Emanuela Keller

Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)

BACKGROUND Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. METHODS In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. FINDINGS In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI -4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (-18%, -45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. INTERPRETATION Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. FUNDING Actelion Pharmaceuticals.

Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling

Background and Purpose— Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. Methods— This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ⩽14 days intravenous clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). Results— CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479–1.289; P=0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275–0.818; P=0.007). Poor outcome (extended Glasgow Outcome Scale score ⩽4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546–1.544; P=0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802–2.227; P=0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. At week 12, mortality was 6%, 4%, and 6% with placebo, clazosentan 5 mg/h, and clazosentan 15 mg/h, respectively. Conclusions— Clazosentan 15 mg/h significantly reduced postaSAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale). Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00940095.

Noninvasive measurement of regional cerebral blood flow and regional cerebral blood volume by near-infrared spectroscopy and indocyanine green dye dilution.

To find a suitable method for measuring regional cerebral blood flow (rCBF) rapidly at the bedside is still a matter of investigation. The purpose here was to develop a noninvasive method for bedside rCBF measurement and to validate it with a standard method such as perfusion-weighted magnetic resonance imaging (MRI). In 11 healthy volunteers 44 measurements with near-infrared spectroscopy (NIRS) and perfusion-weighted MRI without and with a mean continuous positive airway pressure (CPAP) of 10 mbar were carried out. Four (NIRS) optodes were placed bilaterally on the forehead and 25 mg indocyanine green (ICG) was injected. New algorithms were developed to calculate rCBFNIRS and rCBVNIRS. In 6 volunteers data analysis was successful. No complications associated with the method were observed. During CPAP breathing rCBFNIRS decreased from 18.5 + 6.9 16.1 + 6.2 ml/100 g/min (P = 0.034). Mean values for rCBFMRI decreased from 256 +/- 90 to 216 +/- 62 ml/100 g/min (P = 0.012). Bland and Altman plots showed that the differences did not vary in any systematic way over the range of rCBF or rCBV values assessed and 100% of differences were within the interval mean +/- 2 SD of differences. Limits of agreement (mean +/- 2 SD) were +/- 76.4 ml/100 g/min for rCBF and +/- 15.6 ml/100 g for rCBV. The NIRS ICG dye dilution technique is a promising method for serial noninvasive bedside CBF measurements. The preliminary data indicate that measurements are in agreement with values obtained by perfusion-weighted MRI.

THERAPEUTIC HYPOTHERMIA IN PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE, REFRACTORY INTRACRANIAL HYPERTENSION, OR CEREBRAL VASOSPASM

OBJECTIVETo evaluate the feasibility and safety of mild hypothermia treatment in patients with aneurysmal subarachnoid hemorrhage (SAH) who are experiencing intracranial hypertension and/or cerebral vasospasm (CVS). METHODSOf 441 consecutive patients with SAH, 100 developed elevated intracranial pressure and/or symptomatic CVS refractory to conventional treatment. Hypothermia (33–34°C) was induced and maintained until intracranial pressure normalized, CVS resolved, or severe side effects occurred. RESULTSThirteen patients were treated with hypothermia alone, and 87 were treated with hypothermia in combination with barbiturate coma. Sixty-six patients experienced poor-grade SAH (Hunt and Hess Grades IV and V) and 92 had Fisher Grade 3 and 4 bleedings. The mean duration of hypothermia was 169 ± 104 hours, with a maximum of 16.4 days. The outcome after 1 year was evaluated in 90 of 100 patients. Thirty-two patients (35.6%) survived with good functional outcome (Glasgow Outcome Scale [GOS] score, 4 and 5), 14 (15.5%) were severely disabled (GOS score, 3), 1 (1.1%) was in a vegetative state (GOS score, 2), and 43 (47.8%) died (GOS score, 1). The most frequent side effects were electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), and septic shock syndrome (40%). Of 93 patients with severe side effects, 6 (6.5%) died as a result of respiratory or multi-organ failure. CONCLUSIONProlonged systemic hypothermia may be considered as a last-resort option for a carefully selected group of SAH patients with intracranial hypertension or CVS resistant to conventional treatment. However, complications associated with hypothermia require elaborate protocols in general intensive care unit management.

Neurogenic pulmonary edema in patients with subarachnoid hemorrhage.

