Fludrocortisone to treat patients with aneurysmal subarachnoid haemorrhage: Protocol for an international, phase 3, randomised, placebo-controlled, multicentre trial.

The cerebral angiography result is negative for an underlying vascular lesion in 15-20% of patients with nontraumatic subarachnoid hemorrhage (SAH). Patients with angiogram-negative SAH include those with perimesencephalic SAH and diffuse SAH. Consensus suggests that perimesencephalic SAH confers a more favorable prognosis than diffuse SAH. Limited data exist to contextualize the clinical course and prognosis of diffuse SAH in relation to aneurysmal SAH in terms of critical care complications, neurologic complications, and functional outcomes. Here we compare the clinical course and functional outcomes of patients with perimesencephalic SAH, diffuse SAH, and aneurysmal SAH to better characterize the prognostic implications of each SAH subtype. We conducted a retrospective cohort study that included all patients with nontraumatic SAH admitted to a tertiary care referral center between January 1, 2012, and December 31, 2017. Bleed patterns were radiographically adjudicated, and patients were assigned to three groups: perimesencephalic SAH, diffuse SAH, and aneurysmal SAH. Patient demographics, complications, and clinical outcomes were reported and compared. Eighty-six patients with perimesencephalic SAH, 174 with diffuse SAH, and 998 with aneurysmal SAH presented during the study period. Patients with aneurysmal SAH were significantly more likely to be female, White, and active smokers. There were no significant differences between patients with diffuse SAH and perimesencephalic SAH patterns. Critical care complications were compared across all three groups, with significant between-group differences in hypotension and shock (3.5% vs. 16.1% vs. 38.4% for perimesencephalic SAH vs. diffuse SAH vs. aneurysmal SAH, respectively; p < 0.01) and endotracheal intubation (0% vs. 26.4% vs. 48.8% for perimesencephalic SAH vs. diffuse SAH vs. aneurysmal SAH, respectively; p < 0.01). Similar trends were noted with long-term supportive care with tracheostomy and gastrostomy tubes and length of stay. Cerebrospinal fluid diversion was increasingly required across bleed types (9.3% vs. 54.6% vs. 76.3% for perimesencephalic SAH vs. diffuse SAH vs. aneurysmal SAH, respectively, p < 0.001). Vasospasm and delayed cerebral ischemia were comparable between perimesencephalic SAH and diffuse SAH but significantly lower than aneurysmal SAH. Patients with diffuse SAH had intermediate functional outcomes, with significant rates of nonhome discharge (23.0%) and poor functional status on discharge (26.4%), significantly higher than patients with perimesencephalic SAH and lower than patients with aneurysmal SAH. Diffuse SAH similarly conferred an intermediate rate of good functional outcomes at 1-6months post discharge (92.3% vs. 78.6% vs. 47.3% for perimesencephalic SAH vs. diffuse SAH vs. aneurysmal SAH, respectively; p < 0.016). We confirm the consensus data that perimesencephalic SAH is associated with a more benign clinical course but demonstrate that diffuse SAH confers an intermediate prognosis, more malignant than perimesencephalic SAH but not as morbid as aneurysmal SAH. These results highlight the significant morbidity associated with diffuse SAH and emphasize need for vigilance in the acute care of these patients. These patients will likely benefit from continued high-acuity observation and potential support to avert significant risk of morbidity and neurologic compromise.

Subarachnoid hemorrhage (SAH) is a common and frequently devastating condition, accounting for ≈5% of all strokes and affecting as many as 30 000 Americans each year.1,2 The American Heart Association (AHA) previously published “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.”3 Since then, considerable advances have been made in endovascular techniques, diagnostic methods, and surgical and perioperative management paradigms. Nevertheless, outcome for patients with SAH remains poor, with population-based mortality rates as high as 45% and significant morbidity among survivors.4–9 Several multicenter, prospective, randomized trials and prospective cohort analyses have influenced treatment protocols for SAH. However, rapid evolution of newer treatment modalities, as well as other practical and ethical considerations, has meant that rigorous clinical scientific assessment of the treatment protocols has not been feasible in several important areas. To address these issues, the Stroke Council of the AHA formed a writing group to reevaluate the recommendations for management of aneurysmal SAH. A consensus committee reviewed existing data in this field and prepared the recommendations in 1994.3 In an effort to update those recommendations, a systematic literature review was conducted based on a search of MEDLINE to identify all relevant randomized clinical trials published between June 30, 1994, and November 1, 2006 (search terms: subarachnoid hemorrhage , cerebral aneurysm , trial ; Table 1). Each identified article was reviewed by at least 2 members of the writing group. Selected articles had to meet one of the following criteria to be included: randomized trial or nonrandomized concurrent cohort study. Case series and nonrandomized historical cohort studies were reviewed if no studies with a higher level of evidence were available for a particular topic covered in the initial guidelines. These were chosen on the basis of sample size and the relevance of the particular studies to subjects that …

