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E. François Aldrich, Randall Higashida, Abdel Hmissi, Elizabeth J. Le, R. Loch Macdonald, Angelina Marr, Stephan A. Mayer, Sébastien Roux and Nicolas Bruder

OBJECTIVE

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse clinical course and outcome, independently of other known prognostic factors such as age, aneurysm size, and initial clinical grade.

METHODS

In this post hoc analysis, patients with aSAH undergoing surgical clipping (n = 383) or endovascular coiling (n = 189) were pooled from the placebo arms of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS)–2 and CONSCIOUS-3 randomized, double-blind, placebo-controlled phase 3 studies, respectively. Patients without and with thick, diffuse SAH (≥ 4 mm thick and involving ≥ 3 basal cisterns) on admission CT scans were compared. Clot size was centrally adjudicated. All-cause mortality and vasospasm-related morbidity at 6 weeks and Glasgow Outcome Scale–Extended (GOSE) scores at 12 weeks after aSAH were assessed. The effect of the thick and diffuse cisternal aSAH on vasospasm-related morbidity and mortality, and on poor clinical outcome at 12 weeks, was evaluated using logistic regression models.

RESULTS

Overall, 294 patients (51.4%) had thick and diffuse aSAH. Compared to patients with less hemorrhage burden, these patients were older (median age 55 vs 50 years) and more often had World Federation of Neurosurgical Societies (WFNS) grade III–V SAH at admission (24.1% vs 16.5%). At 6 weeks, all-cause mortality and vasospasm-related morbidity occurred in 36.1% (95% CI 30.6%–41.8%) of patients with thick, diffuse SAH and in 14.7% (95% CI 10.8%–19.5%) of those without thick, diffuse SAH. Individual event rates were 7.5% versus 2.5% for all-cause death, 19.4% versus 6.8% for new cerebral infarct, 28.2% versus 9.4% for delayed ischemic neurological deficit, and 24.8% versus 10.8% for rescue therapy due to cerebral vasospasm, respectively. Poor clinical outcome (GOSE score ≥ 4) was observed in 32.7% (95% CI 27.3%–38.3%) and 16.2% (95% CI 12.1%–21.1%) of patients with and without thick, diffuse SAH, respectively.

CONCLUSIONS

In a large, centrally adjudicated population of patients with aSAH, WFNS grade at admission and thick, diffuse SAH independently predicted vasospasm-related morbidity and poor 12-week clinical outcome. Patients with thick, diffuse cisternal SAH may be an important cohort to target in future clinical trials of treatment for vasospasm.

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R. Loch Macdonald, Daniel Hänggi, Poul Strange, Hans Jakob Steiger, J Mocco, Michael Miller, Stephan A. Mayer, Brian L. Hoh, Herbert J. Faleck, Nima Etminan, Michael N. Diringer, Andrew P. Carlson, Francois Aldrich and the NEWTON Investigators

OBJECTIVE

The objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).

METHODS

Patients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.

RESULTS

Fifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.

CONCLUSIONS

Plasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.

Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

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Simone A. Dijkland, Blessing N. R. Jaja, Mathieu van der Jagt, Bob Roozenbeek, Mervyn D. I. Vergouwen, Jose I. Suarez, James C. Torner, Michael M. Todd, Walter M. van den Bergh, Gustavo Saposnik, Daniel W. Zumofen, Michael D. Cusimano, Stephan A. Mayer, Benjamin W. Y. Lo, Ewout W. Steyerberg, Diederik W. J. Dippel, Tom A. Schweizer, R. Loch Macdonald and Hester F. Lingsma

OBJECTIVE

Differences in clinical outcomes between centers and countries may reflect variation in patient characteristics, diagnostic and therapeutic policies, or quality of care. The purpose of this study was to investigate the presence and magnitude of between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage (aSAH).