Neurogenic pulmonary edema (NPE), leading to cardiopulmonary dysfunction, is a potentially life-threatening complication in patients with aneurysmal subarachnoid hemorrhage (SAH). We sought to assess the clinical presentation and risk factors for the development of NPE after SAH. The database contained prospectively collected information on 477 patients with SAH. Baseline characteristics, clinical and radiologic severity of the bleeding, localization of the ruptured aneurysm, and clinical outcome of patients with NPE were compared with those of patients without NPE. Further, in patients with NPE, intracranial pressure, serum cardiac biomarkers, and hemodynamic parameters during the acute phase were evaluated retrospectively. The incidence of NPE was 8% (39 of 477 patients). Most patients with NPE were severely impaired and all of them presented with radiologically severe hemorrhage. The incidence of NPE was significantly higher in patients with ruptured aneurysm in the posterior circulation. Elevated intracranial pressure was found in 67%, pathologically high cardiac biomarkers in up to 83% of patients with NPE. However, no patient suffered from persistent cardiac dysfunction. Compared with patients without NPE, patients with NPE showed poor neurologic outcome (Glasgow outcome scale 1 to 3 in 25% vs.77% of patients). In conclusion, patients with NPE have a high mortality rate more likely due to their severity grade of the bleeding. Morbidity and mortality due to cardiopulmonary failure might be reduced by appropriate recognition and treatment. The awareness of and knowledge about occurrence, clinical presentation, and treatment of NPE, are essential for all those potentially confronted with patients with SAH in the acute phase.

Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications.

&NA; The purpose was to evaluate the feasibility and intensive care complications of long‐term hypothermia (>72 hours) in the treatment of severe brain edema after poor‐grade subarachnoid hemorrhage (SAH) Hunt and Hess grade 4 to 5. Among 156 patients with SAH, 21 patients were treated with mild hypothermia (33.0 to 34.0°C) combined with barbiturate coma because of severe brain edema and elevated intracranial pressure (>15 mm Hg) after early aneurysm clipping. Hypothermia was sustained for at least 24 hours after maintaining an intracranial pressure of <15 mm Hg. Nine patients were treated for <72 hours (group 1: mean 42.2 hours, range 8–66 hours) and 12 for >72 hours (group 2: mean 153.9 hours, range 78–400 hours). Three patients (14%) died during the hypothermia treatment. Good functional outcome after 3 months (Glasgow Outcome Score 4–5) was achieved in 10 patients (48%). The outcome did not differ between the two groups. All patients developed severe infections. In group 2 the mean value of minimal leukocyte counts during hypothermia was significantly lower (6.9 vs. 11.8 × 109/L; P = 0.001), and thrombocytopenia (<150 × 109/L) occurred significantly more often (48 vs. 33%; P = 0.032). In 48% of patients with poor‐grade SAH, good functional outcome was achieved with combined mild hypothermia and barbiturate coma after early aneurysm surgery. This may be a feasible treatment even for longer than 72 hours. All patients developed severe infections as potentially hazardous side effects. To determine whether mild hypothermia alone is effective in the treatment of severe SAH patients, controlled studies to compare the effects of barbiturate coma alone, mild hypothermia alone, and combined barbiturate coma with hypothermia are needed.

Decompressive craniectomy in severe cerebral venous and dural sinus thrombosis

OBJECTIVE To evaluate the outcome of patients with most severe cerebral venous and dural sinus thrombosis (CVT) after decompressive craniectomy. Indications and techniques for decompressive craniectomy and intensive care regimen are discussed. METHODS Between 2000 and 2004 15 patients with CVT and intracerebral hemorrhage were treated at the Department of Neurosurgery, University Hospital Zurich. Among them, four patients with the most severe illness course were treated with decompressive craniectomy. Indications for decompressive craniectomy were deterioration of level of consciousness with CT signs of space occupying brain edema, venous infarction and congestional bleeding with mass effect, midline shift and obliteration of the basal cisterns. RESULTS Among 15 patients with CVT and intraparenchymatous hemorrhage four patients were treated with decompressive craniectomy. Glasgow Coma Scale (GCS) immediately before the operation was in mean 10.2 (range 6 to 13). No patient showed signs of unilateral or bilateral third nerve palsy before surgery. No surgical complications were observed. All four patients who underwent decompressive craniectomy recovered with favourable functional outcome (Glasgow Outcome Scale; GOS 4 and 5). Anticoagulation therapy with heparin was reconvened 12 hours postoperatively with half dosage and 12 hours later with full dosage. No enlargement of existing intraparenchymatous hematoma or other intracranial bleeding complications occurred. CONCLUSIONS Favorable functional outcome in selected patients with most severe courses of CVT can be achieved after decompressive craniectomy. Postoperative anticoagulation therapy with full dose heparin 24 hours after craniotomy seems to be safe. Precise indications and techniques for combined surgical decompression and thrombectomy deserve to be evaluated in future studies.