Abnormal serum sodium levels are frequently observed among patients with aneurysmal subarachnoid hemorrhage (SAH) and may worsen cerebral edema or mass effect. Low serum potassium levels (hypokalemia) are also common among patients with aneurysmal SAH and are associated with prolonged QT interval and ventricular arrhythmia. Recent meta-analysis suggests that MgSO4 infusion improves the clinical outcome in patients after aneurysmal SAH; however, MgSO4 infusion may theoretically exacerbate electrolyte disturbance. We retrospectively reviewed the prospectively collected demographic and laboratory data of 100 patients after aneurysmal subarachnoid SAH in a neurosurgical center in Hong Kong. 51 patients had daily magnesium sulfate infusion for 14 days (Group 1) and 49 patients were managed similarly, without magnesium sulfate infusion (Group 2). Days of hypernatremia (mean+/-SD) were 2.0+/-2.7 for group 1 and 2.0+/-2.5 for group 2, p = 0.999; days of hyponatremia (mean+/-SD) were 2.7+/-3.1 for group 1 and 2.0+/-2.9 for group 2, p = 0.230; days of hypokalemia (mean+/-SD) were 4.5+/-3.1 for group 1 and 4.5+/-3.2 for group 2, p = 0.819. Hyperkalemia was uncommon in both groups. There was also no statistically significant difference between the two groups when the data were re-analyzed as severe hyponatremia, severe hypokalemia and severe hyperkalemia. Magnesium sulfate infusion was safe and did not seem to exacerbate the duration of electrolyte disturbance associated with aneurysmal subarachnoid hemorrhage.

Response

Cerebral Vasospasm: New Strategies in Research and Treatment

Abstracts of literature

Purpose: To investigate the incidence and relative factors of Terson’s syndrome (TS) in patients with subarachnoid hemorrhage (SAH) in China.Materials and Methods: A case series study was conducted from November 2009 to June 2010 on 155 patients (310 eyes) with aneurysmal and traumatic SAH. A thorough, direct funduscopic examination was performed on all participants and the incidence of TS analyzed. Associations between TS and gender, state-of-consciousness, Glasgow Coma Scale (GCS) score, Hunt-Hess grade, anatomical location of ruptured aneurysms, and mortality rates were analyzed.Results: TS was diagnosed in 20 of 155 SAH patients (30 eyes), and detected in 16 (14.16%) of 113 patients with aneurysmal SAH and four (9.52%) of 42 patients with traumatic SAH. No correlations were found between state-of-consciousness, GCS scores, and presence of TS in patients with traumatic SAH. Among patients suffering from aneurysmal SAH, however, significant relationships were observed between state-of-consciousness, GCS scores, Hunt-Hess grades, and incidence of TS (p < 0.01). No statistically significant difference was observed between men and women with regard to the incidence of TS (χ2 = 0.821, p = 0.365). Furthermore, no correlation was found between location of ruptured aneurysms (p = 1.000), mortality rates (p = 0.146), and incidence of TS.Conclusions: Compared with traumatic SAH, a higher incidence of TS was observed in patients with aneurysmal SAH, a condition significantly associated with a person’s overall condition. Therefore, aneurysmal SAH patients with consciousness-disturbance, lower GCS scores, and higher Hunt-Hess grades should be paid particular attention by ophthalmologists when performing fundus examinations. The question of whether SAH with TS is prognostic of spontaneous SAH is an area in need of further study.

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%. To determine whether magnesium improves clinical outcome in patients with aneurysmal SAH. 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. Primary outcome will be poor clinical outcome as measured by the modified Rankin scale at 3 months.

Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Mechanism and Therapies

Abstracts of Literature

See related article, pages 1216–1221. When I began practicing emergency medicine 25 years ago, a stroke patient’s arrival to the emergency department (ED) did not elicit the frenetic burst of activity that it currently does. For that matter, neither did the arrival of a heart attack patient—until the approval of thrombolytic treatment for myocardial infarction. For patients with cerebrovascular emergencies, new treatment options such as thrombolytics and pro-coagulants demand earlier and accurate diagnosis. The shift to early aneurysm obliteration for aneurysmal subarachnoid hemorrhage (SAH) makes its early and accurate diagnosis equally important. Forty percent of patients with SAH die, and 30% of survivors are left with significant neurological disability1; however, nearly half of all patients present in good clinical condition.2 In this group, early treatment prevents rebleeding and results in excellent outcomes. Unfortunately, numerous investigations over several continents and decades document that physicians miss the diagnosis of SAH with a disappointing frequency.3–10 In this issue of Stroke ,11 Vermeulen and Schull present data suggesting that Canadian emergency physicians miss the diagnosis of SAH in 5.4% of cases. Although this may seem like a high miss rate, it is much lower than what has been previously reported. A 2000 review of the subject showed that SAH was misdiagnosed in 32% of 685 cases pooled from 4 large studies.12 The average time delay was 6 days. Most misdiagnosed patients present in good clinical condition but their condition often deteriorates by the time of the second visit. Analysis suggests 3 recurring, largely preventable errors are responsible for physician misdiagnosis: lack of awareness of the spectrum of presentation of SAH, failure to perform (and understand the limitations of) computed tomographic imaging (CT scan), and failure to …

