Clinical Trials in Cardiac Arrest and Subarachnoid Hemorrhage: Lessons from the Past and Ideas for the Future

Introduction. Elevated intracranial pressure that occurs at the time of cerebral aneurysm rupture can lead to inadequate cerebral blood flow, which may mimic the brain injury cascade that occurs after cardiac arrest. Insights from clinical trials in cardiac arrest may provide direction for future early brain injury research after subarachnoid hemorrhage (SAH). Methods. A search of PubMed from 1980 to 2012 and clinicaltrials.gov was conducted to identify published and ongoing randomized clinical trials in aneurysmal SAH and cardiac arrest patients. Only English, adult, human studies with primary or secondary mortality or neurological outcomes were included. Results. A total of 142 trials (82 SAH, 60 cardiac arrest) met the review criteria (103 published, 39 ongoing). The majority of both published and ongoing SAH trials focus on delayed secondary insults after SAH (70%), while 100% of cardiac arrest trials tested interventions within the first few hours of ictus. No SAH trials addressing treatment of early brain injury were identified. Twenty-nine percent of SAH and 13% of cardiac arrest trials showed outcome benefit, though there is no overlap mechanistically. Conclusions. Clinical trials in SAH assessing acute brain injury are warranted and successful interventions identified by the cardiac arrest literature may be reasonable targets of the study.


Introduction
For decades, research efforts in subarachnoid hemorrhage (SAH) have focused on vasospasm and delayed ischemic neurological deficits. However, brain injury at the time of aneurysm rupture is a significant predictor of functional outcome. Indeed, poor admission neurological status (Hunt-Hess or World Federation of Neurological Surgeons Score), which reflects acute brain injury, is a larger contributor to death or severe disability than delayed cerebral ischemia [1,2]. However, the mechanism of early brain injury after aneurysm rupture remains elusive and no current therapies are available.
One possible mechanism of acute injury was described in a small case series of 6 patients with observed recurrent aneurysm rupture either during transcranial Doppler (TCD) or during craniotomy with open skull but intact dura. The investigators report a spike in intracranial pressure (ICP) that developed over 1 minute and then declined over several minutes. This abrupt increase in ICP approached levels near mean arterial pressure and led to a concomitant drop in cerebral blood flow resulting in circulatory arrest, as documented by TCD [61]. This study examined aneurysm rebleeding and does not provide direct evidence that intracranial circulatory arrest occurs with de novo aneurysm rupture. However, inadequate cerebral blood flow is frequently evidenced clinically by the transient loss of consciousness that occurs at SAH ictus. This mechanism of global transient circulatory arrest has been described in animal models of SAH at the time of initial hemorrhage [62,63] and mimics the anoxic/hypoxic ischemic mechanism incurred by cardiac arrest.
In this paper, published and ongoing clinical trials in cardiac arrest are compared to those in aneurysmal SAH to identify overlapping or complementary approaches to treatment as well as new avenues for potential research.

Methods
A search of PubMed was conducted in 11/2012 to identify randomized, controlled trials of aneurysmal SAH and cardiac arrest. Only human studies of adults (≥18 years of age), which 2 Stroke Research and Treatment               tested an intervention published in English between 1980 and 2012, were included. Only trials examining mortality or neurologic outcome as a primary or secondary endpoint were reviewed. Only trials specific to SAH (not trials that included other neurocritical diagnoses or brain injury diagnoses) were included. Cardiac arrest trials included both out-of-hospital and in-hospital arrest and all arrest rhythms were included. Post hoc analyses of preexisting trials were not reviewed. If phase III results of a trial were available, earlier phases of the same trial were not included in analysis unless the patient population or methodology differed substantially. A PubMed search of the term "subarachnoid hemorrhage" and "neurologic outcome" with the limits of human, age > 18, English and randomized, controlled trial yielded 23 results. A PubMed search of the term "subarachnoid hemorrhage" and "mortality" with the limits of human, age > 18, English and randomized, controlled trial yielded 78 results. An additional review of articles identified by a broader search of "subarachnoid hemorrhage" with the limits of human, age > 18, English and randomized, controlled trial yielded 244 results. Review of these studies yielded 57 aneurysmal SAH trials that met inclusion criteria and were analyzed. A pubmed search of the terms "cardiac arrest" and "neurologic outcome" with the limits of human, English, age > 18 and randomized, controlled trial yielded 21 results. A PubMed search of the terms "cardiac arrest" and "mortality" with the limits of human, English, age > 18 and randomized, controlled trial yielded 197 results. Review of these studies yielded 46 cardiac arrest trials that met inclusion criteria and were analyzed.
Clinicaltrials.gov was searched for ongoing interventional trials in cardiac arrest and aneurysmal subarachnoid hemorrhage. Only ongoing studies that were open and recruiting or preparing to recruit were included. Terminated studies were excluded from review. A search of ongoing studies on clinicaltrials.gov for the term "subarachnoid hemorrhage", limited to interventional studies of adults ≥18 years old, produced 86 results and a search for the term "cardiac arrest" limited to interventional studies of adults with neurologic outcomes produced 46 results. Of these, 25 ongoing SAH trials and 14 cardiac arrest trials met the criteria for review.