Decompressive hemicraniectomy in patients with subarachnoid hemorrhage and intractable intracranial hypertension

SummaryBackground and purpose. To evaluate the outcome of patients with aneurysmal subarachnoid hemorrhage (aSAH) developing intractable intracranial hypertension and treated by decompressive hemicraniectomy (DHC).Methods. Of 193 patients with aSAH 38 patients were treated with DHC after early aneurysm clipping. Indications for DHC were 1. Signs of brain swelling during aneurysm surgery (group 1: primary DHC). 2. Intracranial pressure- (ICP)-elevation and epidural, subdural or intracerebral hematoma after aneurysm surgery (group 2: secondary DHC due to hematoma) 3. Brain edema and elevated ICP without radiological signs of infarction (group 3: secondary DHC without infarction). 4. Brain edema and elevated ICP with radiological signs of infarction (group 4: secondary DHC with infarction).Results. Thirty-one patients (81.6%) suffered from high grade aSAH Hunt & Hess 4–5. 21 belonged to group 1, five to group 2, six to group 3 and six to group 4. Of a total of 38 patients a good functional outcome according to Glasgow Outcome Score (GOS 4 & 5) could be reached in 52.6% of the cases. 26.3% survived severely disabled (GOS 3), no case suffered from a vegetative state (GOS 2) but 21.1% died (GOS 1). After 12 months good functional outcome could be achieved in 52.4% of the cases in group 1, in 60% in group 2, in 83.3% in group 3 and in 16.7% in group 4.Conclusions. In more than half of the patients with intractable intracranial hypertension after aSAH a good functional outcome could be achieved after DHC. Patients with progressive brain edema without radiological signs of infarction and those with hematoma may benefit most. The indication for DHC should be set restrictively if secondary infarcts are manifest.

Bedside monitoring of cerebral blood flow in patients with acute hemispheric stroke

Objective: To test the practicability of a new double indicator dilution method for bedside monitoring of cerebral blood flow (CBF) and to assess the clinical value of CBF monitoring as a prognostic tool for outcome and in therapy of elevated intracranial pressure (ICP) in patients with acute hemispheric stroke. Design: Prospective study. Clinical evaluation of a new method. Setting: Neurological intensive care unit of a university hospital. Patients: Ten patients with acute complete middle cerebral artery territory‐ or hemispheric infarctions. Interventions: Two combined fiberoptic thermistor catheters were placed in the right jugular bulb and in the thoracic aorta. Central venous injections of ice‐cold indocyanine green dye were performed. CBF was estimated by calculating the mean translt times of the cold bolus and dye. Measurements and Main Results: A total of 104 reproducible CBF measurements were obtained. No complications associated with the method were observed. Twelve pairs of measurements were performed within 30 mins with unchanged clinical conditions. The standard deviation of repeated measurements was 2.7 mL/100g/min; the interrater reliability was between 0.95 and 0.99. The median CBF in patients who died (n = 4) was lower (27 mL/100g/min) than in those who survived (n = 6) (45 mL/100g/min). Patients who died more frequently had low CBF values of <30 mL/100g/min (22 of 38; 58%) than patients who survived (10 of 54; 19%). A total of 37 CBF measurements were done during ICP elevation of >20 mm Hg. In patients who survived, ICP elevations were only associated with low CBF values in 5 of 26 events; whereas in patients who died, ICP elevations were associated with low CBF values in 8 of 11 events. Conclusions: The new double indicator dilution technique may be suitable for serial bedside CBF measurement. It is easy to perform and can be rapidly repeated in the ICU environment. Validation of the method by comparison with standard methods is needed. The preliminary data indicate that bedside monitoring of CBF may give prognostic information for outcome and may guide therapy of elevated ICP in patients with malignant hemispheric infarction.

Specialized neurocritical care, severity grade, and outcome of patients with aneurysman subarachnoid hemorrhage

IntroductionTo evaluate the impact of specialized neurocritical care on the population admitted to a neurovascular center and on the outcome of patients with severe aneurysmal subarachnoid hemorrhage (aSAH).MethodsAfter exclusion of patients treated with endovascular techniques, between 1999 and 2003, 198 patients with aSAH treated with early aneurysm clipping were analysed. In 1999, a new standardized protocol for intensive care treatment was established in the Department of Neurosurgery, University Hospital Zurich. The results were compared to the earlier time period (1993–1994) immediately after introduction of early aneurysm clipping.ResultsOut of 198 patients with aSAH, 90 patients (45.5%) suffered from mild aSAH World Federation of Neurosurgical Societies (WFNS) grade 1 and 2, 41 (27.3%) from aSAH WFNS grade 3, 36 (18.2%) from grade 4, and 57 (28.8%) from grade 5. From 1999 to 2003, significantly more patients with severe aSAH WFNS grade 4 and 5 underwent (further) treatment (93 out of 198 patients; 47.0%) compared to the former time-period after introduction of early surgery (23 out of 150 patients; 15.3%) (p<0.0001). In the early series, 10 out of 23 patients (43.5%) with WFNS 4 recovered with good outcome Glasgow Outcome Score 4 and 5, whereas in the later series 23 out of 36 (63.9%) with WFNS grade 4 survived in a good functional state. Before 1999, all patients with WFNS grade 5 died or survived in a vegetative state. From 1999 to 2003, 20 out of 57 patients (35.1%) with aSAH WFNS grade 5 survived with good outcome.ConclusionsThe availability of extended specialized neurocritical care seems to induce a change within the patient population towards a higher severity grade. Patients with high-grade aSAH might benefit most from highly specialized neurocritical care treatment.