Inhaled Anesthetic Agents

Educational Objectives

The goal of this program is to improve the awareness of the history of inhaled anesthetics as well as improve the understanding of current practice involving the use of inhaled anesthetics. After hearing and assimilating this program, the clinician will be better able to:

1. Discuss the history of inhaled anesthetics.
2. Describe the mechanisms of action of modern inhaled anesthetics.
3. Identify the comparative differences in pharmacokinetics and pharmacodynamics of modern inhaled anesthetics.
4. Explain occupational safety in the use of inhaled anesthetics.

Summary

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History

Before inhaled anesthetics: several techniques to establish analgesia, if not anesthesia, for rudimentary surgeries; would be inefficacious, dangerous, or barbaric today; performing surgery swiftly with only nerve compression by surgeon or patient, or application of ice or snow to provide analgesia evolved into pharmacologic treatments with various plant extracts, including black nightshade, mandragora, and poppy seeds with or without ethanol

Inhaled anesthetics: era of inhaled anesthetics began with synthesis of diethyl ether; description of process dates back as early as 8th century; in 16th century, Paracelsus, observed and documented anesthetic effect of ether on chickens, but not enough to bring into clinical use; recreational ingestion or inhalation of ether practiced for nearly 3 centuries after Paracelsus’s work; nitrous oxide (N₂O) discovered in 1773 by Joseph Priestley, later documented by Humphry Davy, who coined name laughing gas, described euphoric effect; N₂O swept into recreational substance category for >1 century; ether revisited by William Clarke in 1842; first documented use of inhaled anesthetic; also in 1842, Crawford W. Long demonstrated small-tumor resection on patient anesthetized with diethyl ether, captured public’s attention; attempts at demonstrating ether’s anesthetic capacity followed; in 1846, Massachusetts General Hospital, Sir William Morton anesthetized patient for facial vascular lesion; regarded as beginning of modern anesthetic evolution; other discoveries followed (eg, chloroform, between 1831 and 1847, used during Queen Victoria’s labor

Flammable anesthetics: era of flammable anesthetics (eg, ether, ethyl chloride, cyclopropane) influenced blast chamber–like construction of operating rooms (ORs) and taught lesson in static electricity buildup; discontinued with advent of fluorinated hydrocarbon anesthetics, starting with most recently abandoned halothane; gave way to fluorinated alkene anesthetics

Pharmacology

Mechanisms of action (MOA): many theories on MOA of inhaled anesthetics, still mystery despite >150 years of use in OR; in early 1900s, Meyer and Overton made discovery noting that anesthetic potency directly proportional to lipid solubility; postulated that once certain saturation of neuron cell membrane (lipid bilayer) with anesthetic occurs, causes cessation in signal transmission; exceptions to rule found that certain substances predicted to have anesthetic properties inert, because of difference in size, polarity, or rigidity of molecule; theory became obsolete

Current thought: modern molecular data appeared at end of 20th and into 21st century; gamma-aminobutyric acid (GABA) and glycine receptors — common inhaled anesthetics, except N₂O, appear to enhance activity of GABA and glycine receptors; both receptors responsible for inhibitory signaling; GABA in the CNS, possibly reason behind angiolysis, sedation, amnesia, myorelaxation, and anticonvulsant action similar to GABA effects seen with barbiturates, benzodiazepines, and propofol; glycine receptors postulated as cause of inhibitory spinal cord effects of volatile anesthetics; activation of both receptors results in cell hyperpolarization and inhibition of signal transmission; excitatory glutamate receptors — inhibition of these receptors, notably N-methyl-d-aspartate (NMDA) receptors seen with halogenated alkene type anesthetics (eg, isoflurane, sevoflurane, desflurane) and with N₂O, xenon, cyclopropane, and other exotic anesthetics; seems to indicate common link where inhaled anesthetic may impart effect; anesthetics and compounds called nonimmobilizers (compounds that produce anesthetic effects without immobility) highlighted importance of acetylcholine receptors, excitatory nicotinic receptors implicated in memory formation and learning; direct interaction with protein structure of ion channel (eg, calcium, sodium, potassium) seen with various anesthetics possibly explains effect of negative chronotropic and inotropic effect on heart in addition to anesthetic properties; in contrast, N₂O has no effect on calcium and potassium channels and provides anesthesia with no cardiac depression; no definitive evidence singles out MOA of inhaled anesthetics; cannot explain how inhaled anesthetics function with 1 receptor or ligand mechanism, can only theorize

