Disclosures. What s the Plan? Learning Objectives. Background. Origins of N2O 9/6/2017. Nitrous Oxide: No Laughing Matter. Rhashedah Ekeoduru MD None

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1 Disclosures Nitrous Oxide: No Laughing Matter Rhashedah Ekeoduru MD None What s the Plan? Learning Objectives Background Mechanism of Action Benefits Side effects Occupational exposure Prevention Describe how chronic nitrous oxide exposure can precipitate subacute combined degeneration of the spinal cord. Recognize the risks of occupational exposure to nitrous oxide, including headaches, fatigue, irritability, reproductive risks and nervous system effects. Define the recommended exposure limit for nitrous oxide as described by the National Institute for Occupational Safety and Health (NIOSH). Environmental Origins of N2O Background Created by Priestly 1776 Used recreationally 1799 Davy described potential anesthetic properties Used by Horace Wells :50 mixture of nitrous oxide & oxygen (Entonox) = commonly used for minor procedures Reduces anesthetic & opioid requirements Min effects on HR &BP Low blood solubility - fast recovery 1

2 Pharmacodynamics Non-competitive inhibition of NMDA receptors Inhibition of excitatory neurotransmission Potential Benefits of N2O Analgesic properties due to activation of supraspinal opioid receptors NMDA antagonism may reduce chronic postsurgical pain May reduce opioid-induced hyperalgesia May prevent central and peripheral sensitization Rapid Diffusion N2O is 20x more soluble than Nitrogen N2O rapidly diffuses into closed spaces increased pressure in a closed space increased volume 70% N2O doubles the volume of a PTX in 10 minutes Diffusion hypoxia Surgical Risks Compliant cavities expand: PTX, air embolus, pulmonary blebs Non-compliant cavities increase pressure: cranium, cerebral ventricles, middle ear and eye Increased bowel volume Increased intra-ocular pressure after using intra-ocular gas Volume expansion of air embolus in circulation (VAE) N2O can diffuse into the cuff of the ETT Adverse Systemic Effects Lassen 1956 described aplastic anemia & septicemia s/p prolonged N2O exposure Bone marrow suppression Malnutrition Myocardial effects Immunologic effects Subacute combined spinal cord degeneration Long-lasting cognitive defects Reproductive abnormalities Overview of the Metabolic Effects from Exposure to N2O Nitrous oxide oxidizes the cobalt I (Co ) form of cobalamin (vitamin B12) to Co3 Prevents B12 from acting as a coenzyme for methionine synthase Methionine synthase needed to synthesize DNA, RNA, myelin, and catecholamines Increased homocysteine 2

3 Heme & Neurologic Effects Methionine needed for methylation of myelin sheath Subacute combined degeneration of the spinal cord Limb weakness, numbness, tingling, & imbalance Megaloblastic anemia & possible bone marrow failure after 2-6 hours of N2O exposure Methionine Synthase Methionine synthase needed to synthesize DNA, RNA, myelin, and catecholamines N2O can induce fetotoxicity and fertility defects via inhibition of methionine synthase N2O (70%) >reduction in methionine synthase activity: T 1/2 46 min After 200 min of nitrous oxide anesthesia, methionine synthase activity approaches zero Typically, the enzyme s function will recover within 3 4 days after exposure Patient Population Most Susceptible to Reduced Methionine Synthase Activity induced b12 deficiency Cardiac Manifestations Previous B12 deficiency Vegetarians & Vegans Pernicious Anemia Malnourished Ileal disease Alcoholics Methytetrafolate reductase disorder Recreational drug users 'Whippets' Metformin Methyl THF- important role in the conversion of homocysteine to methionine Patients who receive N2O & have a homozygous mutation in MTHFR show an increase in plasma homocysteine levels Affected by duration of N2O exposure Hypothesized to play a risk in increased peri-operative myocardial morbidity 5,10-methylenetetrahydrofolate reductase (MTHFR) Gene Mutation - How Common is it? Mutations in this gene are relatively common Homozygous mutation of MTHFR gene: 0 3% of African Americans 9 11% of Caucasian Americans 32% of Mexican Americans 20 26% of Southern Italian origin Homozygosity associated with increased homocysteine levels and reduction in MTHFR enzyme activity Hyperhomocysteinemia Badner reports increased CV events in patients exposed to N2O w/resultant homocysteinemia Long-term hyperhomocysteinemia increases the risk of CAD and CVD Endothelial dysfunction Increased platelet aggregation Tempered by pre-op folate and B12 supplements 3

4 ENIGMA Trial The Evaluation of Nitrous oxide In a Gas Mixture for Anesthesia (ENIGMA-I) trial Multi-center randomized control trial 2,050 patients enrolled Use of high concentration of oxygen (80% plus 20% nitrogen) vs nitrous oxide (70% plus 30% oxygen) Patients scheduled for 2+ hours of surgery ENIGMA Study Aim ENIGMA Results No observed difference between the two groups regarding the primary endpoint 4 days to 3.5 days; power 0.9 Primary endpoint: difference in hospital stay Secondary endpoints: PONV, PNA, PTX, PE, wound infection, MI, venous thromboembolism, CVA, awareness and death, within 30 days of surgery Observed differences in several secondary endpoints, with improved outcomes in the nitrous oxide-free group reduction in wound infection from 14% to 10%. reduced incidence of postoperative pulmonary complications Significant reduction of severe nausea and vomiting (after controlling for increased propofol use in the nitrous oxide free group) Nitrous oxide group had increased incidences of: wound infection (odds ratio [OR], 0.72; 95% confidence interval [CI], ) pneumonia (OR, 0.51; 95% CI, ) atelectasis (OR, 0.55; 95% CI, ) No observed difference in major adverse cardiac events of death in either group Conclusions of ENIGMA I Trial Study Limitations Avoidance of nitrous oxide and the concomitant increase in inspired oxygen concentration decreases the incidence of complications after major surgery, but does not significantly affect the duration of hospital stay. The routine use of nitrous oxide in patients undergoing major surgery should be questioned. - Anesthesiology Aug;107(2): Not blinded Difficult to determine whether the abandonment of N2O plus the adoption of high [O2] is necessary to reduce postoperative complications Did not control confounding variables 4

