INHALED ANESTHETICS
From Advances in Anesthetic Practice, sponsored by Loma Linda University School of Medicine
Edmond I. Eger II, MD, Professor of Anesthesiology and Perioperative Care, University of California, San
Francisco, School of Medicine
| Introduction: anesthetics can have adverse or harmless effects on liver and kidney; inhaled anesthetics can
add to problems of administration of toxic substances (eg, carbon monoxide [CO]) to patient; may burst
into flame or explode; also may help in management of muscle relaxation; may protect or hurt brain,
breathing, and circulation
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| Anesthetic degradation by absorbents
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 | Moist absorbents: first anesthetics had obvious adverse effects (eg, nitrous oxide could produce hypoxia;
chloroform classic hepatotoxin); modern inhaled anesthetics fluorinated (also may be chlorinated,
brominated, or entirely halogenated with fluorine); progressive change produced benefits that include
decreased toxicity; chloroform and halothane can produce hepatic injury and death, but incidence
varies greatly (injury with halothane uncommon; death rare); metabolite of chloroform attacks
liver directly, whereas, metabolite of halothane may combine with hepatic proteins and attack liver;
neither halothane nor enflurane had initial reports of hepatic injury (first exposure to halothane only
sensitizing exposure; second or third exposure results in nephrotoxicity); unlike halothane, nephrotoxicity
with enflurane does not increase after 5 yr of usage despite repeated administrations; same
true for isoflurane; incidence of reported hepatic injury with desflurane and sevoflurane extremely
low (may not be connection between administration of drugs and appearance of hepatic injury); hepatic
injury with newer inhaled agents rare due to lack of chlorination (and increase in fluorination);
most newer anesthetics less metabolized (desflurane scarcely metabolized at all; sevoflurane metabolized
to hexafluoroisopropanol and does not attach to liver); methoxyflurane dropped from anesthetic
practice mainly due to possible renal injury (high local concentrations of fluoride in kidney);
sevoflurane not metabolized by kidney (therefore, not nephrotoxic)
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| Compound A: found to attack kidney in rat models; necrosis increases in dose-related manner, with
threshold of 200 ppm-hr in rats; renal injury can occur with sevoflurane given at low flow rate for
long period; isoflurane does not degrade in presence of normal absorbents; no evidence of renal injury;
package label for sevoflurane states that findings taken from patient and animal studies suggest
potential for renal injury, presumably due to compound A; sevoflurane exposure should not exceed 2
minimum alveolar concentration-hours (MAC-hr) at flow rates of 1 to <2 L/min (fresh gas flow rates
<1 L/min not recommended to protect against compound A)
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| Desiccated absorbents: use of high fresh gas flows and failure to turn off gas flow at termination of anesthesia
can cause desiccation of absorbent; can degrade sevoflurane to compound A, but also can cause
production of CO (even in desflurane and isoflurane; greatest concentrations found with desflurane);
degradation also can result in fires and explosions (rare; may cause patient injury); reports of fires and
explosions with sevoflurane interacting with barium hydroxide lime (Baralyme) resulted in change in
package label; any suspicion of desiccated absorbent should prompt change in absorbent or addition of
water to lower absorber; problem nonexistent currently because of elimination of Baralyme from market;
remaining absorbents less inclined to increase temperature
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| Neuromuscular effects: most take safety of neuromuscular blocking drugs for granted; more than half century
ago, Beecher and Todd reported that use of muscle relaxant could lead to 10-fold increase in mortality;
necessary to adequately reverse residual effect of drugs to avoid danger; all potent inhaled
anesthetics currently in use produce muscle relaxation (nitrous oxide does not) and augment effect of
muscle relaxant (adds to safety of muscle relaxants); median minutes to onset of malignant hyperthermia
(MH) longer with newer inhaled anesthetics than with halothane (halothane more potent trigger of MH
than isoflurane, desflurane, or sevoflurane)
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| Respiratory effects: at 2 MAC, desflurane and isoflurane irritate airway, whereas sevoflurane does not; pungency
of desflurane has resulted in package insert warning; desflurane should not be used for induction
