Passing Gas – A Primer on Inhaled Anesthetic Agents: Passing Gas – A Primer on Inhaled Anesthetic Agents Craig J. Railton BSc, MD, PhD, FRCPC Department of Anesthesia and Perioperative Medicine Department of Clinical Pharmacology University of Western Ontario


Outline: Outline History Mechanism of Action Pharmacology Uptake and Distribution Systemic Profiles (effects) Metabolism and Toxicity Pharmacoeconomics


History: History Soporific Sponge Mixture (9th Century, Italy) Opium - one half ounce Juice of mandagora leaves - eight ounces Fresh hemlock juice - Hyposcyanus - three ounces Mix with water to form a liquor absorb into a dry sponge, dry the sponge carefully, dip in warm water then place it over the nose and have the patient breath deep until he sleeps Apply a vinegar soaked sponge to end the sleep


History: History Paracelsus wrote of “sweet vitriol” made from alcohol mixed with sulfuric acid in early 16th century – but little evidence it was used in practice Hypnotism and opium used in early 19th century with mixed effect and some deaths Surgery was done for the most part with no anesthesia until middle of 19th century Patients were told to hold still Patients were held or strapped down Success of surgery depended on speed and brute force


History: History Nitrous oxide was developed in 1844 and Colton demonstrated used for dental surgery in 1846 Several reports of deaths and brain injuries soon followed On October 16, 1846 – Morton demonstrated Ether for anesthesia at Massachusetts General Hospital Within months the use of Ether had spread around the world for treatment of the pain of surgery Very vague descriptions of proper use were available Deaths occurred but ether still widely used


Chloroform 1848: Chloroform 1848 Hannah Greener died in 1848, first known anesthetic related death during the first public demonstration of a chloroform anesthetic “I seated her in a chair, and put a teaspoon of chloroform into a tablecloth, and held it to her nose. After she had drawn her breath twice, she pulled my hand down. I told her to draw her breath naturally, which she did, and in about a half a minute I observed muscles of the arm become rigid, and her breathing a little quickened, but not stertorous. I had my hand on her pulse, which was natural, until the muscles became rigid. It then appeared somewhat weaker-not altered in frequency. I then told Mr. Lloyd, my assistant, to begin the operation, which he did, and took the nail off. When the semicircular incision was made, she gave a struggle or jerk, which I thought was from the chloroform not having taken sufficient effect. I did not apply anymore. Her eyes were closed, and I opened them, and they remained open. Her mouth was open, and her lips and face blanched. When I opened her eyes, they were congested. I called for water when I saw her face blanched, and I dashed some of it in her face. It had no effect. I then gave her some brandy, a little of which she swallowed with difficulty. I then laid her on the floor and attempted to bleed her in the arm and jugular vein, but only obtained about a spoonful. She was dead, I believe, at the time I attempted to bleed her. The last time I felt her pulse was immediately previously to the blanched appearance coming on, and when she gave a jerk. The time would not have been more than 3 min from her first inhaling the chloroform till her death.” Anonymous, Edinburgh Med Surg J 1848; 69: 498


History: History Many mishaps leading to injury secondary to hypoxia and death occurred over the next 125 years Queen Victoria and Catherine Hogarth (Mrs. Charles Dickens) were two celebrity patients that popularized the use of anesthesia for childbirth (chloroform) This led to a more general acceptance despite the risks The specialty of Anesthesia was started during the 1940’s Current regulations mandate that a physician is present during surgery to look after the safety and wellbeing of the patient


History: History


History: History


MAC: MAC Minimum Alveolar Concentration = MAC Anesthetic potency is measured in MAC 1 MAC is the Minimum Alveolar Concentration at which 50% of humans have no response (movement) to surgical stimulus (skin incision) MACawake is the alveolar concentration when 50% of persons will awake to vocal stimulus MAC is directly proportional to the partial pressure of the anesthetic agent in the CNS MAC is consistent within a species and between species MAC is different for each inhaled agent