METHODS

The authors analyzed data from 5972 aSAH patients enrolled in randomized clinical trials of 3 different treatments from the Subarachnoid Hemorrhage International Trialists (SAHIT) repository, including data from 179 centers and 20 countries. They used random effects logistic regression adjusted for patient characteristics and timing of aneurysm treatment to estimate between-center and between-country differences in unfavorable outcome, defined as a Glasgow Outcome Scale score of 1–3 (severe disability, vegetative state, or death) or modified Rankin Scale score of 4–6 (moderately severe disability, severe disability, or death) at 3 months. Between-center and between-country differences were quantified with the median odds ratio (MOR), which can be interpreted as the ratio of odds of unfavorable outcome between a typical high-risk and a typical low-risk center or country.

RESULTS

The proportion of patients with unfavorable outcome was 27% (n = 1599). The authors found substantial between-center differences (MOR 1.26, 95% CI 1.16–1.52), which could not be explained by patient characteristics and timing of aneurysm treatment (adjusted MOR 1.21, 95% CI 1.11–1.44). They observed no between-country differences (adjusted MOR 1.13, 95% CI 1.00–1.40).

CONCLUSIONS

Clinical outcomes after aSAH differ between centers. These differences could not be explained by patient characteristics or timing of aneurysm treatment. Further research is needed to confirm the presence of differences in outcome after aSAH between hospitals in more recent data and to investigate potential causes.

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Matthew E. Eagles, Maria F. Powell, Oliver G. S. Ayling, Michael K. Tso and R. Loch Macdonald

OBJECTIVE

Acute kidney injury (AKI) is associated with death in critically ill patients, but this complication has not been well characterized after aneurysmal subarachnoid hemorrhage (aSAH). The purpose of this study was to determine the incidence of AKI after aSAH and to identify risk factors for renal dysfunction. Secondary objectives were to examine what effect AKI has on patient mortality and functional outcome at 12 weeks post-aSAH.

METHODS

The authors performed a post hoc analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial data set (clinical trial registration no.: NCT00111085, https://clinicaltrials.gov). The primary outcome of interest was the development of AKI, which was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Secondary outcomes of interest were death and a modified Rankin Scale score greater than 2 at 12 weeks post-aSAH. Propensity score matching was used to assess for a significant treatment effect related to clazosentan administration and AKI. Univariate analysis, locally weighted scatterplot smoothing (LOWESS) curves, and stepwise logistic regression models were used to evaluate for associations between baseline or disease-related characteristics and study outcomes.

RESULTS

One hundred fifty-six (38%) of the 413 patients enrolled in the CONSCIOUS-1 trial developed AKI during their ICU stay. A history of hypertension (p < 0.001) and the number of nephrotoxic medications administered (p = 0.029) were independent predictors of AKI on multivariate analysis. AKI was an independent predictor of death (p = 0.028) but not a poor functional outcome (p = 0.21) on multivariate testing. Unresolved renal dysfunction was the strongest independent predictor of death in this cohort (p < 0.001).

CONCLUSIONS

AKI is a common complication following aSAH. Patients with premorbid hypertension and those treated with nephrotoxic medications may be at greater risk for renal dysfunction. AKI appears to confer an increased probability of death after aSAH.

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Mirriam Mikhail, Oliver G. S. Ayling, Matthew E. Eagles, George M. Ibrahim and R. Loch Macdonald

OBJECTIVE

Higher mortality has been reported with weekend or after-hours patient admission across a wide range of surgical and medical specialties, a phenomenon termed the “weekend effect.” The authors evaluated whether weekend admission contributed to death and long-term neurological outcome in patients following aneurysmal subarachnoid hemorrhage.

METHODS

A post hoc analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) study was conducted. Univariable and stepwise multivariable logistic regression analyses were performed to assess the associations between weekend admission and mortality and long-term neurological outcome.