Trials Analyzed.
A total of 142 trials (82 SAH, 60 cardiac arrest) met review criteria. Of these, 103 were published in peer-reviewed journals and 39 were ongoing studies. Fifty-seven published randomized, controlled studies were identified in the SAH population and 46 in the cardiac arrest population. These studies are reviewed in detail in Tables 1  and 2. Additionally, 25 ongoing SAH trials and 14 ongoing cardiac trials were reviewed (Tables 3 and 4).

Trial
Overlap. Though nimodipine has demonstrated mortality and functional outcome benefit in SAH [4-6, 8, 110], it has shown no benefit in cardiac arrest trials [64,65,67]. Similarly, intracisternal thrombolysis showed some benefit in reducing delayed cerebral ischemia and infarction after SAH [36,38], but intravenous tenecteplase showed no long-term benefit and, in fact, increased intracranial hemorrhage after cardiac arrest [69,70]. Neither magnesium [53,54,[81][82][83][84][85] nor intensive insulin [59,87] has proven beneficial after SAH or cardiac arrest. Though hypothermia [88,89] has been the single most effective treatment for cardiac arrest (the number needed to treat to prevent one death is 7 and the number needed to treat to produce favorable neurological outcome is 6), it has not proven useful in the context of aneurysm surgery after SAH [60]. There is little mechanistic overlap in ongoing randomized, controlled trials of SAH and cardiac arrest patients.

