Bert A. Coert

Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia.

Patients with aneurysmal subarachnoid hemorrhage (SAH) who experience delayed cerebral ischemia (DCI) have an increased risk of poor outcome. Delayed cerebral ischemia is considered to be caused by vasospasm. However, not all patients with DCI have vasospasm. Inversely, not all patients with vasospasm develop clinical symptoms and signs of DCI. In the past, treatments aiming at vasospasm were not successful in preventing ischemia. The purpose of this review is to give an overview of clinical data showing that DCI cannot always be attributed to vasospasm, and to present an in-depth analysis of clinical and autopsy studies on the role of microthrombosis in the pathogenesis of DCI. Clinical studies show that DCI is associated with an activation of the coagulation cascade within a few days after SAH, preceding the time window during which vasospasm occurs. Furthermore, impaired fibrinolytic activity, and inflammatory and endothelium-related processes, lead to the formation of microthrombi, which ultimately result in DCI. The presence of microthrombi is confirmed by autopsy studies. Insight in the pathophysiology of DCI is crucial for the development of effective therapies against this complication. Because multiple pathways are involved, future research should focus on drugs with pleiotropic effects.

Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial

Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality. It was hypothesized that the beneficial effect resulted from pleiotropic effects of statins. The purpose of this study was to investigate the biologic effects of acute statin treatment in patients with SAH. We performed an exploratory single-center, prospective, randomized, double-blind, placebo-controlled trial. Patients were randomized to simvastatin 80 mg or placebo once daily. A total of 32 patients were included. There were no statistically significant differences in clinical baseline characteristics. With regard to primary outcomes, there were significant differences by treatment group for total cholesterol and low-density lipoprotein (LDL) cholesterol (P < 0.0001), but not for parameters of coagulation, fibrinolysis, endothelium function, and inflammation. With regard to secondary outcomes, no differences were observed in the incidence of transcranial Doppler vasospasm, clinical signs of DCI, and poor outcome. We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH (ISRCTN45662651).

Decompressive hemicraniectomy in cerebral sinus thrombosis: consecutive case series and review of the literature

Background and Purpose— Thirteen percent of patients with cerebral venous and sinus thrombosis (CVST) has a poor clinical outcome. In patients with a poor prognosis, endovascular thrombolysis can be considered, but this procedure does not appear to be beneficial in patients with impending transtentorial herniation because of large hemorrhagic venous infarcts. Therefore, halfway through 2006, we changed our policy to decompressive hemicraniectomy in these patients. Methods and Results— Patients with CVST and impending herniation attributable to venous infarcts were eligible for surgical intervention. Since 2006 we consecutively treated 3 patients with decompressive hemicraniectomy. Two patients had an excellent outcome. The third patient, who had been comatose for at least 12 hours before surgery, died despite intervention. Conclusions— Our data suggest that decompressive hemicraniectomy can be life-saving and can result in an excellent outcome in patients with severe CVST.

Hyperglycemia and Clinical Outcome in Aneurysmal Subarachnoid Hemorrhage A Meta-Analysis

Background and Purpose— Hyperglycemia may worsen outcome after aneurysmal subarachnoid hemorrhage. We performed a systematic review to investigate the relation between admission hyperglycemia and outcome after aneurysmal subarachnoid hemorrhage. Methods— We included cohort studies or clinical trials of patients with aneurysmal subarachnoid hemorrhage admitted within 72 hours that documented admission glucose levels or the rate of hyperglycemia. Outcome had to be assessed prospectively after 3 or more months. The overall mean glucose level was calculated by weighting for the number of patients included in each study. To calculate the effect size, we pooled the ORs and 95% 95% CIs of poor clinical outcome in patients with or without hyperglycemia. Results— We searched MEDLINE, EMBASE, Science Citation Index, and the bibliographies of relevant studies. We included 17 studies totaling 4095 patients. The mean admission glucose level was 9.3 mmol/L (range, 7.4 to 10.9 mmol/L; 14 studies, 3373 patients) and the median proportion of patients with hyperglycemia was 69% (range, 29 to 100; 16 studies, 3995 patients; cutoff levels of hyperglycemia, 5.7 to 12.0 mmol/L). The pooled OR (8 studies, 2164 patients) for poor outcome associated with hyperglycemia was 3.1 (95% CI, 2.3 to 4.3). Cutoff points for defining hyperglycemia varied across studies (6.4 to 11.1 mmol/L), but this had no clear effect on the observed OR for poor outcome. Conclusions— After aneurysmal subarachnoid hemorrhage, admission glucose levels are often high and hyperglycemia is associated with an increased risk of poor clinical outcome. A randomized clinical trial is warranted to study the potential benefit of glycemic control after aneurysmal subarachnoid hemorrhage.

Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial.

BackgroundA frequent complication in patients with subarachnoid hemorrhage (SAH) is recurrent bleeding from the aneurysm. The risk is highest within the first 6 hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult owing to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome.Methods/DesignThis is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in 3 years.DiscussionThe strengths of this study are: 1. the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, which should reduce the risk for delayed cerebral ischemia (DCI), an important risk factor in the long-term treatment with antifibrinolytics; 2. the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; and 3. the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols.Trial registrationNederlands Trial Register (Dutch Trial Registry) number NTR3272

Yield of spinal imaging in nonaneurysmal, nonperimesencephalic subarachnoid hemorrhage

Objective: We studied the yield of MRI of the spinal neuraxis in patients with nonperimesencephalic subarachnoid hemorrhage (NPSAH). Methods: In a prospective, multicenter study, we performed T1-weighted and T2-weighted MRI of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging. Results: A spinal origin of the hemorrhage was found in 3 of 75 patients (4%; 95% confidence interval 0–8.4). The lesions were 1 lumbar ependymoma and 2 cervical cavernous malformations. All 3 patients presented without focal neurologic deficits and 2 had a CT-negative subarachnoid hemorrhage but positive lumbar puncture. Patients with a spinal origin were younger than patients without a spinal origin (38 vs 56 years; p < 0.05), which was the only significant difference between groups. Conclusions: The yield and clinical relevance of MRI of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MRI of the spinal axis in this patient population, but it might be justified in a subgroup of patients.

A strategy to expeditious invasive treatment improves clinical outcome in comatose patients with aneurysmal subarachnoid haemorrhage

In patients with poor clinical condition after aneurysmal subarachnoid haemorrhage (aSAH), treatment is often deferred until patients show signs of improvement. Early external ventricular drainage and aneurysm occlusion may improve prognosis also in poor grade patients. The clinical outcome of an expeditious approach was compared with that of a conservative approach.

Association of Automatically Quantified Total Blood Volume after Aneurysmal Subarachnoid Hemorrhage with Delayed Cerebral Ischemia

The authors retrospectively studied clinical and radiologic data of 333 consecutive patients with aneurysmal SAH between January 2009 and December 2011. Adjusted odds ratios werecalculated for the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia (clinical, radiologic, and both). The adjusted OR of total blood volume for delayed cerebral ischemia was 1.02 per milliliter of blood. They conclude that a higher total blood volume measured with the automated quantification method is significantly associated with delayed cerebral ischemia. BACKGROUND AND PURPOSE: The total amount of extravasated blood after aneurysmal subarachnoid hemorrhage, assessed with semiquantitative methods such as the modified Fisher and Hijdra scales, is known to be a predictor of delayed cerebral ischemia. However, prediction rates of delayed cerebral ischemia are moderate, which may be caused by the rough and observer-dependent blood volume estimation used in the prediction models. We therefore assessed the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia. MATERIALS AND METHODS: We retrospectively studied clinical and radiologic data of consecutive patients with aneurysmal SAH admitted to 2 academic hospitals between January 2009 and December 2011. Adjusted ORs with associated 95% confidence intervals were calculated for the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia (clinical, radiologic, and both). The calculations were also performed for the presence of an intraparenchymal hematoma and/or an intraventricular hematoma and clinical delayed cerebral ischemia. RESULTS: We included 333 patients. The adjusted OR of total blood volume for delayed cerebral ischemia (clinical, radiologic, and both) was 1.02 (95% CI, 1.01–1.03) per milliliter of blood. The adjusted OR for the presence of an intraparenchymal hematoma for clinical delayed cerebral ischemia was 0.47 (95% CI, 0.24–0.95) and of the presence of an intraventricular hematoma, 2.66 (95% CI, 1.37–5.17). CONCLUSIONS: A higher total blood volume measured with our automated quantification method is significantly associated with delayed cerebral ischemia. The results of this study encourage the use of rater-independent quantification methods in future multicenter studies on delayed cerebral ischemia prevention and prediction.

