Volatile Anesthetics in Subarachnoid Hemorrhage-related Vasospasm: Protective or Not?

The role of volatile versus intravenous anesthetics has always been debated in patients with intracranial pathology, particularly in patients with acute neurological insults like traumatic brain injury and aneurysmal subarachnoid hemorrhage (aSAH). Both agents have variable effects on cerebral physiology and intracranial hemodynamics. The literature to date has been contentious with no robust evidence of superiority of one agent over the other in terms of their clinical effects. Nevertheless, an intriguing property of volatile anesthetics is its ability to produce cerebral vasodilation. However, this property may result in raised intracranial pressure by virtue of its propensity to increase cerebral blood flow. One question that always resonated in my mind was whether the exposure to volatile anesthetics in patients with aSAH can be protective against cerebral vasospasm and delayed cerebral ischemia (DCI). The concept of cerebral vasodilation resulting from volatile anesthetics comes primarily from experimental studies, including a recent clinical study that observed an increase in the cerebral vessel luminal diameter with the use of sevoflurane in patients with aSAH.1 Various mechanisms have been proposed through which volatile anesthetics cause cerebral vasodilation. A simplified mechanistic representation incorporates endothelial nitric oxide synthase (eNOS), endothelin (ET), and KATP channels in facilitating volatile-anesthetics–induced cerebral vasodilation (Fig. 1).2–4 However, most of the data comes from preclinical studies in which supratherapeutic concentration of anesthetics were used, and more studies are required in clinical settings to understand the molecular mechanisms of cerebral vasodilation following exposure to volatile anesthetics.FIGURE 1: Schematic representation of pathways in volatile anesthetic-induced cerebral vasodilation. VA indicates volatile anesthetic agent; NO, nitric oxide, eNOS, endothelial nitric oxide synthase; sGC, soluble guanylyl cyclase; cGMP, cyclic guanosine monophosphate; VSMC, vascular smooth muscle cells; ET-1, endothelin 1; ET-A, endothelin A; PLC, phospholipase C; , endothelium; , vascular smooth muscle cell.The role of volatile anesthetics in protection against cerebral vasospasm and DCI has gained interest from past one decade. There is extensive review on preclinical studies demonstrating the effect of isoflurane on cerebral vasospasm and DCI.5 The use of sevoflurane and desflurane in experimental model of SAH observed the attenuation of large artery vasospasm and improvement of neurological functions.6 Inflammatory responses influence the development of symptomatic vasospasm following aSAH.7 Besides the impact of volatile anesthetics on cerebral vasodilatation, the data from animal experimentation also point towards their favorable impact on inflammation, autoregulation, blood-brain barrier, cerebral edema, neuronal apoptosis, and microvascular thrombosis.5 There is a need for important insights into the mechanism of volatile anesthetics associated effects on cerebral vasospasm and DCI in patients with aSAH. These effects could be related to cerebral vasodilatation or activation of biochemical mechanisms that may confer protection against cerebral vasospasm/DCI. It is possible that a combination of both these processes may be in place.1,5 The translation of outcomes of animal models may be fraught with limitations due to the controlled environment of experimental studies versus those of patients being anesthetized in clinical settings. The biological difference in the species, strains, sex, and age group of animals used in experimental studies may be few precluding factors in translation from bench to bedside. There is recent clinical data demonstrating the beneficial effects of volatile anesthetics on cerebral vasospasm and DCI.5,8,9 On the contrary, there are studies that did not observe any beneficial effect.8 The shortcomings of clinical data are that they are either retrospective or those with small sample size. In this issue, the systematic review and meta-analysis conducted by Wang et al10 compared the use of volatile anesthetics with intravenous anesthetics on cerebral vasospasm following aSAH using data from nine studies (5 cohort and 4 RCTs). The pooled data of cohort studies found an association between the use of volatile anesthetics and a reduced incidence of postoperative vasospasm and DCI. However, the analysis of randomized controlled trials did not find a difference between volatile and intravenous anesthetics on postoperative vasospasm, infarction, and intraoperative brain swelling in patients with aSAH. Focusing specifically on postoperative vasospasm, the variation in the outcome in cohort studies as compared with RCTs appears to be related to methodological issues, sample size, and geographical differences. The cohort data on cerebral vasospasm included five studies, out of which four of them are retrospective.10 The patients included in the cohort studies were heterogeneous, as they included both coiling and clipping procedures. Similarly, pooled data of cohort studies included patients who had anesthetic exposure to isoflurane, sevoflurane, or desflurane. In contrast, only 2 RCTs enrolled a homogenous patient population who underwent aneurysmal neck clipping with the use of single-agent desflurane.10 Though RCTs represent higher quality evidence, the wide discrepancy in pooled sample size should be accounted for when comparing the data of the cohort studies with that of the RCTs. There were total of 1109 patients with postoperative vasospasm in cohort studies, while it was only 164 in RCTs. A dive into the studies included in the meta-analysis by Wang and colleagues reveals that four studies with an Asian population (2 RCTs and 2 cohort studies) did not detect a significant effect of volatile anesthetics on symptomatic/angiographic vasospasm or cerebral infarction. In contrast, 3 cohort studies with North American population demonstrated a benefit with the use of volatile anesthetics on angiographic vasospasm and/or DCI. The geographical diversity is interesting and may account for some of the variability in the results. These contrasting results also raise the possibility of population-based differences in the response of intracranial vessels when exposed to volatile anesthetics. Currently, preclinical studies demonstrate a clear benefit of volatile anesthetics on attenuation of cerebral vasospasm and neurological outcome. The existing clinical evidence and the meta-analysis by Wong et al leave us at a crossroads regarding the benefits of volatile anesthetics on cerebral vasospasm and DCI.10 Going forward, we need to generate good quality, prospective large databases to assess real-world effectiveness of volatile anesthetics on cerebral vasospasm, DCI, and long-term neurological outcomes. Subsequently, large multicenter randomized controlled trials will be necessary to generate definitive evidence for the protective efficacy of volatile anesthetics on aSAH-related vasospasm. Whether volatile anesthetics can breathe life into the injured brain by protecting against aSAH-related vasospasm remains a question that only time will answer.