Potency: more lipid-soluble inhaled anesthetics generally more potent; to quantify and compare various inhaled anesthetics, concept of minimal alveolar concentration (MAC); MAC — originally defined as alveolar concentration of agent at 1 atmosphere of ambient pressure required to produce immobility in 50% of patients exposed to noxious stimulus (usually defined as skin incision in humans); analogous to ED₅₀ concentration when comparing intravenous (IV) drugs; MAC values of common anesthetics — halothane 0.75%, enflurane 1.63%, isoflurane 1.17%, sevoflurane 2.2%, desflurane 6.6%, N₂O 104%, xenon 63%; values obtained without using additional medications commonly supplemented in anesthetic practice (eg, anxiolytics, analgesics); if clinician desires only to establish amnesia, value of 0.5 MAC, or half concentration needed for immobility, usually sufficient; since inception of MAC concept, other derivatives, such as MAC₉₅, equivalent to ED₉₅, translates to approximately 1.3 times original MAC value; MAC awake, meaning 50% of subjects open eyes to command exists somewhere between 0.15 MAC and 0.5 MAC, value exhibits significant hysteresis; other variations exist (eg, MAC values associated with blocking sympathetic response) not necessary to memorize; seldom rely on inhaled anesthetics alone for sympathetic control; MAC values additive; half of MAC of 1 anesthetic added to half MAC of another produces effect equivalent to 1 MAC of anesthetic; allows clinicians to supplement weaker anesthetic, more favorable side effect profile in some cases; N₂O alone only provides ≤0.07 MAC of anesthesia; usually needs to be accompanied by potent inhalational agent to deepen anesthetic plane without creation of hypoxic mixture, but doing so lowers exposure of patient to volatile anesthetic, possibly advantage on each gas under specific clinical conditions; factors affecting MAC values — many factors make patients more resistant to anesthetic, effectively increasing MAC value, and vice versa; age major factor when dosing inhaled anesthetic, MAC values in textbooks derived from population in 40s; chronologically, MAC value highest at age ~1 yr, declines progressively at rate of ~6% per decade; would expect same effect of 2.8% sevoflurane on 1-yr-old as 2.2% on 40-yr-old and 1.7% on 80-yr-old; modern anesthetic machines calculate adjustment of MAC value if patient age entered; factors that increase MAC, necessitating higher dose for same effect — increased excitatory neurotransmitter concentrations caused by monoamine oxidase inhibitors (MAOIs), acute amphetamine or cocaine ingestion, administration of ephedrine or levodopa; patients with hypermetabolic states, hyperthermia, hypernatremia, or chronic alcohol abuse also tend to have higher MAC values; redheads reported to have as much as 20% higher MAC values, suggests genetically based modulation of response; another genetic factor reported with sevoflurane with lower MAC values of 1.6 to 1.8 in early Japanese studies, but probably not clinically significant, regarded as controversial; factors that decrease MAC value, make patients more susceptible to volatile anesthetics — some factors exploited in OR daily to supplement inhaled anesthesia; advanced age, hypoxia, hypercarbia, and acidemia, as well as decreased excitatory neurotransmitter levels caused by reserpine administration or chronic amphetamine use, administration of alpha-2 agonists (eg, clonidine, dexmedetomidine), hypothermia hyponatremia, administration of lithium, acute ethanol ingestion; opioids, barbiturates, benzodiazepines, and IV local anesthetics lower MAC; obstetric practitioners noted that high progesterone levels as seen in pregnancy can decrease MAC by as much as 25% to 40%, allowing use of nitric oxide, which does not impart uterine contraction during cesarean delivery, with minimal supplementation of other volatile anesthetics; thyroid dysfunction has no significant effect on MAC value

Pharmacokinetics of common anesthetics: several values complement MAC, illustrate how anesthetics behave during induction or emergence, how they accumulate within tissues and their kinetics within vaporizer

