinical international multicenter trial to study the effect of magnesium sulfate after aneurysmal SAH. Magnesium is a neuroprotective agent that acts as a blocker of both the NMDA-glutamate receptor and voltage dependent calcium channels. Patients who are admitted within 4 days after aneurysmal SAH are asked to participate. Study medication (magnesium sulfate 64 mmol/ day or placebo) is given via continuous infusion until 20 days after the hemorrhage. Outcome is determined with the modified Rankin scale 3 months after the hemorrhage. Analysis will be according to the intention-to-treat principle. So far, in May 2007 over 425 patients have been included in five Dutch and one Chilean hospital. Based on the results of the phase II study sample size calculations indicate that 1200 patients are needed to give a statistically significant result (with α = 5% and a power of 80%). We aim to include these patients before 2010. New centers are still very welcome to join the study.

Timing of Aneurysm Treatment After Subarachnoid Hemorrhage Relationship With Delayed Cerebral Ischemia and Poor Outcome

Background and Purpose— The ideal timing of coiling or clipping after aneurysmal subarachnoid hemorrhage is unknown. Within the International Subarachnoid Aneurysm Trial we assessed differences in incidence of delayed cerebral ischemia and clinical outcome between different timings of treatment. Methods— The treated 2106 patients randomized to coiling or clipping were divided into 4 categories: treatment <2 days, on days 3 to 4, on days 5 to 10, and >10 days after the hemorrhage. ORs with 95% CI were calculated with logistic regression analysis for delayed cerebral ischemia, poor outcome at 2 months, and 1 year for the different timing categories, with treatment <2 days as reference. Analyses were performed for all patients, and for coiled and clipped patients separately, and were adjusted for baseline characteristics. Results— Adjusted ORs of delayed cerebral ischemia for treatment on days 5 to 10 were 1.18 (95% CI, 0.91–1.53) for all patients, 1.68 (95% CI, 1.17–2.43) after coiling, and 0.79 (95% CI, 0.54–1.16) after clipping. ORs for poor outcome at 2 months were 1.16 (95% CI, 0.89–1.50) for treatment (clipping and coiling combined) at 3 to 4 days, 1.39 (95% CI, 1.08–1.80) for treatment at 5 to 10 days, and 1.84 (95% CI, 1.36–2.51) for treatment >10 days. ORs for coiled and clipped patients separately were in the same range. Results for outcome at 1 year were similar. Conclusions— Our results support the current practice for early aneurysm treatment in subarachnoid hemorrhage patients. The risk for poor outcome was highest when treatment was performed after day 10; postponing treatment in patients who are eligible for treatment between days 5 to 10 after subarachnoid hemorrhage is not recommended.

Fever After Aneurysmal Subarachnoid Hemorrhage Relation With Extent of Hydrocephalus and Amount of Extravasated Blood

Background and Purpose— Fever after aneurysmal subarachnoid hemorrhage is associated with poor outcome. Because hydrocephalus and extravasated blood may influence thermoregulation, we determined whether these factors increase the risk for fever after subarachnoid hemorrhage. Methods— Fever within 14 days (subdivided into infectious and noninfectious) was defined as a mean daily body temperature above 38.0°C for at least 2 consecutive days in a prospectively collected cohort of 194 patients with subarachnoid hemorrhage. Hazard ratios were calculated to assess the impact of hydrocephalus (bicaudate index) and cisternal and intraventricular blood (Hijdra score) on the occurrence of fever. Adjusted hazard ratios were calculated in one multivariate model, including other possible confounding factors. Results— Infectious fever occurred in 34% of patients and noninfectious fever in 9%. Adjusted hazard ratios of intraventricular blood were 2.2 (95% CI, 1.3 to 3.8) for any fever, 2.4 (95% CI, 1.3 to 4.4) for infectious fever, and 2.0 (95% CI, 0.7 to 5.9) for noninfectious fever. Adjusted hazard ratios of cisternal blood and hydrocephalus for infectious and noninfectious fever ranged from 0.6 to 1.5, all with wide CIs. Conclusion— Intraventricular blood is an independent risk factor for the development of fever. In this study, noninfectious fever was rare and not related to extravasated blood or hydrocephalus.

