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Subarachnoid hemorrhage
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Essentials of Anesthesia for Neurotrauma, 2018
Emily G.Y. Koo, Mandy H.M. Chu, Patricia K.Y. Kan, Eunice Y.L. Dai, Matthew T.V. Chan
Prophylactic treatment for vasospasm after traumatic SAH with calcium channel blockers has been studied in eight randomized trials,33–40 including 2101 patients with severe head injury.38,41 Intravenous nimodipine (a calcium channel blocker) (seven trials, 2079 patients) did not reduce the risk of unfavorable outcome after severe head injury (nimodipine 42.5% vs. controls 40.7%); relative risk (95% confidence intervals): 0.92 (0.78–1.10), p = 0.37; random effect model (34–40). Similarly, nicardipine (one trial, 22 patients) had no effect on outcome in severe head injury, relative risk (95% confidence intervals): 0.43 (0.15–1.24), p = 0.12.40 These data suggested that calcium channel blockers should not be prescribed routinely in patients with traumatic SAH. Currently, there are no studies that evaluate other agents, such as an endothelial antagonist (eg, clazosentan), to counteract vasospasm after traumatic SAH. It should be clear that therapeutic techniques that are commonly used in aneurysmal SAH, including induced hypertension, hypervolemia, and hemodilution,42 may be detrimental in the treatment of severe TBI.
Investigational drugs for vasospasm after subarachnoid hemorrhage
Published in Expert Opinion on Investigational Drugs, 2018
Roberta T. Tallarico, Michael A. Pizzi, William D. Freeman
Since 2008, endothelin receptor antagonists, as clazosentan, have been studied. The physiopathology theory of VSP includes overproduction of endothelin (ET) leading to vasoconstriction what can increase the changes of delayed deterioration during time [1]. The clazosentan is a selective ET-1 receptor agonist that acts in the vascular smooth cells and when compared to placebo can reduce angiographic VSP [7].The CONSCIOUS (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) 2 and 3 trials were an attempt to use intravenous clazosentan in order to prevent and treat VSP [63]. CONSCIOUS-2 was a prospective, double-blinded, placebo-controlled, phase III study that enrolled 1157 patients, divided in two groups: control (389 patients) and treatment with intravenous clazosentan 5 mg/h (728 patients). All the patients had the clipping treatment for the aneurysm. Most of the side effects were pulmonary edema, hypotension, pleural effusion, and cerebral infarction what leaded to discontinuing the treatment. The outcomes were poor in the treatment group and no superiority was found [7,63].
An overview of pharmacotherapy for cerebral vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage
Published in Expert Opinion on Pharmacotherapy, 2021
Tatsuya Maruhashi, Yukihito Higashi
The presence of hypotension can be related to cerebral hypoperfusion and worse clinical outcomes [179,180]. Therefore, the lack of a beneficial effect of some vasodilatory drugs on clinical outcome despite their effectiveness against vasospasm may be in part due to decreased blood pressure and subsequent decreased cerebral blood flow. Systemic drug administration potentially causes internal adverse effects. For instance, the internal pulmonary adverse effect profile of clazosentan may contribute in part to the insignificant effect of clazosentan on functional outcome or morality in major placebo-controlled trials, which brings physicians to the local application option. EG-1962, a liquid sustained-release microparticle formulation of nimodipine, was developed for direct administration of nimodipine into the subarachnoid space to produce higher concentrations of nimodipine in cerebrospinal fluid and potentially better efficacy with fewer systemic side effects in patients with aneurysmal subarachnoid hemorrhage. The NEWTON (Nimodpine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage) trial, a phase 1/2a, multicenter, randomized controlled trial, was conducted to investigate the safety, tolerability, and pharmacokinetics of EG-1962. The NEWTON trial showed that EG-1962 was safe and tolerable to 800 mg and that EG-1962 reduced DCI and rescue therapy in patients with aneurysmal subarachnoid hemorrhage[181]. However, a subsequent double-blind, double-dummy, randomized controlled phase III trial (NEWTON-2) that was designed to investigate the efficacy and safety of a single intraventricular administration of EG-1962 at a dose of 600 mg compared with standard oral nimodipine treatment in patients with aneurysmal subarachnoid hemorrhage, was halted after a planned interim analysis of 210 subjects with day 90 outcome due to a low likelihood of achieving the primary endpoint; although EG-1962 reduced vasospasm and hypotension, there was no significant difference in the proportion of patients with a favorable outcome at day 90 after subarachnoid hemorrhage between the two groups[182]. The NEWTON study did not show a beneficial effect of a liquid sustained-release microparticle formulation of nimodipine administered directly into the subarachnoid space. As for NPRIs and intracranial administration of nicardipine, further randomized controlled trials are needed for clinical use.