Vapor pressure: inversely related to boiling point, value used to derive bypass flow of specific vaporizer or how much fresh gas required for mixing with saturated anesthetic vapor to arrive at appropriate blend selected on dial; vaporizers for agents with similar boiling points and vapor pressures can be used interchangeably without significant loss of calibration (but clinically seldom done); vapor pressures of sevoflurane and now-discontinued enflurane 157 mm Hg and 172 mm Hg, respectively; isoflurane and now-defunct halothane have vapor pressures of 238 mm Hg and 243 mm Hg, respectively; despite that internal workings of vaporizers in each pair similar enough to be interchangeable, accidental or intentional vaporizer cross-filling reason to take vaporizer out of use and have serviced as soon as practical; modern vaporizers employ safeguards to prevent inappropriate filler from engaging wrong anesthetic bottle and fillers unique to respective vaporizer systems; desflurane, with high vapor pressure of 669 mm Hg and low boiling point of 24°C, has its own unique vaporizer that heats up and pressurizes desflurane to ensure uniform output; remaining 2 anesthetics, N₂O and xenon, exist only as gases under normal temperature and pressure conditions; N₂O liquified under modest pressure of 750 psi, stored this way in pressure vessels; partial pressure of anesthetic driving force for anesthetic diffusion from liquid to gas phase in vaporizer, from alveolar air to bloodstream, then to target organ (ie, brain and spinal cord in) and nontarget tissue (eg, fat, muscle); partial pressure equilibration between alveolar air and brain results in onset of anesthesia; time required to achieve influences rapidity of induction; starting with higher partial pressure of anesthetic produces higher gradient for anesthetic concentration equilibration, speeds up induction; increasing output of vaporizer or minute ventilation both result in this effect, more pronounced with anesthetics that ordinarily have slow induction times

Distribution: conventionally thought that anesthetic gas distributed from alveoli to several compartments within human body, behavior predicted using multicompartment distribution model; compartments commonly considered — vessel-rich group comprised of brain, heart, liver and kidneys (10% of body mass, receives 75% of blood flow(; muscle group ( 50% of body mass, receives 20% of cardiac output); fat compartment (20% of body weight, receives only 6% of cardiac output) 

Partition coefficients: partition coefficients of anesthetics between blood and specific tissue or substance describe behavior of inhaled anesthetic within compartments, simply ratio of anesthetic quantity on both sides of blood to tissue interface once partial pressure at equilibrium; oil-gas partition coefficient — another term for lipid solubility; predicts MAC value of anesthetic according to Meyer-Overton rule; coefficient blood-gas partition coefficient — describes how anesthetic will equilibrate between alveolar gas and pulmonary capillary blood flow; higher blood-gas partition coefficient, more soluble agent in blood; when anesthetic gas delivered into alveoli through spontaneous or controlled ventilation, taken up by first compartment (blood), diminishing alveolar concentration and slowing induction; more blood-soluble anesthetics have slower induction because blood absorption decreases rate of rise of alveolar concentration of anesthetic gas, prolonging time to build up necessary partial pressure of anesthetic in alveoli

Solubility coefficients of modern inhaled anesthetic in blood (in ascending order): desflurane 0.42, N₂O 0.46, sevoflurane 0.65, isoflurane 1.46; reasonable to expect inductions with N₂O and desflurane to occur faster under similar conditions because of low blood solubility; as anesthetic delivered to brain and rest of vessel rich compartment from alveolar gas via bloodstream, anesthetic depth increased, vessel-poor groups (muscle and fat) lag behind in saturation with anesthetic gas; in course of steady-state anesthesia when vessel rich group at equilibrium with alveolar air, compartments continue to equilibrate until partial pressure gradient ceases to exist for each separate compartment; not important during short anesthetic cases because no significant accumulation of anesthetic in vessel-poor tissues to prolong emergence from anesthesia when gradient reversed; anesthetics egress from brain through circulation and into alveolar gas to be exhaled

Contact-sensitive half-time: phenomenon that occurs with prolonged exposure to fat- and muscle-soluble anesthetics;, if 2 patients provided same depth of anesthesia for different durations, patient with longer exposure will require longer time to emerge from anesthesia due to saturation of vessel-poor compartments, effectively experiencing longer half-time of agent; comparative blood-fat solubility (from lowest to highest) — N₂O 2.3, 10-fold lower than desflurane, 27; isoflurane 45, sevoflurane 48; prolonged anesthesia with sevoflurane and isoflurane results in more significant accumulation of agent, may cause prolonged elimination time; muscle-to-blood solubilities do not vary dramatically, follow same hierarchy, difference from lowest, N₂O, to highest, sevoflurane, only 2.5-fold, solubility in muscle compartment of all agents 10- to 20-fold lower than in fat, decreasing importance of muscle compartment on contact-sensitive half-time