5 ENIGMA II 7,112 non cardiac surgery patients N2O (70% in 30% O2) vs N2O free anesthetic Evaluated association btw N2O, severe PONV & effectiveness of prophylaxis 45yrs or older Known or suspected coronary artery disease Results of ENIGMA II Increased risk of PONV with N2O nearly eliminated by antiemetic prophylaxis Choice and dose of antiemetic was not standardized 32% dexamethasone 39% 5-HT3 antagonist 6% droperidol or haloperidol Chronic N2O Exposure Mask induction poor mask fit high concentrations median concentration of N2O 95 ppm for the anesthetist and 42 ppm for the circulating nurse Severe PONV in 12.4% Max acceptable exposure level of N2O Is exposure reduced w/an airway device? Europeans recommend exposure limits for N2O ranging from ppm Time-weighted average over an 8 hr work day National Institute of Environmental Health and Safety (NIOSH) recommends a time-weighted average of 25 ppm for N2O LMA : N2O peak level ranged from 15±37 ppm OR w/ac without recirculation, but a scavenging system + ETT in2o of 50% = <0.5 ppm N2O for the anesthetist <2 ppm for the surgeon (time-weighted average) OR without sufficient AC or scavenging devices + ETT in2o of 50% = 179 ppm for the surgeon 168 ppm for the anesthetist 5

6 But the PACU is Safe Risks to Clinical Staff A study measured 207 patients in a recovery room Time-weighted average was under 12 ppm, although peak concentrations of > 40 ppm occurred Exhalation of anesthetic gases into the recovery room air is unscavengable Increased contamination if AC malfunctions Increased fetal loss & impaired postnatal development with 1,000 ppm Boivin performed a meta-analysis of 19 studies - relative risk of spontaneous abortion with nitrous oxide exposure of 1.48 (95% CI, ) Nigh exposure (greater than 6 h a week for 10 yr) : tingling, numbness, and weakness Neurocognitive performance effects NMDA receptor antagonism >attentional deficits, impulsivity, autism spectrum disorders What Can We Do? Recreational Exposure Modern regularly serviced anesthesia machines Scavenging systems w/high suction flow Sufficient AC with no air recirculation Secure the airway w/ett Periodically evaluate the OR waste anesthetic gas level Pop Culture Glorifies N2O Abuse is on the rise in teenagers Know the risks: Myeloneuropathy Subacute combined degeneration Psychosis Low B12 Elevated homocysteine Environmental Effects Atmospheric N2O accounts for 5% of the global greenhouse gases Global warming potential nearly 300 times that of CO2 N2O destroys stratospheric ozone N2O is produced naturally when nitrogen in soil or water is eaten by bacteria. N2O reacts with high-energy oxygen atoms to produce nitric oxide NO 6

7 Expansion of PTX, VAE Failure to close abdomen s/p ex lap Vision loss PONV Tracheal stenosis Hypoxia Neuropathy Fetotoxicity/Miscarriage Ozone depletion Conclusion: Do NOT Use N2O References Klaus H. Hoerauf MD. Nitrous oxide: workplace concentrations/ecology. Best Practice & Research Clinical AnaesthesiologyVol. 15, No. 3, pp. 389±396, 2001 Brown, SM and Sneyd JR. Nitrous Oxide in Modern Anaesthetic Practice. British Journal of Anaesthesia 2016; 16 (3): Marie, RM, Biez, EL, et al. Nitrous Oxide Anesthesia-Associated Myelopathy. Arch Neurol 2000; 57: Wronska-Nofer, T, Nofer, JR, et al. Oxidative DNA damage and oxidative stress in subjects occupationally exposed to nitrous oxide. Mutation Research 2012; 731: Garakani, A, Jaffe, RJ, et al. Neurologic, Psychiatric, and Other Medical Manifestations of Nitrous Oxide Abuse: A Systemic Review of the Case Literature. American Journal on Addictions 2016; 25: Robert D. Sanders, B.Sc., M.B., B.S., F.R.C.A.,Jorg Weimann, M.D., D.E.A.A., Mervyn Maze, M.B., Ch.B., F.R.C.P., F.R.C.A., F.Med.Sci. Biologic Effects of Nitrous Oxide:A Mechanistic and Toxicologic Review. Anesthesiology 2008; 109: References Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E; ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology Aug;107(2): Lane GA, Nahrwold ML, Tait AR, et al. Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not. Science 21 Nov 1980 Vol. 210, Issue 4472, pp Fluegge K. Does environmental exposure to the greenhouse gas, N2O, contribute to etiological factors in neurodevelopmental disorders? A mini-review of the evidence. Environmental Toxicology and Pharmacology, , Volume 47, Pages Fagan D., Paul D.L., Tiplady B., and Scott D.B. A dose-response study of the effects of inhaled nitrous oxide on psychological performance and mood. Psychopharmacology (Berl). 1994; 116: Thank you rhashedah.a.ekeoduru@uth.tmc.edu 7