of anesthesia in children because of possible laryngospasm and desaturation (instead use sevoflurane or
propofol, then convert to desflurane); at 1 MAC, potent inhaled anesthetics not pungent; subtle effects of
inhaled anesthetics on airway resistance; during maintenance of anesthesia, potent inhaled anesthetics affect
airway resistance minimally; also may cause respiratory depression and hypoxemia at time when
caregiver’s attention diverted; regaining airway control not possible until anesthesia level <0.1 MAC
(less soluble anesthetics eliminated more quickly)
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| Circulatory effects: avoid circulatory stimulation in patient with coronary artery disease (CAD); on induction
of anesthesia, change from 1 MAC to 1.5 MAC sevoflurane shown to decrease heart rate (HR);
same change with desflurane causes increase in HR for 5 to 10 min (no difference with maintenance of
anesthesia); initial stimulation may be exaggerated; minimize increase in HR and blood pressure by giving
opioid (eg, fentanyl, 100 µg); avoid cardiac response by maintaining desflurane level <6%, increasing
desflurane concentration slowly, or by giving opioid or other medications that deal with sympathetic
response; potent inhaled anesthetics also may increase safety of surgical experience by protecting ischemic
heart; mechanisms for protection parallel those underlying preconditioning; in rabbits subjected
to coronary artery occlusion, inhaled anesthetics (eg, isoflurane, halothane, and enflurane) given at 1.5
MAC before and during experimental occlusion significantly decrease area of myocardium infarcted;
studies also found inhaled anesthetics protect myocardium of animals after period of hypoxia; another
study anesthetized rabbits with intravenous (IV) anesthetics, then subjected animals for 30 min of 1
MAC desflurane, isoflurane, or sevoflurane, or IV anesthetic alone followed by 30-min period of washout;
coronary artery then occluded; found that desflurane (more than sevoflurane) significantly decreases
area of myocardium infarcted; human studies also find desflurane (and sevoflurane) preconditioning protects
myocardium
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| Brain-protective effects: sevoflurane can cause epileptiform activity and convulsions (not reported with desflurane
or isoflurane); no obvious harm comes from such increases in cerebral activity; all potent inhaled
anesthetics plus xenon can protect ischemic brain; Kawaguchi found that protective effect in animals
may not last beyond first several days after occlusion of middle cerebral artery; in humans, relative to
thiopental, desflurane sustains cerebral oxygenation during cerebral artery clipping; relative to etomidate,
desflurane may provide greater cerebral protection 3 to 5 days after hypoxia (35 min of middle cerebral
artery occlusion); suggests that potent inhaled anesthetic protective relative to IV anesthetic
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| Renal effects: inhaled anesthetics protect against renal hypoxia; some mechanisms probably same as those
that underlie preconditioning of heart; study found desflurane least protective of all inhaled anesthetics,
particularly at 1 day after hypoxic experience (all inhaled anesthetics more protective than IV anesthetics)
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| Summary: inhaled anesthetics both hurt and protect patient; previous anesthetics caused hepatic injury, but
hepatic injury no longer issue; renal injury may be produced by older anesthetics, but no longer issue
with current anesthetics (particularly isoflurane, sevoflurane, and desflurane); inhaled anesthetics augment
effect of muscle relaxants and help to reduce residual paralysis; problems with fire and explosions
greatly reduced; convulsions with sevoflurane minor concern at most; sevoflurane, halothane, and desflurane
protect brain; inhaled anesthetics can irritate airway and cause oxyhemoglobin desaturation in
children; desflurane allows more rapid return of protective airway reflexes than other potent inhaled anesthetics;
circulatory stimulation can occur with desflurane (may provide best protection for heart)
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Educational Objectives
| The goal of this program is to educate the listener about inhaled anesthetics. After hearing and assimilating
this program, the participant will be better able to:
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| 1. Review anesthetic degradation by absorbents and associated problems, including renal injury and
fires.
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| 2. Discuss dangers consequent to neuromuscular blockade.