Other factors: effects of ventilation rate, variations in cardiac output, concentration effect and second gas effect; increase in ventilation provides more rapid equilibration between alveolar and inspired concentrations of anesthetic (also known as FA:FI ratio); faster equilibrium due to increased ventilation more pronounced in gases more absorbed by blood (eg, isoflurane, sevoflurane); blood carrying anesthetic away from alveoli, diminishing alveolar concentration and slowing rate at which alveolar concentration rises; more blood-soluble anesthetics affected to greater extent by variations in cardiac output, noticeably faster induction in setting of low cardiac output; higher cardiac output means more anesthetic carried away from alveoli, alveolar concentration rises more slowly, causes prolonged time to build up sufficient partial pressure of anesthetic in alveoli; effect more pronounced with blood-soluble anesthetics (eg, isoflurane, sevoflurane)

Concentration effect: another concept related to rate of rise of alveolar concentration of anesthetic as influenced by inhaled anesthetic concentration; when constant proportion of anesthetic absorbed by blood, higher inspired anesthetic concentration will yield greater concentration of gas in alveolar air after absorption occurs; N₂O has partition coefficient of 0.47, so from breath of 35% N₂O in O₂ mixture, 11 parts of N₂O will be absorbed and 24 left behind for effective alveolar concentration of 24/89, or 27%; if 70% N₂O in O₂ administered, same proportion, or 22 parts, of N₂O will be absorbed, 48 parts will remain in alveoli, and result on alveolar concentration will be 48/78 parts, or 61.5%; alveolar concentration appears to increase disproportionately with doubled inspired concentration of anesthetic

Second gas effect: tightly related to concentration effect; phenomenon of apparent increase in concentration of volatile anesthetic when accompanied by another gas rapidly taken up from alveolar gas mix; consider 1% mixture of volatile anesthetic with 70% N₂O and O₂ in balance; with rapid absorption of 50% nitric oxide from gas mixture, which would equal 35 parts, and assuming negligible absorption of other gases, new concentration of volatile anesthetic, 1/29 parts O₂ and 35 parts N₂O or 1/65 or 0.015 parts, or 1.5%; if missing volume left over from absorption of 35 parts of N₂O replaced with original fresh gas mixture described above, proportionately adding 0.35 parts potent volatile agent, 24.5 parts N₂O and 10.15 parts O₂, final concentration of potent volatile anesthetic in alveolus still 1.35%, significantly higher than fresh gas delivered to patient; for second gas effect to be clinically significant, gas mixture must contain large fraction of rapidly absorbed gas that creates rise in concentration of potent inhaled anesthetic; aside from N₂O, no other gases included in anesthetic mixture in high-enough concentrations to create second gas effect, as volatile anesthetics have MAC values of ≤6%, absorption does not appreciably disturb balance of alveolar gas; absorption of O₂ from alveolar gas comparatively insignificant to proportion delivered to alveoli during semiopen-circuit anesthetic deliveries that comprise majority of anesthesia practices

N₂O: although N₂O one of most insoluble anesthetics, absorption by absolute volume not insignificant, because of high MAC value, therefore high inspiratory concentration necessary for clinical effect; solubility constant of N₂O (0.46) 30-fold higher than nitrogen’s blood-gas partition coefficient (0.015), so theoretical air-space chamber in body of patient exposed to 50% inspired N₂O concentration will rapidly equilibrate to nitrous partial pressure and double in size before nitrogen can equilibrate out; 75% N₂O inhalation will quadruple size of air chamber, as final concentration will have to match 75%; clinically significant in enclosed spaces during middle-ear or retinal surgery, where increase in volume or pressure of air bubble highly undesirable; gastrointestinal (GI) surgery can be impeded by distending of gas-filled bowel; pneumothoraces may expand to potentially double or triple in size as well as air filled cuffs in endotracheal tubes or Swan-Ganz catheters; if patient recovering from N₂O anesthesia and placed on room air before anesthetic has chance to egress sufficiently, equilibration of partial pressure of N₂O between tissues and now room air in alveolus can pose problem; assume a patient still has partial pressure of N₂O equivalent to 30% and breathing spontaneously on room air, egressing N₂O will rapidly equilibrate with alveoli and new composition of alveolar gas will be 21 parts O₂, 79 parts nitrogen, and now 30 parts N₂O; final O₂ concentration then calculated at 21/130, or 16%; dilutional effect also affects concentration of carbon dioxide, lowering it, potentially decreasing respiratory drive and worsening hypoxia; recommended that all patients recovering from N₂O anesthesia receive 100% O₂ for first 5 mins to 10 mins, when outpouring of N₂O from tissues highest

