Perioperative pharmacogenetics: Nitrous oxide and anesthetic outcomes

Summary

Principal Investigator: Peter Nagele
Abstract: Postoperative morbidity and mortality is an under-recognized, yet significant public health problem. In 2004. 1.4% of all inpatients died after surgery. Myocardial infarction is a major contributor to postoperative mortality. Perioperative (pharmaco-)genetics may reduce adverse outcomes by individualizing therapeutic options and drug therapy ("personalized medicine"). However, there is currently a significant paucity of Studies investigating the potential benefits of perioperative pharmacogenetics. This K23 proposal is for a career development program in perioperative pharmacogenetics. The research component centers on a randomized blinded controlled trial investigating the association between gene variants in intermediary metabolic pathways known to be altered by nitrous oxide and postoperative myocardial ischemia. Nitrous oxide is the most commonly used general anesthetic in the world. It inhibits vitamin 812 and increase homocysteine concentrations. Chronic homocysteinemia has been associated with adverse cardiac events.The MTHFR 677 C>T polymorphism is the most important genetic determinant for elevated homocysteine and is also associated with significantly higher homocysteine after nitrous oxide anesthesia. Thus, this investigation will test the hypothesis that patients with this gene variant have a higher incidence of postoperative myocardial ischemia after nitrous oxide, anesthesia than wild-type patients (aim 1). We will also determine if this risk can be ameliorated by blinded, randomized perioperative supplementation of vitamin B12 and folate (aim 2). The trial will target patients at high risk for cardiac events undergoing major noncardiac surgery. The didactic training component of the K23 proposal will be the Masters of Science program in Genetic Epidemiology. The overall long-term career objective is to become an independent investigator in perioperative pharmacogenetics. PUBLIC HEALTH RELEVANCE: Postoperative myocardial ischemia is one of the most important contributors to surgical morbidity and mortality with 2-3 million Americans at risk annually. This research will answer if nitrous oxide is a risk factor for postoperative myocardial ischemia and if this risk can be ameliorated by B-vitamins. Thus, this research might serve as important evidence to assess the safety of nitrous oxide in high-risk patients.
Funding Period: 2010-01-04 - 2013-12-31
more information: NIH RePORT

Top Publications

  1. pmc Pre-operative vitamin B infusion and prevention of nitrous oxide-induced homocysteine increase
    L K Rao
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anaesthesia 65:710-5. 2010
  2. pmc The effect of nitrous oxide anesthesia on early postoperative opioid consumption and pain
    Andreas Duma
    From the Department of Anesthesiology, Washington University in St Louis, St Louis, MO and Department of Anesthesiology and General Intensive Care, Medical University of Vienna, Vienna, Austria
    Reg Anesth Pain Med 39:31-6. 2014
  3. pmc High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery
    Peter Nagele
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, MO 63110, USA
    Am Heart J 166:325-332.e1. 2013
  4. pmc Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial
    Peter Nagele
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri 63110, USA
    Anesthesiology 119:19-28. 2013
  5. pmc Perioperative torsade de pointes: a systematic review of published case reports
    Joshua Johnston
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave, Box 8054, St Louis, MO 63110
    Anesth Analg 117:559-64. 2013
  6. pmc A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics
    C M Blake
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA
    Clin Pharmacol Ther 94:394-9. 2013
  7. pmc Postoperative QT interval prolongation in patients undergoing noncardiac surgery under general anesthesia
    Peter Nagele
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anesthesiology 117:321-8. 2012
  8. pmc Perioperative genomics
    Peter Nagele
    Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Best Pract Res Clin Anaesthesiol 25:549-55. 2011
  9. pmc Genetic variation, β-blockers, and perioperative myocardial infarction
    Peter Nagele
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Anesthesiology 115:1316-27. 2011
  10. pmc Nitrous oxide anesthesia and plasma homocysteine in adolescents
    Peter Nagele
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anesth Analg 113:843-8. 2011