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| 3. Describe positive and negative respiratory effects.
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| 4. Illustrate the cardioprotective effects.
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| 5. Examine the neuroprotective effects.
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Discussed on This Program
Chloroform
Desflurane [Suprane]
Disulfiram [Antabuse]
Enflurane [Ethrane]
Etomidate [Amidate]
Halothane [Fluothane]
Isoflurane [Forane]
Ketamine HCl [Ketalar]
Methoxyflurane [Penthrane]
Nitrous oxide (N2 O)
Phenobarbital [Bellatal, Luminal Sodium, Solfoton]
Sevoflurane [Ultane]
Thiopental sodium [Pentothal]
Vecuronium bromide [Norcuron]
Xenon Xe 133 [MPI Xenon Xe 133 Gas, Xenon Xe 133-V.S.S.]
Xylazine hydrochloride [Rompun]
Suggested Reading
Beecher HK et al: A study of the deaths associated with anesthesia and surgery: based on a study of 599, 548
anesthesias in ten institutions 1948-1952, inclusive. Ann Surg 140:2, 1954; Conzen PF et al: Low-flow sevoflurane
compared with low-flow isoflurane anesthesia in patients with stable renal insufficiency. Anesthesiology
97:578, 2002; Ebel D et al: Role of tyrosine kinase in desflurane-induced preconditioning.
Anesthesiology 100:555, 2004; Eger EI 2nd et al: Nephrotoxicity of sevoflurane versus desflurane anesthesia
in volunteers. Anesth Analg 84:160, 1997; Eger EI 3rd: Stability of I-653 in soda lime. Anesth Analg 66:983,
1987; Goff MJ et al: Absence of bronchodilation during desflurane anesthesia: a comparison to sevoflurane
and thiopental. Anesthesiology 93:404, 2000; Higuchi H et al: Effects of sevoflurane and isoflurane on renal
function and on possible markers of nephrotoxicity. Anesthesiology 89:307, 1998; Hoffman WE et al: Comparison
of the effect of etomidate and desflurane on brain tissue gases and pH during prolonged middle cerebral
artery occlusion. Anesthesiology 88:1188, 1998; Hoffman WE et al: Thiopental and desflurane
treatment for brain protection. Neurosurgery 43:1050, 1998; Holak EJ et al: Carbon monoxide production
from sevoflurane breakdown: modeling of exposures under clinical conditions. Anesth Analg 96:757, 2003;
Kharasch ED et al: Long-duration low-flow sevoflurane and isoflurane effects on postoperative renal and
hepatic function. Anesth Analg 93:1511, 2001; McKay RE et al: Airway reflexes return more rapidly after
desflurane anesthesia than after sevoflurane anesthesia. Anesth Analg 100:697, 2005; Piriou V et al: Pharmacological
preconditioning: comparison of desflurane, sevoflurane, isoflurane and halothane in rabbit myocardium.
Br J Anaesth 89:486, 2002; Preckel B et al: Beneficial effects of sevoflurane and desflurane against
myocardial reperfusion injury after cardioplegic arrest. Can J Anaesth 46:1076, 1999; Saidman LJ et al:
Safety of low-flow sevoflurane anesthesia in patients with chronically impaired renal function is not
proven. Anesthesiology 99:752; author reply 752, 2003; Sundman E et al: Pharyngeal function and airway
protection during Subhypnotic concentrations of propofol, isoflurane, and sevoflurane. Anesthesiology
95:1125, 2001; Wu J et al: Spontaneous ignition, explosion, and fire with sevoflurane and barium hydroxide
lime. Anesthesiology 101:534, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any
significant financial relationship with the manufacturer or provider of any commercial product or service
discussed. The following has been disclosed: Dr Eger is a paid consultant to Baxter International Inc.
Dr. Eger was recorded at Advances in Anesthetic Practice, presented February 19-23, 2005, by Loma Linda University
School of Medicine and held in Rancho Mirage, California. The Audio-Digest Foundation thanks Dr. Eger and
the sponsor for their cooperation in the production of this program.
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