Kingdom Argon : A Noble Foe for Subarachnoid Hemorrhage *

1456 www.ccmjournal. org July 2016 • Volume 44 • Number 7 Subarachnoid hemorrhage (SAH) is a serious health issue with a worldwide incidence of approximately 9 per 100,000 and a 6-month mortality of around 60% (1). Those patients who survive are often severely impaired with associated long-term care and rehabilitation costs. Surgical management of SAH as a result of a cerebral aneurysm focuses on stopping bleeding through direct surgical clipping or endovascular repair (coil or glue embolization). Noninvasive management involves drugs to avoid vasospasm and maintain cerebral perfusion pressure, aimed at limiting the effects of early brain injury thought to underlie the majority of the disability burden in SAH survivors. Argon is a member of the series of inert or “noble” gases with helium being the lightest and xenon the heaviest nonradioactive member. Despite having low chemical reactivity, certain noble gases have biological activity; xenon is a general anesthetic at atmospheric pressure (minimum alveolar concentration = 0.63 atm), whereas krypton and argon are anesthetics at elevated pressure (4.5 and 15 atm, respectively), but are without measurable anesthetic effect at 1 atm. Xenon has clearly identified pharmacological targets (e.g., N-methyl-D-aspartate receptors; TREK-1 potassium channels, K-ATP channels) and has been demonstrated to be neuroprotective in a variety of models of ischemic and traumatic brain injury (2–6). Argon has been less widely studied but has been shown to be neuroprotective in in vitro models of ischemic and traumatic brain injury (5, 7) and in vivo in models of ischemic injury (8–10). Argon is more abundant and less expensive to produce than xenon and, if equally safe and effective as a neuroprotectant, may be advantageous. In this issue of Critical Care Medicine, Höllig et al (11) report the first study to evaluate the potential of argon as a treatment for SAH in a rodent model. They used a rat model of SAH involving isolation of a common carotid artery and surgical insertion of a suture or wire into the internal carotid artery. The suture is advanced to the region of the branch of the middle cerebral artery/anterior cerebral artery (ACA). The filament is further advanced to rupture the ACA and is then withdrawn. This results in a severe and poorly controlled bleeding that resembles a ruptured cerebral aneurysm. Mortality is high in this rat SAH model, up to 40% in the first few days, which mirrors the clinical scenario. The induction of SAH in this model involves surgery under general anesthesia, with monitoring of intracranial pressure and cerebral blood flow to confirm SAH. One hour after induction of SAH or sham surgery (insertion and removal of filament without vessel rupture), the rats breathed either 50% Ar:50% oxygen or 50% N 2 :50% oxygen through a facemask for a period of 1 hour. The primary outcome measure was survival up to 6, 24, and 72 hours after SAH. Secondary outcomes were neurological scoring at 24 hours, open field test at 24 hours (a measure of locomotor function and exploratory behavior), brain tissue analysis for the stress-response proteins hypoxia-inducible factor (HIF-1α) and heme-oxygenase (HO-1) at 6, 24, and 72 hours and hippocampal cell counting at 6, 24, and 72 hours. The authors found that survival was improved in the argontreated groups when compared with nitrogen-treated groups at each time point. Multivariate statistical analysis indicated a significant reduction in risk of premature death of 20.6 % in the argon-treated groups (p < 0.05). One potential confounder is the pooling of different timepoints for the mortality analysis. The data shown in Figure 3 of the study by Höllig et al (11) show that there are fewer deaths in the argon-treated groups than in the nitrogen controls. This is striking at the two early time-points (6 and 24 hr) but less so at 72 hours. However, because of the experimental design, each of the time-points, 6, 24, and 72 hours consists of a separate control and argon group (surviving animals are euthanized at each timepoint). The reasons for this design are related to the requirement for postmortem tissue samples at each time-point for the secondary outcomes. Unfortunately, this reduces the power of the study to determine treatment-effect on survival when compared with the ideal scenario of two larger groups all surviving until 72 hours. With the current design, it is impossible to tell whether argon treatment improves survival up to 72 hours or simply delays death within a 72-hour period (at 72 hr, the number of deaths in each group only differs by one animal out of nine). This information is of high clinical relevance and could be provided by a study with larger groups of animals all of which are monitored for survival at each time-point, and ideally for longer survival times. Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001680 *See also p. e520.