MAC: MAC


MAC: MAC


MAC: MAC MAC decreases with decreasing body temperature MAC increases with increasing pressure more anesthetic agent required higher pressures to achieve same MAC Ion concentrations in CNS alter MAC Na – MAC increases with concentration K – no effect Ca – no effect Mg – inversely proportional increase with concentration MAC decreases with age (greatest at 6 months) MAC is altered by other drugs MAC decreases as patient medical condition deteriorates


MAC: MAC


Mechanism of Action: Mechanism of Action We don’t know… much, but let me tell you about what we do know…


Meyer – Overton Rule: Meyer – Overton Rule Anesthetic potency correlates with lipid solubility Holds true across species Implies when a specific hydrophobic region is occupied – anesthesia results


Meyer-Overton Exceptions: Meyer-Overton Exceptions Isomers – isoflurane and enflurane are isomers with similar oil/gas partition but MAC is 50% different Enantiomers: have different potencies Convulsive Compounds: - terminal CF3 groups Cutoff Effect: decane is soluble but not anesthetic – also perfluorocarbons Non-anesthetics: some compounds predicted to be anesthetic by MO are not – may have some effects though


Critical Volume Hypothesis: Critical Volume Hypothesis Myer-Overton Rule predicts/implies that anesthesia will occur when a specific number of anesthetic molecules dissolve (implies actual binding sites) This doesn’t seem to be true The Critical Volume Hypothesis is a modification of Meyer-Overton that states anesthesia occurs when a “critical region” volume is sufficiently changed by a certain degree that anesthesia results This also doesn’t seem to be true


Membrane Hypotheses: Membrane Hypotheses Some membrane channels behavior is changed by anesthetic agents Some channels slowed Some channels sped up Different channels different effect with different agents Postulated that lipid bilayer may be site of action Lipid permeability is changed Synaptic vesicles behavior changes Thickness of lipid bilayer is changed - thicker


Membrane Hypotheses: Membrane Hypotheses Proteins are site of actions Ligand gated ion channel behavior changes neurotransmitters Voltage gated channel behavior changes Ion channels Metabotrobic and G-proteins are affected Serotonin Glutamate Non-synaptic proteins


Receptor Theory: Receptor Theory Inhaled anesthetic agents interact with many neuronal cell surface proteins GABA receptor is thought to be a likely target GABAA sub-unit is thought to be area of interest – not all GABAA are the same GABA receptors containing alpha-5 sub-unit are also implicated GABA receptors outside the synapse are also thought to be implicated Orser B, Lifting the fog around anesthesia, Scientific American, June 2007, pp. 54-61.


Mechanism – Bottom Line: Mechanism – Bottom Line No one knows Likely more than one site Neuronal transmission is disrupted Pre-synaptic, post-synaptic and extra synaptic effects are found See the following for interest Anesthesia Safety: Model or Myth? Lagasse RS, Anesthesiology 2002;97:1609. Molecular and Neuronal Substrates for General Anaesthetics. Rudolph U, Antkowiak B, Nature Reviews Neuroscience 2004;5:709. Emerging Molecular Mechanisms of General Anesthetic Action. Hemmings HC et al., Trends in Pharmacological Sciences 2005;6:503. α5GABAA Receptors Mediate the Amnestic but Not Sedative-Hypnotic Effects of the General Anesthetic Etomidate. Cheng VY et al., Journal of Neuroscience 2006;26:3713.