Pharmacodynamics

Cardiac: all volatile anesthetics except N₂O and xenon produce dose-dependent decrease in blood pressure (BP); older agents like halothane and enflurane had negative inotropy as source of effect, not seen with modern anesthetics like sevoflurane, isoflurane, and desflurane (cause decrease in BP through decrease in systemic vascular resistance); N₂O produces either no change or only slight increase in BP; chronotropy, or heart-rate effects, variable among modern anesthetics; isoflurane and desflurane produce dose-dependent increase in heart rate, especially pronounced with rapidly uptitrated high doses of desflurane; N₂O and sevoflurane not associated with substantial changes in heart rate; myocardial contractility depression, seen with older agents (eg, halothane and enflurane), seen to lesser extent with isoflurane, sevoflurane, and desflurane (some argue effect no longer clinically significant); N₂O has slight sympathomimetic activity, increases cardiac contractility; isoflurane known to induce coronary artery vessel dilation, hypothesized to cause redistribution of coronary blood flow away from atherosclerotic areas to areas with normal coronaries (coronary steal syndrome; not validated in clinical practice); N₂O, desflurane, and sevoflurane weaker coronary artery vessel dilators than isoflurane; cardiac dysrhythmias induced with older agents particularly halothane), especially in combination with administration of catecholamines (eg, epinephrine); not seen with ether-based anesthetics, less pronounced in pediatric population

Respiratory: all agents, except sevoflurane and N₂O, respiratory irritants, not suitable for inhalational induction; halothane, potent anesthetic and bronchodilator, excellent choice for inhalational induction of reactive airway but no longer in clinical use; sevoflurane next best agent, relaxes smooth muscle as well and has pleasant smell; all inhaled anesthetics cause dose-dependent decrease in tidal volume and increase in respiratory rate; net result, decrease in minute ventilation and increase in PaCO₂ if patient allowed to breathe spontaneously; inhaled anesthetics also blunt respiratory response to hypoxia and hypercarbia via central nervous system (CNS) respiratory center depression and alteration of a carotid body response; impairment of response to hypoxia seen at subanesthetic doses as low as 0.1 MAC (factor to consider during postanesthetic care); N₂O increases pulmonary vascular resistance, especially in patients with preexisting pulmonary hypertension; all other inhalational agents may decrease pulmonary vascular resistance and blunt hypoxic pulmonary vasoconstriction reflex, potentially exacerbating shunting through nonventilated alveoli

CNS: all inhalational agents except N₂O exert similar effects on CNS; cerebral metabolic rate decreased in nonlinear fashion and to varying degrees when compared among anesthetics; cerebral blood flow increased in dose-dependent manner, resulting in uncoupling of supply and demand; increased cerebral blood flow thought to be clinically significant with older halothane, but modern anesthetics do so minimally at clinical doses; intracranial pressure (ICP) important in neurosurgical cases, halothane may be worst agent due to strong propensity to increase cerebral blood flow; hypercarbia associated with respiratory depression seen with all anesthetics further exacerbates phenomenon; when increase in ICP must be avoided, hyperventilation preinduction and use of modern inhalational agent warranted, pretreatment with barbiturate may lessen effect; pungency of desflurane and isoflurane may trigger coughing on induction and transient rise of ICP, some may argue sevoflurane better choice for avoidance of ICP spike; N₂O — seldom used alone in neurosurgery, weak anesthetic; when supplemented to another volatile agent, appears to cause cerebral vasodilation and increase in cerebral blood flow (but finding controversial); cerebral metabolic rate reports highly variable, with either minimal depression, no change, or increase in metabolic demand; always coadministered with another potent volatile agent, may be confounding variable behind variability of response; rat models of cerebral ischemia with N₂O and isoflurane anesthetic had worse outcomes than isoflurane alone, but translation to humans controversial; concern of expanding pneumocephalus (venous air embolus) in setting of craniotomy in sitting position with N₂O administration adds further argument against application in neurosurgery; benefits of N₂O in neurosurgery not sufficient to warrant attempts at use 