RESULTS

Of 413 subjects included in the CONSCIOUS-1 study, 140 patients had been admitted during the weekend. A significant interaction was identified between weekend admission and neurological grade on presentation, suggesting that the outcomes of patients who had initially presented with a poor grade were disproportionately influenced by the weekend admission. On stepwise multivariable logistic regression in the subgroup of patients who had presented with a poor neurological grade (29 of 100 patients), admission on the weekend was found to be independently associated with death (OR 6.59, 95% CI 1.62–26.88, p = 0.009). Weekend admission was not associated with long-term neurological outcome.

CONCLUSIONS

Weekend admission was an independent risk factor for death within 12 weeks following aneurysmal subarachnoid hemorrhage in patients presenting with a poor neurological grade. Further work is required to identify and mitigate any mediating factors.

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R. Loch Macdonald

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Matthew E. Eagles, Michael K. Tso and R. Loch Macdonald

OBJECTIVE

Fluctuations in patient serum sodium levels are common after aneurysmal subarachnoid hemorrhage (aSAH), but their effect on patient outcome is not well described in the literature. The goal of this work was to better characterize the relationship between fluctuations in serum sodium levels, outcome, and the development of delayed cerebral ischemia (DCI) after aSAH.

METHODS

The authors performed a post hoc analysis of data from the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. Patients had their serum sodium values recorded daily for 14 days post-aSAH. Average and average absolute daily differences in sodium levels were calculated for each patient based on 3 reference points: admission sodium levels, a normal sodium level (defined as 140 mmol/L), and the previous day’s sodium level. These variables were also calculated for the classic “vasospasm window” (days 3–12) post-aSAH. A stepwise logistic regression model, locally weighted scatterplot smoothing curves, and receiver operator characteristic curve analysis were used to evaluate the relationship between alterations in serum sodium levels and clinical outcome or the development of DCI after aSAH. Poor outcome was defined as a modified Rankin Scale (mRS) score of > 2 at 3 months.

RESULTS

The average daily difference in sodium values from baseline (p < 0.001), average daily difference from a normal sodium level (p < 0.001), average absolute daily difference from a normal sodium level (p = 0.015), and average absolute daily difference from the previous day’s sodium level (p = 0.017) were significant predictors of poor outcome in a stepwise multivariate regression model. There was a trend toward significance for average absolute daily difference from admission sodium levels during the vasospasm window as an independent predictor of DCI (p = 0.052). There was no difference in the predictive capacity for DCI when sodium fluctuations from post-aSAH days 1–14 were compared with those from the classic vasospasm window (days 3–12).

CONCLUSIONS

Fluctuations in serum sodium levels may play a role in clinical outcome and the development of DCI after aSAH. The timing of these fluctuations appears to have no significant effect on the development of DCI.

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Tim E. Darsaut, Robert Fahed, R. Loch Macdonald, Adam S. Arthur, M. Yashar S. Kalani, Fuat Arikan, Daniel Roy, Alain Weill, Alain Bilocq, Jeremy L. Rempel, Michael M. Chow, Robert A. Ashforth, J. Max Findlay, Luis H. Castro-Afonso, Miguel Chagnon, Guylaine Gevry and Jean Raymond

OBJECTIVE

Ruptured intracranial aneurysms (RIAs) can be managed surgically or endovascularly. In this study, the authors aimed to measure the interobserver agreement in selecting the best management option for various patients with an RIA.

METHODS

The authors constructed an electronic portfolio of 42 cases of RIA in which an angiographic image along with a brief clinical vignette for each patient were displayed. Undisclosed to the responders was that the RIAs had been categorized as International Subarachnoid Aneurysm Trial (ISAT) (small, anterior-circulation, non–middle cerebral artery location, n = 18) and non-ISAT (n = 22) aneurysms; the non-ISAT group also included 2 basilar apex aneurysms for which a high number of endovascular choices was expected. The portfolio was sent to 132 clinicians who manage patients with RIAs and circulated to members of an American surgical association. Judges were asked to choose between surgical and endovascular management, to indicate their level of confidence in the choice of treatment on a quantitative 0–10 scale, and to determine whether they would include the patient in a randomized trial in which both treatments are compared. Eleven clinicians were asked to respond twice at least 1 month apart. Responses were analyzed using kappa statistics.