Ruptured Intracranial Aneurysms and the Timing of Embosurgery

Science, Medicine, and the Anesthesiologist

Background: Many patients experience impaired cerebral oxygen delivery secondary to vasospasm and delayed cerebral ischemia following aneurysmal subarachnoid haemorrhage (SAH). Anaemia is common after SAH affecting up to 50% patients, which may decrease cerebral oxygen delivery and is associated with worse clinical outcomes. Transfusion of allogeneic red cells increases the oxygen content of the blood but it not consistently associated with improved physiologic markers of clinical outcomes. The threshold for transfusion is not clear in patients with SAH. A recent survey found that most physicians would alter their transfusion threshold in SAH patients who develop delayed ischemia. The objective of our study is to identify the predictors of transfusion and to determine if the diagnosis of delayed ischemia increases the transfusion rates in patients with aneurysmal subarachnoid haemorrhage. Materials and Methods: We retrospectively reviewed the charts of 100 consecutive patients with SAH who were admitted to ICU for mechanical ventilation, and collected demographic and clinical data. Data were analyzed for the association between clinical factors and transfusion the differences in transfusion between the patients with and without vasospasm. Statistical methods included the t-test, univariate analysis and multivariate analysis. Results: Data from 96 patients were included in the analysis. Incidence of anaemia haemoglobin (Hb) &lt; 100 gm/l and vasospasm were 67% (64/96) and 39% (38/96) respectively. Of 64 patients with anaemia, 27 patients received transfusion, while 38 patients did not receive a transfusion. The transfusion rates were similar between those who had vasospasm and who did not. However, out of the 14 patients with vasospasm who received a transfusion, 11 patients had been transfused after experiencing vasospasm, while only 3 were transfused before. On multivariate analysis only female sex, starting Hb levels and lowest Hb levels were found to be predictors of transfusion. Presence or absence of vasospasm was not found to be a predictor. Conclusions: From our retrospective review, we conclude that the incidence of anaemia is higher in patients with vasospasm. Sex and starting and lowest Hb levels were the only predictors of transfusion likelihood in aneurysmal subarachnoid haemorrhage while presence of vasospasm was not.

Objective To investigate the effect of early cerebrospinal fluid replacement on nuclear factor-κB (NF-κB) level and clinical outcomes in patients with aneurismal subarachnoid hemorrhage (aSAH) after endovascular embolization. Methods Patients with aSAH received aneurysm embolization were enrolled. They were divided into a cerebrospinal fluid replacement group and a non-cerebrospinal fluid replacement group according to the treatment scheme. All patients were treated with cerebral aneurysm coil embolization within 3 days after admission. The cerebrospinal fluid replacement group performed lumbar puncture cerebrospinal fluid replacement within 24 h after coil embolization, once every other day, 20-30 ml of cerebrospinal fluid was replaced each time and 3 mg dexamethasone was injected intrathecally. The NF-κB levels in cerebrospinal fluid were detected at day 1, 7 and 14 after the coil embolization. The primary outcome measures were the clinical outcomes determined by the modified Rankin scale (mRS) and the Glasgow outcome scale (GOS) at 3 months after onset. Good outcome was defined as mRS score 0-2 or GOS >3. The secondary outcome measures included severe complications (hydrocephalus, cerebral vasospasm, cerebral infarction, and rebleeding) and death. Results A total of 81 patients with aSAH received aneurysm embolization were enrolled, including 42 in the cerebrospinal fluid replacement group and 39 in the non-cerebrospinal fluid replacement group. There was no significant differences in the baseline data between the cerebrospinal fluid replacement group and the non-cerebrospinal fluid replacement group (all P>0.05). The duration of neck stiffness in the cerebrospinal fluid replacement group was significantly shorter than that in the non-cerebrospinal fluid replacement group (11.3±3.2 d vs. 16.5±3.5 d; t=6.985, P<0.001). The cerebrospinal fluid NF-κB levels were progressively reduced at day 1, 7 and 14 after coil embolization in the cerebrospinal fluid replacement group and non-cerebrospinal fluid replacement group (all P<0.05), but the ccerebrospinal fluid levels of NF-κB in the cerebrospinal fluid replacement group at each time point were significantly lower than those in the non-cerebrospinal fluid replacement group (all P<0.01). The good outcome rates evaluated according to the mRS score (92.9% vs. 56.4%; χ2=14.446, P<0.001) and GOS score (97.6% vs. 76.9%; χ2=8.004, P=0.005) in the cerebrospinal fluid replacement group at 3 months were significantly higher than those in the non-cerebrospinal fluid replacement group, and the incidence of cerebral vasospasm was significantly lower than that in the non-cerebrospinal fluid replacement group (14.3% vs. 33.3%; χ2=4.086, P=0.043). Conclusions Cerebrospinal fluid replacement therapy can reduce the incidence of cerebral vasospasm in patients with aSAH receiving aneurysm embolization and improve clinical outcomes. Its mechanism may be associated with the decrease of NF-κB level in cerebrospinal fluid. Key words: Subarachnoid Hemorrhage; Intracranial Aneurysm; Embolization, Therapeutic; Drainage; NF-κB; Treatment Outcome