Detail Information

Publications16

  1. pmc Pre-operative vitamin B infusion and prevention of nitrous oxide-induced homocysteine increase
    L K Rao
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anaesthesia 65:710-5. 2010
    ..Patients not receiving nitrous oxide had no homocysteine change (0.5 micromolxl(-1); 95% CI -0.8-1.9 micromolxl(-1)), indicating that pre-operative intravenous B-vitamins may not prevent nitrous oxide-induced hyperhomocysteinaemia...
  2. pmc The effect of nitrous oxide anesthesia on early postoperative opioid consumption and pain
    Andreas Duma
    From the Department of Anesthesiology, Washington University in St Louis, St Louis, MO and Department of Anesthesiology and General Intensive Care, Medical University of Vienna, Vienna, Austria
    Reg Anesth Pain Med 39:31-6. 2014
    ..A similar effect of N₂O is plausible, yet understudied. The goal of this study was to determine the effects of N₂O anesthesia on early postsurgical opioid consumption and pain...
  3. pmc High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery
    Peter Nagele
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, MO 63110, USA
    Am Heart J 166:325-332.e1. 2013
    ..We hypothesized that preoperative cardiac troponin T detected with a novel high-sensitivity (hs-cTnT) assay will identify patients at risk for acute MI and long-term mortality after major noncardiac surgery...
  4. pmc Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial
    Peter Nagele
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri 63110, USA
    Anesthesiology 119:19-28. 2013
    ....
  5. pmc Perioperative torsade de pointes: a systematic review of published case reports
    Joshua Johnston
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave, Box 8054, St Louis, MO 63110
    Anesth Analg 117:559-64. 2013
    ..To improve our understanding, we performed a systematic review and meta-analysis of all published case reports of perioperative torsade de pointes...
  6. pmc A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics
    C M Blake
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA
    Clin Pharmacol Ther 94:394-9. 2013
    ..This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer-specific metabolism of metoprolol...
  7. pmc Postoperative QT interval prolongation in patients undergoing noncardiac surgery under general anesthesia
    Peter Nagele
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anesthesiology 117:321-8. 2012
    ..Many perioperatively administered drugs and conditions prolong the QT interval. Despite several reports of perioperative torsades de pointes, systematic evidence regarding perioperative QT interval prolongation is limited...
  8. pmc Perioperative genomics
    Peter Nagele
    Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Best Pract Res Clin Anaesthesiol 25:549-55. 2011
    ..This article summarises the basics of genetic inheritance, the human genome and modern sequencing methods, as well as genetic variation and how this knowledge may be applied to patient care and research in the perioperative setting...
  9. pmc Genetic variation, β-blockers, and perioperative myocardial infarction
    Peter Nagele
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Anesthesiology 115:1316-27. 2011
    ....
  10. pmc Nitrous oxide anesthesia and plasma homocysteine in adolescents
    Peter Nagele
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anesth Analg 113:843-8. 2011
    ..Prolonged exposure to nitrous oxide can lead to neuropathy, spinal cord degeneration, and even death in children. We tested the hypothesis that nitrous oxide anesthesia causes a significant increase in plasma tHcy in children...
  11. pmc Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification
    Peter Nagele
    Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA
    Pharmacogenet Genomics 21:426-31. 2011
    ..This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy...
  12. pmc Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis
    Michael Hüpfl
    Department of Anesthesiology, Critical Care and Pain Therapy, Medical University of Vienna, Vienna, Austria
    Lancet 376:1552-7. 2010
    ..We aimed to establish the association of chest-compression-only CPR with survival in patients with out-of-hospital cardiac arrest...
  13. pmc Postoperative myocardial injury after major head and neck cancer surgery
    Peter Nagele
    Department of Anesthesiology, Washington University, St Louis, MO 63110, USA
    Head Neck 33:1085-91. 2011
    ..The aim of this study was to determine the risk of postoperative myocardial injury in patients undergoing major head and neck cancer surgery...
  14. ncbi Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes
    Fernando Botto
    From the Hamilton General Hospital, David Braley Cardiac, Vascular, and Stroke Research Institute, Population Health Research Institute, Hamilton, Ontario, Canada P J D and Members of The VISION Writing Group and VISION Investigators, who are listed in appendix 1 and appendix 2, respectively Population Health Research Institute, Hamilton, Ontario, Canada Department of Clinical Research, Estudios Clinicos Latino America ECLA, Rosario, Argentina Biomedical Research Institute Sant Pau IIB Sant Pau, Barcelona, Spain The Chinese University of Hong Kong, Shatin, N T, Hong Kong Universidad Autónoma de Bucaramanga and Fundación Cardioinfantil, Colombia St John s Medical College and Research Institute, Bangalore, India Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada Department of Clinical Epidemiology and Biostatistics and Department of Medicine, McMaster University, Hamilton, Ontario, Canada Hospital General Universitario Gregorio Maranon, Madrid, Spain University of Alberta, Edmonton, Alberta, Canada University of Malaya, Kuala Lampur, Malaysia Research Institute Hcor Hospital do Coracao, Sao Paulo, Brazil Barts and The London School of Medicine and Dentistry
    Anesthesiology 120:564-78. 2014
    ..The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS...

Research Grants30

  1. Cardiac Remote Ischemic Preconditioning Prior to Elective Major Vascular Surgery
    Santiago Garcia; Fiscal Year: 2013
    ..We believe a positive signal in this pilot study could lay the foundation for planning and executing a multicenter clinical trial with enough power to detect clinical events. ..