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

Abstract

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.

Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

“…The induction of Il1b and Il6 may be due in part to the direct action of ET-1 (Rikimaru et al, 2009;Stankova et al, 1996) with no previously documented effects on Ifnb or Tnf. Interestingly, we also observed a small but significant increase in the expression of Ndfip1, Nedd4 family interacting protein 1, which has recently been shown to be critical for CD4 T-cell differentiation into the Th17 subset by inhibiting production of IL-4 (Frontera, 2013). This establishes that transient vasoconstriction and the accompanying ischemic time frame is capable of inducing a potent inflammatory reaction.…”

“…For example, IL-6 inhibitors such as tocilizumab are clinically used as treatments for rheumatoid arthritis (Yoshida and Tanaka, 2014), and COX2 inhibitors such as the NSAIDs, celecoxib and acetylsalicylic acid, have been used to treat cardiovascular disease (Spektor and Fuster, 2005). Metal protoporphyrins function as potent pharmacological inhibitors of heme oxygenase 1 while caveolin-1 depletion has been shown to increase endogenous heme oxygenase 1 activity (Gozzelino et al, 2010). To assess the specific impact of these gene inductions, the use of inhibitors and agonists would provide an avenue for determination of the therapeutic benefits of such treatments.…”

The Role of Platelet Activation and Inflammation in Early Brain Injury Following Subarachnoid Hemorrhage

“…For decades, clinical research in SAH has focused on preventing and treating secondary injury after SAH (i.e. DCI/vasospasm), while EBI has been understudied 34 . Multiple groups have found an association of elevated platelet activating factor (PAF), platelet aggregability, platelet microparticles (CD41+), elevated thromboxane levels, and microthrombosis with the development of DCI 33, 35 .…”

Acute ischaemia after subarachnoid haemorrhage, relationship with early brain injury and impact on outcome: a prospective quantitative MRI study

“…Since the brain injury cascade following intracranial circulatory arrest at the time of aneurysm rupture may be similar to the global insult that occurs with cardiac arrest, it may be reasonable to explore the cardiac arrest literature for possible therapeutic interventions 35. Therapeutic hypothermia 36 37 and induced normothermia 38 are the only therapies that have been shown to improve mortality and neurological outcome after cardiac arrest 35. Hypothermia has been shown to reduce platelet function and inflammation and improve outcome in animal models of brain injury, including rat models of SAH 39–43.…”