Discussion
In this paper, a direct comparison is made between randomized, controlled clinical trials that evaluate mortality or neurologic outcome after SAH and cardiac arrest. Though 28% of SAH studies showed some neurologic outcome benefit in the intervention group, only nimodipine [4-6, 8, 110], fasudil [57,58], and endovascular coiling [29][30][31] have been found to consistently improve outcome in multiple, multicenter randomized controlled trials. Smaller studies [8,41,58], single center [21,44], or phase II safety and feasibility studies [13,25,45] have shown outcome benefit, but still require larger efficacy trials before integration into standard practice. Among cardiac arrest trials, only mild therapeutic hypothermia has been shown to improve both mortality and neurologic outcome [88,89]. Little overlap in trial results or mechanisms of study was identified in these different patient populations.
Methodological differences in the timing, duration, neurological severity, and outcomes studied may explain some of the differences in trial results between SAH and cardiac arrest populations. First, the timing of intervention for SAH and cardiac arrest trials is quite different. With the exception of aneurysm repair and aneurysm rebleeding trials (some of which were carried out in the era of delayed surgical treatment), the vast majority of SAH trials focus on the delayed cerebral ischemia period. Conversely, all cardiac arrest trials are directed at intervening against early brain injury. The difference in time frames studied may explain, in part, the variable results for mild therapeutic hypothermia in each population. Unlike the cardiac arrest trials, which applied hypothermia either prior to ED arrival [88] or within a median of 105 minutes from return of spontaneous circulation (ROSC) [89] for a duration of 12-24 hours, hypothermia was applied in the IHAST trial at a median of two days from SAH onset and only for a brief time (median 5-6 hours) [60]. Second, patient selection may result in variable trial results for hypothermia. For example, hypothermia for cardiac arrest was used for comatose survivors, while relatively neurologically intact patients (WFNS I-III) were studied in the IHAST trial. Finally, outcome measures differ in the cardiac arrest and SAH literature. Many cardiac trials measure 30day or discharge mortality or neurologic outcome, while SAH trials measure outcomes from 3 months to 1 year. Though the majority of cardiac arrest trials measure neurologic outcome using the Pittsburgh cerebral performance scale, while SAH trials utilize the Glasgow outcome scale or modified Rankin scale, all of these scales are very similar and provide gross estimates of disability. Despite the aforementioned methodological differences, certain interventions, such as magnesium and intensive insulin, have not proven effective in either population.
Another reason for variable outcome in clinical trials may be due to pathophysiological differences in SAH and cardiac arrest. Though early brain injury in SAH may mechanistically mirror the cascade of injury occurring after cardiac arrest, SAH differs from cardiac arrest in that it is not a monophasic disease. Break down of blood products initiates a distinctive series of delayed clinical events that characteristically can lead to ischemia or infarction between SAH days 3-14. The fact that nimodipine has been so successful in SAH trials, but shown no effect at similar doses in cardiac arrest trials suggests it is acting on a distinct pathway. Indeed, the absolute risk reduction for poor outcome after SAH in a meta-analysis of 16 trials of nimodipine is 5.3% with a number needed to treat for benefit of 19 [111]. No such signal for benefit was seen in cardiac arrest trials [64,65,67]. The mechanism of beneficial effect of nimodipine in SAH has been widely debated and may be related to its effect on fibrinolysis [112], spreading cortical depression [113], or excitotoxicity. Though nimodipine improves ischemic neurological deficits by clinical criteria and CT-documented infarction (with a pooled relative risks of 0.66 (95% CI 0.59-0.75) and 0.78 (95% CI 0.70-0.87), resp.) [111], it has little effect on angiographic vasospasm or cerebral blood flow [4,5]. The corollary to this observation is that interventions that improve angiographic vasospasm, such as clazosentan, do not necessarily improve cerebral infarction or outcome. [49,50,114,115]. While angiographic vasospasm seems to be related to infarction [116], other mechanisms may play a role in neurological deficits, cerebral infarction, and outcome. Such pathophysiological differences may make extrapolation of results from cardiac arrest trials to an SAH population problematic. Indeed, delayed cerebral ischemia (DCI) may blunt the positive effect of hypothermia on early brain injury. Further animal research may better identify mechanistic differences of early brain injury in cardiac arrest and SAH.
Despite a second wave of neurological injury in SAH, poor-grade (Hunt Hess 4-5) SAH patients, who are at higher risk for secondary neurological injury, still have comparable, if not better, outcomes compared to cardiac arrest patients who are not cooled. Among Hunt-Hess grade 4-5 patients, the 12-month mortality rate with aggressive treatment is 43%, while 40% had no or slight-moderate disability (mRS 0-3) [117]. By comparison, the 6-month death rate in the control (nonhypothermia) group of the HACA trial was 55%, while good neurologic outcome (defined as Pittsburgh cerebral performance scale 1-2; good outcome or moderate disability) occurred in 26-39% [88,89]. We have additionally shown that DCI does not predict mortality after SAH with aggressive vasospasm treatment, while early brain injury (measured by Hunt-Hess grade) does [1]. Thus, despite secondary neurologic insults and delayed cerebral ischemia risk, poor-grade SAH patients do at least as well as normothermic cardiac arrest patients, who may face risks to survival and functional outcome related to the underlying cause of the cardiac arrest. Also, the median age of cardiac arrest patients tends to be older than SAH patients, which may also explain why even the sickest SAH patients have relatively good outcomes by comparison. If nihilism can be overcome in the management of poor-grade SAH patients, the early application of mild therapeutic hypothermia may improve outcomes further.
There are some limitations to this review that should be mentioned. A medical librarian was not used and only MED-LINE/PubMed and clinicaltrials.gov were used to identify literature for review. An Embase search was not performed. Additionally, an exhaustive search for all neurologic outcome based RCTs was not performed, rather only English studies in humans were included.
In conclusion, while the mechanisms of early brain injury after SAH and cardiac arrest may be similar, the preponderance of SAH clinical trials do not focus on interventions addressing early brain injury. Clinical trials in SAH assessing interventions that have proven successful in the cardiac arrest literature, such as early mild therapeutic hypothermia, are warranted.