Interobserver Variability of Grading Scales for Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Worldwide, different scales are used to assess the clinical condition on admission after aneurysmal subarachnoid hemorrhage. In addition to the prognostic value, the inter-rater variability should be taken into account when deciding which scale preferably should be used. We assessed the interobserver agreement of the commonly used World Federation of Neurological Surgeons, the Hunt and Hess, and the Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scales. Methods— In a cohort of 50 subarachnoid hemorrhage patients, 103 paired assessments were performed on the 3 admission scales by 2 independent observers per assessment with a total of 57 different raters. Patients were assessed during the first week after the hemorrhage. The interobserver agreement was calculated using quadratic (weighted) kappa statistics. Results— The weighted kappa value of the Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scale was 0.64 (95% CI, 0.49–0.79), of the World Federation of Neurological Surgeons scale was 0.60 (95% CI, 0.48–0.73), and of the Hunt and Hess scale was 0.48 (95% CI, 0.36–0.59). Conclusions— The Hunt and Hess scale showed the lowest interobserver agreement, whereas agreement of the World Federation of Neurological Surgeons and Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scales was similar with overlapping CI.

Extent of Acute Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage as a Risk Factor for Delayed Cerebral Infarction

Background and Purpose— Delayed cerebral infarction (DCI) is an important cause of poor outcome after subarachnoid hemorrhage. Cerebral perfusion is a predictor for DCI. Because acute hydrocephalus may impair cerebral perfusion, we evaluated the predictive value of the extent of acute hydrocephalus on the development of DCI. Methods— We retrieved data on 321 patients admitted within 4 days after aneurysmal subarachnoid hemorrhage from our prospectively collected database. Ventricular enlargement was quantified by measuring the bicaudate index and the width of the third ventricle. Ventricular sizes were analyzed as continuous variables and after categorization into quartiles. The relationship between these variables and the development of DCI was analyzed by means of the Cox proportional hazards model. Results— DCI occurred in 76 patients (23.7%). Hazard ratios for occurrence of DCI of the continuous variables were 1.01 (95% CI: 0.97 to 1.06) for the bicaudate index, 1.00 (95% CI: 1.00 to 1.01) for the age-adjusted bicaudate index, and 0.99 (95% CI: 0.92 to 1.06) for the width of the third ventricle in univariable analysis. The adjusted hazard ratio for the highest quartile of the bicaudate index versus the lowest quartile was 0.9 (95% CI: 0.5 to 1.8). No linear trend could be recognized in consecutive quartiles. Conclusions— Acute hydrocephalus is not a risk factor for occurrence of DCI, even when the extent of hydrocephalus is taken into account. However, we cannot exclude the possibility that extensive hydrocephalus leading to coma does increase the risk for DCI if no therapeutic intervention were done.

Achieved serum magnesium concentrations and occurrence of delayed cerebral ischaemia and poor outcome in aneurysmal subarachnoid haemorrhage

Background: Magnesium therapy probably reduces the frequency of delayed cerebral ischaemia (DCI) in subarachnoid haemorrhage (SAH) but uncertainty remains about the optimal serum magnesium concentration. We assessed the relationship between serum magnesium concentrations achieved with magnesium sulphate therapy 64 mmol/day and the occurrence of DCI and poor outcome in patients with SAH. Methods: Differences in magnesium concentrations between patients with and without DCI and with and without poor outcome were calculated. Quartiles of last serum magnesium concentrations before the onset of DCI, or before the median day of DCI in patients without DCI, were related to the occurrence of DCI and poor outcome at 3 months using logistic regression. Results: Compared with the lowest quartile of serum magnesium concentration (1.10–1.28 mmol/l), the risk of DCI was decreased in each of the higher three quartiles (adjusted odds ratio (OR) in each quartile 0.2; lower 95% CI 0.0 to 0.1; upper limit 0.8 to 0.9). The OR for poor outcome was 1.8 (95% CI 0.5 to 6.9) in the second quartile, 1.0 (95% CI 0.2 to 4.5) in the third quartile and 4.9 (95% CI 1.2 to 19.7) in the highest quartile. Discussion: Magnesium sulphate 64 mmol/day results in a stable risk reduction of DCI over a broad range of achieved serum magnesium concentrations, and strict titration of the dosage therefore does not seem necessary. However, concentrations ⩽1.28 mmol/l could decrease the effect on DCI while concentrations ⩾1.62 might have a negative effect on clinical outcome.