Unfavorable Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage WFNS Grade I

BACKGROUND Patients with an aneurysmal subarachnoid hemorrhage (aSAH) and World Federation of Neurosurgical Societies (WFNS) grade I on admission are generally considered to have a good clinical outcome. OBJECTIVE The objective of this study was to assess the actual clinical outcome of WFNS grade I aSAH patients, and to determine which factors are associated with unfavourable outcome. METHODS For this prospective cohort study, 132 consecutive patients (age 18 years or older) with a WFNS grade I aSAH admitted to our hospital between December 2011 and January 2016 were eligible. Clinical outcome was measured using the modified Rankin Scale (mRS) at 6-month follow-up. Unfavorable outcome was defined as an mRS score of 3-6. Univariable analyses were performed using logistic regression models. RESULTS Of 116 patients, only 5 patients (4%) had an mRS score of 0 and most (65%) had an mRS score of 2. Twenty-five patients (22%) had an unfavorable outcome. Nine (8%) patients died, of whom 4 died during admission. Factors associated with unfavorable outcome were age (per increasing decade: odds ratio [OR]. 1.78; 95% confidence interval [CI], 1.16-2.72), delayed cerebral ischemia (OR, 4.32; 95% CI, 1.63-11.44), pneumonia (OR, 10.75; 95% CI, 1.94-59.46) and meningitis (OR, 28.47; 95% CI, 1.42-571.15). CONCLUSIONS Despite their neurologically optimal clinical condition on admission, 1 in 5 patients with WFNS grade I aSAH has an unfavorable clinical outcome or is dead at 6-month follow-up. Additional multivariable analysis in larger patient cohorts is necessary to identify the extent to which preventable complications contribute to unfavorable outcomes in these patients.

High-Dose Nadroparin Following Endovascular Aneurysm Treatment Benefits Outcome After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND Delayed cerebral ischemia (DCI) is one of the major causes of delayed morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE To evaluate the effect of high‐dose nadroparin treatment following endovascular aneurysm treatment on the occurrence of DCI and clinical outcome. METHODS Medical records of 158 adult patients with an aSAH were retrospectively analyzed. Those patients treated endovascularly for their ruptured aneurysm were included in this study. They received either high‐dose (twice daily 5700 AxaIE) or low‐dose (once daily 2850 AxaIE) nadroparin treatment after occlusion of the aneurysm. Medical charts were reviewed and imaging was scored by 2 independent neuroradiologists. Data with respect to in‐hospital complications, peri‐procedural complications, discharge location, and mortality were collected. RESULTS Ninety‐three patients had received high‐dose nadroparin, and 65 patients prophylactic low‐dose nadroparin. There was no significant difference in clinical DCI occurrence between patients treated with high‐dose (34%) and low‐dose (31%) nadroparin. More patients were discharged to home in patients who received high‐dose nadroparin (40%) compared to low‐dose (17%; odds ratio [OR] 3.13, 95% confidence interval [95% CI]: 1.36‐7.24). Furthermore, mortality was lower in the high‐dose group (5%) compared to the low‐dose group (23%; OR 0.19, 95% CI: 0.07‐0.55), also after adjusting for neurological status on admission (OR 0.21, 95% CI: 0.07‐0.63). CONCLUSION Patients who were treated with high‐dose nadroparin after endovascular treatment for aneurysmal SAH were more often discharged to home and showed lower mortality. High‐dose nadroparin did not, however, show a decrease in the occurrence of clinical DCI after aSAH. A randomized controlled trial seems warranted.