Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT)

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making

Dissecting Inflammatory Complications in Critically Injured Patients by Within-Patient Gene Expression Changes: A Longitudinal Clinical Genomics Study

By studying gene expression changes over time in a cohort of trauma patients, Keyur Desai and colleagues identify genes and pathways strongly associated with longer-term complications, which could lead to improved outcome prediction in the first 80 hours after injury

Aorto-ventricular tunnel

Aorto-ventricular tunnel is a congenital, extracardiac channel which connects the ascending aorta above the sinutubular junction to the cavity of the left, or (less commonly) right ventricle. The exact incidence is unknown, estimates ranging from 0.5% of fetal cardiac malformations to less than 0.1% of congenitally malformed hearts in clinico-pathological series. Approximately 130 cases have been reported in the literature, about twice as many cases in males as in females. Associated defects, usually involving the proximal coronary arteries, or the aortic or pulmonary valves, are present in nearly half the cases. Occasional patients present with an asymptomatic heart murmur and cardiac enlargement, but most suffer heart failure in the first year of life. The etiology of aorto-ventricular tunnel is uncertain. It appears to result from a combination of maldevelopment of the cushions which give rise to the pulmonary and aortic roots, and abnormal separation of these structures. Echocardiography is the diagnostic investigation of choice. Antenatal diagnosis by fetal echocardiography is reliable after 18 weeks gestation. Aorto-ventricular tunnel must be distinguished from other lesions which cause rapid run-off of blood from the aorta and produce cardiac failure. Optimal management of symptomatic aorto-ventricular tunnel consists of diagnosis by echocardiography, complimented with cardiac catheterization as needed to elucidate coronary arterial origins or associated defects, and prompt surgical repair. Observation of the exceedingly rare, asymptomatic patient with a small tunnel may be justified by occasional spontaneous closure. All patients require life-long follow-up for recurrence of the tunnel, aortic valve incompetence, left ventricular function, and aneurysmal enlargement of the ascending aorta

Strategies to prevent intraoperative lung injury during cardiopulmonary bypass

During open heart surgery the influence of a series of factors such as cardiopulmonary bypass (CPB), hypothermia, operation and anaesthesia, as well as medication and transfusion can cause a diffuse trauma in the lungs. This injury leads mostly to a postoperative interstitial pulmonary oedema and abnormal gas exchange. Substantial improvements in all of the above mentioned factors may lead to a better lung function postoperatively. By avoiding CPB, reducing its time, or by minimizing the extracorporeal surface area with the use of miniaturized circuits of CPB, beneficial effects on lung function are reported. In addition, replacement of circuit surface with biocompatible surfaces like heparin-coated, and material-independent sources of blood activation, a better postoperative lung function is observed. Meticulous myocardial protection by using hypothermia and cardioplegia methods during ischemia and reperfusion remain one of the cornerstones of postoperative lung function. The partial restoration of pulmonary artery perfusion during CPB possibly contributes to prevent pulmonary ischemia and lung dysfunction. Using medication such as corticosteroids and aprotinin, which protect the lungs during CPB, and leukocyte depletion filters for operations expected to exceed 90 minutes in CPB-time appear to be protective against the toxic impact of CPB in the lungs. The newer methods of ultrafiltration used to scavenge pro-inflammatory factors seem to be protective for the lung function. In a similar way, reducing the use of cardiotomy suction device, as well as the contact-time between free blood and pericardium, it is expected that the postoperative lung function will be improved

Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18–75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5mg/h, 15mg/h or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale (GOSE) at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively. Introduction Advances have been made in the management of patients with aneurysmal subarachnoid hemorrhage (aSAH). Mortality among those who reach hospital alive has decreased 0.9% per year since 1980 [1]. Nevertheless, case fatality is still 40% and half of all survivors suffer some form of physical, emotional or cognitive impairment [2–4]. The causes of morbidity and mortality are mainly initial effects of the aSAH and delayed ischemic neurological deficit (DIND), which is usually due to cerebral vasospasm [5]. Indeed, vasospasm is considered to be one of the main preventable causes of morbidity and mortality [6]. Angiographic vasospasm (vasospasm that is visible on an angiogram) occurs in up to 70% of patients after aSAH [6]; DIND has been estimated to account for 50% of deaths in people surviving the initial SAH [7]. Current management options for the prevention and treatment of vasospasm and DIND include hemodynamic therapy, nimodipine, fasudil (in Japan), intra-arterial vasodilators and angioplasty, but none are very effective [7–12]. Clazosentan is an endothelin receptor antagonist under investigation for the prevention of vasospasm and subsequent morbidity and mortality. A phase 2a proof-of-principle trial administered 0.2 mg/kg/h clazosentan (corresponding to 15 mg/h for an individual weighing 75 kg) beginning within 48 h of the aneurysm securing procedure and continuing until Day 14 after aSAH. Clazosentan reduced moderate/severe angiographic vasospasm by 55% relative to placebo (angiographic vasospasm was observed in 88% and 40% of placebo- and clazosentan-treated patients, respectively, P = 0.008) [13]. These results supported conduct of a dose-finding safety trial (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage CONSCIOUS-1; phase 2b]). The primary outcome was angiographic vasospasm. The sample size was estimated from the effect on angiographic vasospasm in the phase 2a trial and the doses selected based on the phase 2a trial and also phase 1 clinical trials administering clazosentan to healthy volunteers and observing clinical and cardiovascular effects [13,14]. CONSCIOUS-1 recruited 413 patients from 11 countries [15]. Patients were randomized to intravenous clazosentan (1, 5 or 15 mg/h) or placebo, beginning within 56 h of aSAH and continuing until Day 14 after aneurysm rupture. Clazosentan significantly and dose-dependently reduced moderate/severe angiographic vasospasm relative to placebo; the highest dose (15 mg/h) led to a 65% risk reduction (P < 0.0001) [15]. CONSCIOUS-1 was not powered to detect a change in morbidity, mortality or patient-centered clinical outcome, but has been repeatedly and incorrectly cited as evidence that angiographic vasospasm does not contribute to poor outcome after aSAH [16]. This idea was put forth at least 35 years ago, but the basis remains as speculative now as it was then [17]. Post hoc, central analysis of all-cause mortality and vasospasm-related morbidity in CONSCIOUS-1 found a trend towards improved outcomes with clazosentan [15]. Two large, multinational phase 3 studies, CONSCIOUS-2 and CONSCIOUS-3, have now been initiated, based on the results of the CONSCIOUS-1 trial, to further investigate the effect of clazosentan on outcome after aSAH. This manuscript describes the rationale for the design and methodology of these studies. Methods Study design CONSCIOUS-2 and CONSCIOUS-3 are prospective, multinational, double-blind, placebo-controlled studies. The primary objective is to determine if clazosentan decreases vasospasm-related morbidity and all-cause mortality in patients with aSAH. Patients are randomized within 56 h of aSAH to intravenous clazosentan (5 mg/h in CONSCIOUS-2; 5 or 15 mg/h in CONSCIOUS-3) or placebo administered until Day 14 after aSAH, with a post-aSAH follow-up period of up to 12 weeks (Figure 1). Randomization is by an independent contract research organization using an interactive web response system, which assigns a randomization number according to a predefined randomization scheme. Randomization is stratified by site. In both studies, patients are managed according to procedures for aSAH at the study center (i.e., study drug is added to usual care) although patient management guidelines have been implemented (see below) to standardize care between centers. Drugs or procedures that are not standard care are forbidden including intravenous magnesium or statins when prescribed for the prevention of cerebral vasospasm, thrombolytics and antifibrinolytics, hypertonic saline without hyponatremia or increased intracranial pressure, calcineurin inhibitors, and endothelin receptor antagonists other than the study drug. Oral nimodipine is permitted, but not intravenous nimodipine or intravenous nicardipine. The study protocols are approved by local institutional review boards. The trials are registered on clinicaltrials.gov: registration numbers: NCT00558311 (CONSCIOUS-2) and NCT00940095 (CONSCIOUS-3). CONSCIOUS-2 enrolled 1157 patients in 102 centers in 27 countries; CONSCIOUS-3 is expected to enroll more than 1400 patients in approximately 150 centers in more than 25 countries. The rationale for separate studies of clipped and coiled patients was based on CONSCIOUS-1 analyses, indicating differences in endpoint occurrence when patients were stratified by securing procedure. Specifically, in CONSCIOUS-1 patients secured by clipping, the incidence of the composite endpoint in the placebo group was 45% compared with 46%, 25% and 40% in 1 mg/h, 5 mg/h and 15 mg/h groups, respectively. In contrast, in patients secured by coiling, the incidence of the composite endpoint in the placebo group was lower at 34% compared with 31%, 32% and 20% in 1 mg/h, 5 mg/h and 15 mg/h groups, respectively. Furthermore, an exploratory, retrospective analysis of CONSCIOUS-1 data showed that, relative to coiled patients, clipped patients had significantly higher rates of angiographic vasospasm (36% vs. 55%, respectively) and DIND (15% and 23%, respectively) [18]. Together these observations supported the conduct of separate trials for clipped and coiled patients and suggested that while the 5 mg/h dose might be most appropriate for clipped patients a potentially higher dose was additionally worth investigating in coiled patients