Pharmacology: Pharmacology Uptake Pharmacokinetics Physiologic effects Metabolism Toxicity


Uptake: Uptake Organ of uptake is the lungs – large surface area Uptake occurs quickly but slower than oxygen Anesthetic agents are more soluble than O2 or N2 Uptake = [(l) x (Q) x (PA-PV)] / Barometric Pres. l = solubility Q = cardiac output PA-PV = alveolar venous partial pressure difference


Uptake and Solubility: Uptake and Solubility The more soluble the anesthetic agent is in blood the faster the drug goes into the body The more soluble the anesthetic agent is in blood the slower the patient becomes anesthetized (goes to sleep) To some degree this can be compensated for by increasing the inhaled concentration but there are limits


Q = Cardiac Output: Q = Cardiac Output Q = Stroke Volume x rate amount of AA in each alveolus is fixed between breaths Increasing the volume of blood improves the amount of AA absorbed, but the concentration of agent in blood is lower Higher Q creates lower Pv concentrations A lower arterial/tissue solubility ratio slows the rate at which the patient goes to sleep Blood returning to lung has less lower AA concentration Increased Cardiac Output slows the rate at which the patient goes to sleep


PA - PV: PA - PV PA – PV (PAlveolar – PVenous) anesthetic agent partial pressure difference is the result of uptake of anesthetic agent by the patients tissues This difference remains until the tissues are saturated and at equilibrium Tissue/blood solubility Tissue blood flow


Other Uptake Issues: Other Uptake Issues Increased minute ventilation increases rate of uptake Inspired concentration a higher Fi (inspired concentration) will increase alveolar partial pressures increasing PA-PV Uptake declines as tissues become saturated plateaus in about an hour but is never zero


Second Gas Effect: Second Gas Effect Second Gas Effect – addition of a second more soluble gas (usually N2O) increases the rate of uptake Korman B, Mapleson WW, BJA 1997; 78:618


Uptake: Uptake


Distribution: Distribution Determinants Solubility partition coefficient (blood vs. tissue) Tissue perfusion – vessel rich groups saturated first Time Multi-compartment model Minimum of 4 More than 7 in some models For most anesthetics “equilibrium” is essentially reached in about 0.5 – 2 h


Tissue Group Characteristics: Tissue Group Characteristics


Partition Coefficients: Partition Coefficients


Waking Up: Waking Up Agent used Length of anesthetic Patient Age Mental state (MR, Alzheimer's…) Medical condition (sepsis, Parkinson’s) Other Medications benzodiazepines, opiates, neuroleptics, local anesthetics, intoxicants Obesity All agents, especially soluble agents, dissolve in fat creating a depot of drug Sleep apnea Airway obstruction


Waking Up in OR: Waking Up in OR


Waking Up – Complex Tasks: Waking Up – Complex Tasks


Waking Up – Level of MAC: Waking Up – Level of MAC


CVS: CVS Heart Rate Halthane reduces HR Sevo and Enf are neutral Des >> Iso can cause an Initial tachycardia heart rate eventually slows initial SNS response leading to catecholamine release Dose dependent effect Rapid increases in MAC Rate of administration plays a role


CVS: CVS Contractility All agents are depressants To some degree lung attenuates this effect At 1 MAC the approximatel order is: Halo = Enfl >> Des = Iso = Sevo Cardiac Output is fairly well preserved Des and Iso > rest Baroreceptor reflexes are preserved


CVS: CVS Vasculature All inhaled agents are smooth muscle relaxants All cause vasodilation (decreased SVR) Variable effects on different vascular leading to hypotension via Protein Kinase C inhibition – cAMP and Ca Troponin binding Life threatening hypotension can result at high enough doses – threshold varies for each patient ALL decrease SVR except Nitrous Oxide Some evidence that Inhaled anesthetics are cardio-protective following ischemic insult Mechanism? Dilation of coronaries Limits degree of ischemic insult


CVS: CVS All inhaled agents are cardio toxic will lead to death at high enough concentrations Arrhythmias are induced by all anesthetic agents Halothane is worst Potentates Catecholamine induced arrhythmias Children are less affected than adults Lidocaine has been shown to double ED50 at 1.25 MAC ED50 of epinephrine at 1.25 MAC halothane 2.1 g•kg-1 isoflurane 6.9 g•kg-1 enflurane 10.9 g•kg-1


