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Hogan

Major Support Received

Federal PI NIH Subcontract - "Multicenter Intra-operative Hypothermia for Aneurysm Trial (IHAST2),"
NIH #38554-01 (7/00-6/05) $40,000 (total)

This is a randomized, multicenter, partially blinded trial to examine the impact of intraoperative hypothermia (target temp = 33°C) on long-term outcome in adult patients who have suffered a recent subarachnoid hemorrhage and undergo an open craniotomy to clip the aneurysm. Patients will be randomized to normothermic or hypothermic groups. Long-term (3mo) outcome will be assessed using the Glasgow Outcome Score (primary outcome variable), NIH Stroke Score, Rankin Disability Score, Barthel's Activities of Daily Living Index, the Mini-Mental Status Exam and a 5-exam battery of neuropsychologic tests.

Federal PI NIH Small Business Investigator Awards Subcontract (with Third Wave
Technologies) - "Perioperative Genomic Invader Profiles,"
NIH #IR43GM64317 (7/01-6/02) $46,642 (phase 1)

The goal of this project over Phase I is to create and test the analytical validity of novel Invader mutation detection assays designed for applications specific to surgery and anesthesia. Invader technology, based on a highly specific enzyme-substrate reaction, enables direct analysis of genomic DNA without prior amplification, conferring advantages in rapidity, cost, and accuracy. The initial series of experiments will test 200 patients for 23 alleles of established clinical validity and utility at 12 loci predicting differences in patient responses to neuromuscular blocking agents (BchE, RYR1, CACNA1S), opiods and antiarrythmics (CYP2D6), nitrous oxide (MTHFR, MTR, MTRR, CBS), volatile anesthetics (RYR1, CACNA1S), and the risk and severity of sepsis (TNF-a, TNF-ß), and thrombosis (FVL, Prothrombin). The surgical- and anesthesia-specific Invader assays will be compared to conventional PCR-based methods with disparities resolved by DNA sequencing. Subsequent Phase II investigations will add alleles of proven predictive value to multiplexed Invader patient panels designed for specific applications, and test whether these can favorably alter clinical outcomes. These data represent the necessary first steps in the assembly of high-throughput, automated perioperative genomic profiles incorporating hundreds of genotypes that can directly modulate risk and enhance the safety of all patients undergoing surgery.

Non-Federal PI - "Genomic Predictors of Homocysteinemia after Nitrous Oxide," Doris Duke Innovation in Clinical Research Award (7/01-6/03) $200,000(total)

The aim of this investigation is to test whether patients with mutations in genes encoding enzymes responsible for folate and cobalamin metabolism are at special risk for increased blood levels of homocysteine after nitrous oxide anesthesia. Acute elevations of homocysteine promote coagulation and impair vascular relaxation setting the stage for venous and arterial thrombosis. Thrombotic complications, including myocardial ischemia, stroke and pulmonary emolus, are particularly prevalent during the immediate post-operative interval coinciding with nitrous oxide-induced hyper-homocysteinemia. In turn, common polymorphisms in genes expressing enzymes which regulate folate and cobalamin metabolism (the C677T and A1298C alleles of 5, 10 methylene tetrahydrofolate reductase the A256G allele of methionine synthase, the A66G allele of methionine synthase reductase, and the 844ins68 variant of cystathionine beta-synthase) have recently been shown to be independent predictors of homocysteinemia. In this investigation, two hundred patients undergoing vascular procedures for disorders associated with a disproportionate prevalence of hyper-homocysteinemia and thrombosis formation (i.e. carotid endarterectomy, lower extremity arterial bypass) will have blood drawn before nitrous oxide anesthesia for detection of the 5 cited mutations, together with folate, cobalamin, pyridoxine and baseline homocysteine levels. Serial homocysteine levels will then be measured immediately after surgery, at 24 and 48 hours. Severity of homocysteinemia and allele frequency will be compared in two hundred age- and gender-matched patients having non-vascular procedures (i.e. craniotomy) of similar duration and inspired nitrous oxide concentration. If folate and cobalamin cycle genotypes correlate with perioperative elevations in serum homocysteine, patient safety will be enhanced for those at heightened risk by prophylaxis e.g. pre-surgical folate and cobalamin administration, and by selection of alternative perioperative management e.g. regional or intravenous anesthetics avoiding use of nitrous oxide.