Hepatic: dual nature of blood supply to liver affected differently by various anesthetics; hepatic artery flow increased or maintained by modern anesthetics such as isoflurane, sevoflurane and desflurane; portal vein flow decreases to various extents; halothane decreased both arterial and venous flow, implicated in causing hepatitis, both via blood flow reduction as well as immune-mediated effects and metabolic byproducts of halothane degradation; more common reasons for jaundice than halothane hepatitis postanesthesia include viral hepatitis, malperfusion due to hypertension of sepsis, hemolysis, or other drug-induced hepatitides

Renal: dose-dependent decrease in renal blood flow, glomerular filtration rate (GFR), and urine output seen with all potent inhalational anesthetics; older anesthetic methoxyflurane metabolized to high extent in kidney, with resultant release of inorganic fluoride ion, causing occasional high-output renal failure; not seen with newer anesthetics metabolized to lesser extent; sevoflurane has unique interaction with renal system, capable of reacting with CO₂ absorber to form nephrotoxic haloalkene, compound A; production of compound A highest in setting of high sevoflurane concentration with calcium hydroxide and barium hydroxide (Baralyme) instead of soda lime absorber; desiccated absorbers increase CO₂ production in higher CO₂-absorber temperatures; low fresh gas flow decreases CO₂-absorber cooling, lowers dilutional washout of compound A from circle system; sevoflurane package insert recommends <2 MAC-hr of anesthesia at fresh gas flow rates of 1 L/min to 2 L/min, flows <1 L min not recommended

Neuromuscular: all ether-derived potent volatile anesthetics relax skeletal muscle directly and to greater extent than halothane due to direct inhibition of nicotinic acetylcholine receptor, also potentiate action of nondepolarizing neuromuscular blockers; N₂O does not relax skeletal muscle, may cause rigidity under hyperbaric conditions (effect that would seldom be seen in clinical practice); malignant hyperthermia (MH) — more potent inhalational agents appear to have greater ability to trigger MH, an autosomal dominant disorder of ryanodine receptor; all agents listed as unsafe in MH literature; N₂O generally regarded as safe, though minimally potentiates muscle contraction in MH-specific caffeine-induced contraction tests; scattered case reports of N₂O anesthesia triggering MH episode in setting of otherwise nontriggering agent exist, but stress may also be factor; given availability of excellent nontriggering IV anesthetics, use of N₂O may become unnecessary, but no ground to abandon use in MH-susceptible population based on clinical evidence so far; xenon inhalational agent also considered MH safe, can be considered in areas where available for clinical use

Hematologic: all volatile anesthetics degrade in presence of calcium hydroxide and barium hydroxide or soda lime to release CO; effect more pronounced with desiccated absorbers; desflurane releases CO most, followed by isoflurane, then sevoflurane; high CO₂-absorber temperature, calcium hydroxide and barium hydroxide over soda lime, and high anesthetic concentrations enhances CO formation; breakdown process of inhaled anesthetics exothermic reaction, combination of older, desiccated absorber with sevoflurane produces most heat, ≤300°C, and melting parts of circuit; good practice to turn off anesthetic machine at end of case and for prolonged downtime (overnight and weekends); if desiccated absorber situation discovered, replace with new absorber canister; newer CO₂ absorbers have less propensity to break down anesthetics to CO and compound A, exhibit less heat production; effects of N₂O on vitamin B₁₂ — another hematologic effect unique to N₂O, oxidation of cobalt 1 to cobalt 2 or cobalt 3 in vitamin B₁₂ molecule; irreversible process; prolonged or repetitive exposure can cause symptoms consistent with B₁₂deficiency, even in patients who had normal B₁₂ levels; case reports of patients developing megaloblastic anemia due to impairment of DNA synthesis pathway, or even subacute combined spinal cord degeneration due to inhibition and methionine synthase enzyme and demyelination of axons, have been reported both in clinical administration of N₂O and recreational use; when treated early and appropriately with cyanocobalamin (B₁₂), prognosis generally favorable, but making critical diagnosis challenging because of esoteric presentation of disease (anemia, ataxia, incontinence, dizziness, visual disturbances); if B₁₂ plasma level <125 pg/mL, clinical suspicion should be elevated and should guide treatment