CVS: CVS Coronary Blood Flow Isoflurane shown to be potent coronary vasodilator Sevoflurane and Desflurane seem to be less potent in animal models (not all tissue beds behave the same) Concern that blood can be directed away from stenotic coronaries Coronary Steal theoretically possible One vessel highly stenosed Practically, does not seem to be a real problem


Respiratory: Respiratory Patients will only willingly breath Sevoflurane and Halothane All other agents are respiratory irritants Tidal Volume is decreased Respiratory rate is increased Minute ventilation is decreased No change in mucociliary clearance


Respiratory: Respiratory Chemoreceptors Response to CO2 blunted Apneic Threshold raised PCO2 raised during spontaneous ventilation Enf > Des = Iso > Sevo = Halo Hypoxic drive abolished early at about 0.1 MAC


Respiratory: Respiratory Musculature All agents cause smooth muscle relaxation Reduction in Vagal Tone Inhibit Protein Kinase C cAMP reduction Decreased binding of Troponin to Ca2+ ? Dose Dependent reduction in Airway Resistance (RAW) occurs Useful in Treatment of Status Asmaticus Isoflurane thought best


Respiratory: Respiratory PVR is decreased Hypoxic pulmonary vasoconstriction impaired Increased shunting Gas exchange is less efficient (decreased FRC, increased shunt) Shunt and oxygenation largely not affected by one lung ventilation Changes in PVR Difficult to assess Effects of many things affect numbers Positon Cardiac Output PA pressure Nitrous oxide worsens pulmonary hypertension - causes increased PVR


CNS: CNS The CMRO2 is decreased by anesthetic agents Increased Cerebral Blood Flow auto regulation of cerebral blood flow is impaired Increased ICP Via blood flow Via induced hypercapnea Seizure activity may be increased (Enflurane at 2.0 MAC) Ventilatory Responses Blunted Sleep apnea Narcotics add synergistically Benzodiazepines add synergistically


CNS: CNS EEG Decreased Amplitude Increased Latency Neurologic function is effectively stopped EEG is flat line at high concentrations Useful in the treatment of status epilepticus Must give a very deep anesthetic Memory? Do deep anesthetics cause memory impairment? EEG monitoring BIS = Bispectral Index (Aspect Medical) uses EEG changes to monitor depth of anesthesia AKA – BIS, Entropy, Evoked Potentials


CNS: CNS Intraoperative Awareness Estimated at 0.15% of all cases Risk Factors Paralytic use Type of Surgery Cardiac Obstetrics (GA for C/S) Trauma Poor Machine Maintenance Patient Factors Age Gender Substance Use/Abuse Underlying medical Condition Drugs Used Nitrous, Ketamine, Xenon, TIVA Less Problematic with inhaled AA


Kidney: Kidney Kidney Dose dependant decreases in: Renal blood flow GFR Urine Output Related to changes in Cardiac Output and BP not ADH


Kidney: Kidney Some agents (enflurane, sevoflurane) can be toxic due to F- production during metabolism in liver or in the kidney Fluoride nephrotoxicity Sevoflurane produces Compound A which is a renal toxin Not known in humans Anesthetized patients are heavily dependent on renin - angiotensin system to regulate volume status


Liver: Liver Hepatic blood flow decreased Drug metabolism is altered (slowed) Some agents are potentially hepatotoxic Most agents cause a transient increase in LFT’s Cause is unknown Hypoxia? Reactive intermediates?


Other Organs: Other Organs Muscle Potentate NMBA Skeletal Muscle is relaxed by inhaled AA MH? Fat Gut Endocrine


Obstetrics: Obstetrics Nitrous Oxide little effect acutely Halogenated inhaled AA Dose Dependent Uterine relaxation Decreased Uterine blood flow


Metabolism: Metabolism


Toxicity - Hepatitis: Toxicity - Hepatitis Reported since first use of halogenated anesthetics Most common cause of post operative jaundice is hematoma resorbtion “Halothane hepatitis” was reported very shortly after anesthetic introduced Incidence 1:10 000 with halothane Usually requires multiple exposures Most patients given halothane have evidence of liver injury Not as common with newer anesthetic agents One confirmed case with isoflurane Two case reports with desflurane – some suspect Many with Sevoflurane Hepatitis and Pancreatitis are known complications of surgery estimated rate ca. 1: 1 000 000


Hepatic Toxicity: Hepatic Toxicity All inhaled AA can cause hepatic injury in animal studies All inhaled AA have immunohistochemical evidence of binding to hepatocytes Thought that Trifluoroacetic acid metabolites are root cause Njoku, Anest Analg 1997; 84:173.