RESULTS

Eighty-five clinicians (58 cerebrovascular surgeons, 21 interventional neuroradiologists, and 6 interventional neurologists) answered the questionnaire. Overall, endovascular management was chosen more frequently (n = 2136 [59.8%] of 3570 answers). The proportions of decisions to clip were significantly higher for non-ISAT (50.8%) than for ISAT (26.2%) aneurysms (p = 0.0003). Interjudge agreement was only fair (kappa 0.210, 95% CI 0.158–0.276) for all cases and judges, despite high confidence levels (mean score > 8 for all cases). Agreement was no better within subgroups of clinicians with the same specialty, years of experience, or location of practice or across capability groups (ability to clip or coil, or both). When agreement was defined as > 80% of responders choosing the same option, agreement occurred for only 7 of 40 cases, all of which were ISAT aneurysms, for which coiling was preferred.

CONCLUSIONS

Agreement between clinicians regarding the best management option was infrequent but centered around coiling for some ISAT aneurysms. Surgical clipping was chosen more frequently for non-ISAT aneurysms than for ISAT aneurysms. Patients with such an aneurysm might be candidates for inclusion in randomized trials.

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Naif M. Alotaibi, Justin Z. Wang, Christopher R. Pasarikovski, Daipayan Guha, Fawaz Al-Mufti, Muhammad Mamdani, Gustavo Saposnik, Tom A. Schweizer and R. Loch Macdonald

Elevated intracranial pressure (ICP) is a well-recognized phenomenon in aneurysmal subarachnoid hemorrhage (aSAH) that has been demonstrated to lead to poor outcomes. Despite significant advances in clinical research into aSAH, there are no consensus guidelines devoted specifically to the management of elevated ICP in the setting of aSAH. To treat high ICP in aSAH, most centers extrapolate their treatment algorithms from studies and published guidelines for traumatic brain injury. Herein, the authors review the current management strategies for treating raised ICP within the aSAH population, emphasize key differences from the traumatic brain injury population, and highlight potential directions for future research in this controversial topic.

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Menno R. Germans, Blessing N. R. Jaja, Airton Leonardo de Oliviera Manoel, Ashley H. Cohen and R. Loch Macdonald

OBJECTIVE

In this study the authors sought to investigate the sex differences in the risk of delayed cerebral ischemia (DCI), delayed cerebral infarction, and the role of hormonal status.

METHODS

Ten studies included in the SAHIT (SAH International Trialists) repository were analyzed using a fitting logistic regression model. Heterogeneity between the studies was tested using I2 statistics, and the results were pooled using a random-effects model. Multivariable analysis was adjusted for the effects of neurological status and fixed effect of study. An additional model was examined in which women and men were split into groups according to an age cut point of 55 years, as a surrogate to define hormonal status.

RESULTS

A pooled cohort of 6713 patients was analyzed. The risk of DCI was statistically significantly higher in women than in men (OR 1.29, 95% CI 1.12–1.48); no difference was found with respect to cerebral infarction (OR 1.17, 95% CI 0.98–1.40). No difference was found in the risk of DCI when comparing women ≤ 55 and > 55 years (OR 0.87, 95% CI 0.74–1.02; p = 0.08) or when comparing men ≤ 55 and > 55 years (p = 0.38). Independent predictors of DCI were World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, age, and sex. Independent predictors of infarction included WFNS grade, Fisher grade, and aneurysm size.

CONCLUSIONS

Female sex is associated with a higher risk of DCI. Sex differences may play a role in the pathogenesis of DCI but are not associated with menopausal status. The predictors of DCI and cerebral infarction were identified in a very large cohort and reflect experience from multiple institutions.