Passing Gas A Primer on Inhaled Anesthetic Agents

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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

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Outline

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

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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

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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

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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

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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

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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 1940s
• Current regulations mandate that a physician is
  present during surgery to look after the safety
  and wellbeing of the patient

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History
9
History
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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

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MAC
12
MAC
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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

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MAC
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Mechanism of Action

• We dont know much, but let me tell you about
  what we do know

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Meyer Overton Rule

• Anesthetic potency correlates with lipid
  solubility
• Holds true across species
• Implies when a specific hydrophobic region is
  occupied anesthesia results

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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

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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 doesnt 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 doesnt seem to be true

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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

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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

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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.

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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 2002971609.
• Molecular and Neuronal Substrates for General
  Anaesthetics. Rudolph U, Antkowiak B, Nature
  Reviews Neuroscience 20045709.
• Emerging Molecular Mechanisms of General
  Anesthetic Action. Hemmings HC et al., Trends in
  Pharmacological Sciences 20056503.
• a5GABAA Receptors Mediate the Amnestic but Not
  Sedative-Hypnotic Effects of the General
  Anesthetic Etomidate. Cheng VY et al., Journal of
  Neuroscience 2006263713.

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Pharmacology

• Uptake
• Pharmacokinetics
• Physiologic effects
• Metabolism
• Toxicity

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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

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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

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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

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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

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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

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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 78618

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Uptake
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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

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Tissue Group Characteristics
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Partition Coefficients
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Waking Up

• Agent used
• Length of anesthetic
• Patient
• Age
• Mental state (MR, Alzheimer's)
• Medical condition (sepsis, Parkinsons)
• 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

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Waking Up in OR
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Waking Up Complex Tasks
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Waking Up Level of MAC
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CVS

• Heart Rate
• Halthane reduces HR
• Sevo and Enf are neutral
• Des gtgt 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

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CVS

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

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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

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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 ?gkg-1
• isoflurane 6.9 ?gkg-1
• enflurane 10.9 ?gkg-1

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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

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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

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Respiratory

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

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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

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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

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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

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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

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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

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Kidney

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

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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

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Liver

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

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Other Organs

• Muscle
• Potentate NMBA
• Skeletal Muscle is relaxed by inhaled AA
• MH?
• Fat
• Gut
• Endocrine

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Obstetrics

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

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Metabolism
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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 110 000 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

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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 84173.

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Hepatic Toxicity
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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

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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)

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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 gt enfl gt sevo gtgtgt iso gtdes
• Results in potentially permanent renal injury
• Less of a problem with modern anesthetics

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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

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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 gt enfl gtgtgt iso gt sevo gthalo
• 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?

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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 gt 12 h exposure
• Megoloblastic anemia
• Marked depression if exposure longer than 24
  hours

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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)

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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

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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
• Cant be used for gas induction

70
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)
• Cant be used for gas induction
• CO production (not relevant)

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Sevoflurane

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

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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

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Pharmacoeconomics
74
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 (lt1 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

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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

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References

• Miller RD (ed.), Millers 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 200461(20)S10-S17.

77
References

• Eger EI (II), Characteristics of anesthetic
  agents used for induction and maintenance of
  general anesthesia, Am J Healt-Sys Pharm
  200461(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.