Hepatic Toxicity: Hepatic Toxicity


Toxicity – Malignant Hyperthermia: Toxicity – Malignant Hyperthermia AD genetic condition with variable penetrance producing a myopathy Most patients are aware of family history of condition More common Europeans (northern) Multiple genes are involved Incidence is 1: 4200-250000 anesthetics Some patients can receive triggering agents and have no reaction – case reports of up to six exposures prior to MH reaction Reactions tend to occur at extremes of age In some cases, a rise in Cpk following anesthesia is the only symptom of condition MH reaction can be caused by other conditions than inhaled anesthetics Stress Succinyl choline


Toxicity – Malignant Hyperthermia: Toxicity – Malignant Hyperthermia Genes are involved in intracellular Ca regulation Ryanodyne receptor (dihydropyridine receptor) called RYR1 is thought to be most commonlyinvolved Over 90 mutations known and associated with MH Uncontrolled muscle contraction results from exposure to trigger causing hyper metabolism and skeletal muscle necrosis Resultant rhabdomyolysis causes renal failure Hyperthermia can also cause direct tissue damage Treatment is active cooling of patient and dantrolene (2 mg/Kg doses q 15 minutes up to 10-12 mg/kg)


Fluoride Nephrotoxicty: Fluoride Nephrotoxicty F- is nephrotoxic F- is a byproduct of metabolism in liver and kidney Fluoride nephrotoxicity [F-] = 50 mol/l F- opposes ADH leading to polyuria methoxyflurane 2.5 MAC-hours (no longer used) enflurane 9.6 MAC-hours Methoxy > enfl > sevo >>> iso >des Results in potentially permanent renal injury Less of a problem with modern anesthetics


Toxins – Sevoflurane and Compound A: Toxins – Sevoflurane and Compound A Sevoflurane reacts with soda lime used in anesthetic circuit to form “compound A” fluoromethyl-2-2-difluoro-1-(trifluoromethyl) vinyl ether Some reports of fires and explosions Compound A is renal toxin Large amounts are produced at low gas flow rates Recommended 2 L / min flow rate Little evidence of harm unless Low flows Long exposure Some evidence for changes in markers of damage but not clinically significant


Anesthetics and CO: Anesthetics and CO All anesthetic agents react with soda lime to produce CO CO is toxic and binds to Hgb in preference to oxygen Des > enfl >>> iso > sevo >halo Risk Factors Dryness of soda lime Temperature of soda lime Fi(agent) Barylime produces more than soda lime Barylime removed from market In general, not clinically significant No deaths reported Do you want your anesthetic first Monday morning?


Toxicities – Nitrous Oxide: Toxicities – Nitrous Oxide Hematologic: N2O antagonizes B12 metabolism inhibition of methionine-synthetase Decreased DNA production RBC production depressed post a 2 h N2O exposure ca. 12 later Leukocyte production depressed if > 12 h exposure Megoloblastic anemia Marked depression if exposure longer than 24 hours


Toxicities – Nitrous Oxide: Toxicities – Nitrous Oxide Neurologic Long term exposure to N2O (vets, dentists and assistants) is hypothesized to result in neurologic disease similar to B12 deficiency Evidence only shows an association Increased risk of spontaneous abortion in dental/vetrinarian and OR personel (RR 1.3) Teratogenic in rats (prolonged exposure of weeks)