Environmental Exposure

Exposure and toxicity: given toxicity of N₂O and evidence of detrimental effects of prolonged exposure to potent volatile anesthetic, Occupational Safety and Health Administration (OSHA) limits exposure of health care personnel to anesthetic contamination; when N₂O used as sole inhaled anesthetic, recommended exposure limit 25 ppm, measured as time-weighted average during period of anesthetic administration; also recommended that no worker be exposed to ceiling concentration >2 ppm for any halogenated anesthetic agent over sampling period not to exceed 1 hr; when N₂O and volatile anesthetics used together, maximal exposure 25 ppm and 0.5 ppm, respectively; achievement of goals relies on engineering controls (eg, properly functioning anesthetic scavenging system) and appropriate work practices to avoid spillage of agent and gas-mixture leakage from mask airway; testing done on administrative-control level to ensure proper function and compliance; fire risk pronounced with N₂O, a nonflammable gas by itself, but potent oxidizer, on par with molecular O₂, used in high enough concentration enhances chance of OR fire; fortunately, other inhaled anesthetics nonflammable

Xenon

Background: name comes from Greek word xenos, meaning foreign, strange, or guest; noble gas with heavy molecule, atomic number 54, atomic weight 131 for its most stable isotope; 4 times denser than air; only exists as gas under normal conditions; found in atmosphere at concentration of 87 ppb; considered trace element; not synthesized but distilled off during processing of raw air to extract O₂ and nitrogen as byproduct; virtually nonreactive with other elements; first use as anesthetic reported by Stuart Cullen, 1951; still far from widespread use

Anesthetic properties: MAC value 60%, blood-gas partition coefficient 0.115 (lowest among all current anesthetics); results in fast induction and emergence; nonflammable, does not support combustion; mechanism of action not entirely known; evidence that xenon inhibits plasma membrane calcium pump, altering excitability; xenon-driven CNS depression results in lower respiratory rate with compensatory increase in tidal volume, at high doses may lead to apnea; diffusion hypoxia mild, as blood gas partition of nitrogen (0.014) and xenon (0.115) more similar to each other rather than to N₂O, so diffusion occurs in more balanced manner; no apparent inhibitory effects on cardiac ion channels such as calcium, sodium, and potassium; causes no significant chronotropic or inotropic effects; does not affect systemic vascular resistance; no sensitization of myocardium to epinephrine; systemic effects — in CNS, xenon may increase cerebral blood flow, but magnitude of effect remains to be elucidated; no known liver or kidney toxicities, no hematologic disturbances reported when used at routine anesthetic level; not reported to trigger MH; advantages and disadvantages — environmentally friendly; derived from air and any loss in the atmosphere creates no personal hazard or contribution to greenhouse effect or pollution; expensive because of complex nature of extraction from air; thorough denitrogenation preinduction and use of circle system with excellent scavenging and recycling of anesthetic required; measurement of xenon levels generally difficult because diamagnetic, does not absorb infrared radiation; low reactivity precludes use of specific fuel cell or electrode-type device; mass spectrometry only way to detect reliably (expensive)

Readings

Eckenhoff RG: Promiscuous ligands and attractive cavities: how do the inhaled anesthetics work? Mol Interv. 2001;1(5):258-68; Robinson DH et al: Historical development of modern anesthesia. J Invest Surg. 2012;25(3):141-9; Sonner JM: A hypothesis on the origin and evolution of the response to inhaled anesthetics. Anesth Analg. 2008;107(3):849-54; Whalen FX et al: Inhaled anesthetics: an historical overview. Best Pract Res Clin Anaesthesiol. 2005;19(3):323-30.

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For this activity, the faculty and planning committee reported nothing to disclose.

Acknowledgements

CME/CE INFO

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