RESUMO
Background: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted approach will improve the probability of efficacious neuroprotection. But to properly test this hypothesis the nature and importance of the multiple contributing pathways needs elucidation. Our aim is to demonstrate, using functional genomics, in human cardiac surgery procedures associated with cerebral ischemia, that the pathogenesis of perioperative human ischemic brain damage involves the function of multiple variably weighted proteins involving several pathways. We then use these data and literature to develop a proposal for rational design of human neuroprotection protocols. Methods: Ninety-four patients undergoing deep hypothermic circulatory arrest (DHCA) and/or aortic valve replacement surgery had brain damage biomarkers, S100ß and neurofilament H (NFH), assessed at baseline, 1 and 24 h post-cardiopulmonary bypass (CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) (selected by co-author WAK) related to important proteins involved in pathogenesis of cerebral ischemia. Results: At the nominal significance level of 0.05, changes in S100ß and in NFH at 1 and 24 h post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not individually significant after multiple comparison adjustments. Variable weights for the several evaluated SNPs are apparent on regression analysis and, notably, are dissimilar related to the two biomarkers and over time post CPB. Based on our step-wise regression model, at 1 h post-CPB, SOD2, SUMO4, and GP6 are related to relative change of NFH while TNF, CAPN10, NPPB, and SERPINE1 are related to the relative change of S100B. At 24 h post-CPB, ADRA2A, SELE, and BAX are related to the relative change of NFH while SLC4A7, HSPA1B, and FGA are related to S100B. Conclusions: In support of the proposed hypothesis, association SNP data suggest function of specific disparate proteins, as reflected by genetic variation, may be more important than others with variation at different post-insult times after human brain ischemia. Such information may support rational design of post-insult time-sensitive multifaceted neuroprotective therapies.
RESUMO
BACKGROUND: Many authors have reported that general anesthesia (GA), as a generic and uncharacterized therapy, is contraindicated for patients undergoing endovascular management of acute ischemic stroke (EMAIS). The recent American Heart Association update cautiously suggests that it might be reasonable to favor conscious sedation over GA during EMAIS. We are concerned that such recommendations will result in patients undergoing endovascular treatment without consideration of the effects of specific anesthetic agents and anesthetic dose, and without appropriate critical consideration of the individual patient's issues. We hypothesized that significant variation in anesthetic practice comprises GA, and that outcome differences among types of GA would arise. METHODS: With IRB approval, we examined the records of patients who underwent anterior circulation EMAIS at the University of Pennsylvania from 2010 to 2015. Patients were managed by different anesthesiologists with no specific protocol. We analyzed American Society of Anesthesiologists status, NIH Stroke Scale, type of stroke, procedure, different types of anesthetic, blood pressure control, and outcome metrics. Modified Rankin Scale (mRS) scores were determined from medical records. RESULTS: GA was used in 91% of patients. Several types of GA were employed: intravenous, volatile, and intravenous/volatile combined. mRS scores ≤2 at discharge were observed in 42.8% of patients receiving volatile anesthesia and were better in patients receiving only volatile agents after induction of anesthesia (p<0.05). CONCLUSIONS: Our data support the notion that anesthetic techniques and associated physiology used in EMAIS are not homogeneous, making any statements about the effects of generic GA in stroke ambiguous. Moreover, our data suggest that the type of GA may affect the outcome after EMAIS.