Other Toxicity Issues: Other Toxicity Issues Reproduction Increased miscarriage rate in pregnant patients given GA Related to underlying medical condition responsible for need for surgery Low birth rate Getting and staying pregnant (veterinary and dental workers less for OR personnel) Teratogenicity No evidence that the halogenated agents N2O is suspect risk but not proven in human studies Carcinogenicity OR, dental and vet personnel have increased rates of cancer (1.3-1.9 increase in rate in dental workers) But studies have been negative for AA as cause


Isoflurane: Isoflurane Cost = $60 / 250 mL Advantages Cheap Very soluble – slow to leave patient Cardio-protective Disadvantages Solubility – high residuals at end of case Requires more skill to use Risk of awareness May slow OR turnover Can’t be used for gas induction


Desflurane: Desflurane Cost $100 / 250 mL Advantages Insoluble Fast on off Easy to use Faster turnover of OR Low residual at end of case Faster PACU turnover Disadvantages Cost SNS stimulation (minor) Pollution of environment (minor) Can’t be used for gas induction CO production (not relevant)


Sevoflurane: Sevoflurane Cost $300 / 250 mL Advantages Can be used for gas induction Less SNS activation Cardio-protective Disadvantages Cost Solubility Compound A


Pharmacoeconomics: Pharmacoeconomics Cost per MAC Hour ($US) = {[agent] x FGF x (time) x MW x (cost/mL)}/ 2412 x (D) [concentration of agent] FGF = Fresh Gas Flow (L/min) Time in minutes MW = molecular weight Cost in US dollars 2412 fudge factor D = density of the agent in use Isoflurane 23 cents per mL Desflurane 41 cents per mL Sevoflurane 83 cents per mL


Pharmacoeconomics : Pharmacoeconomics


Pharmacoeconomics: Pharmacoeconomics Anesthesia is usually second most expensive department in hospital Volatile anesthetic agents ca. 20% of budget OR time is ~$2400 per hour Saved OR time needed to pay for bottle Sevoflurane (8 minutes) Desflurane (3 minutes) Isoflurane (<1 minute) Patient turnover in OR and PACU length of stay is a big issue for day surgery If a day surgery pt gets admitted cost is ~$1200 for overnight stay Waiting lists are affected by OR turnover and PACU time These factors need to be considered for agent choice


Pharmacoeconomics: Pharmacoeconomics Low flow anesthesia New machines Better monitoring required Most important factor to save inhaled agents Use of Circle – re-breathing gas circuits Agent switching during case Use isoflurane for most of case then switch to higher cost agent or switch to isoflurane Using IV agent to facilitate wake-up from isoflurane Agent Choice Length of Case


References: References Miller RD (ed.), Miller’s Anesthesia, Elsevier (Churchill – Livingstone), New York, 2005. Chapter 1 Chapters 4 to 9 Stoelting RK and Hillier SC, Pharmacology and Physiology in Anesthetic Practice, Lippincott Williams and Wilkins, New York, 2006, Chapter 2. Chernin EL, Pharmacoeconomics of Inhaled Anesthetic agents: Considerations for the Pharmacist, Am J Health-Sys Pharm 2004; 61(20):S18-22. Golembiewski J, Considerations in Selecting an Inhaled Anesthetic Agent: Case Studies. Am J Health-Sys Pharm 2004;61(20):S10-S17.


References: References Eger EI (II), Characteristics of anesthetic agents used for induction and maintenance of general anesthesia, Am J Healt-Sys Pharm 2004;61(20):S3-10. Odin I, Feiss P, Low flow and economics o f inhalational anesthesia, Best Pract Res Clin Anestheisol 2005, 19(3):399-413. Suttner S, Kumle B, Boldt J, Pharmacoeconomic Considerations in Anaesthetic Use, Expert Opin Pharmcother 2002; 3(9):1267. Whalen FX, Bacon DR, Smith HM, Inhaled Anesthetics: an historical overview, Best Pract Clin Anaesthesiol 2005; 19(3):323-30.