METABOLISM OF INHALED ANESTHETICS
Nonhalogenated Inhaled Anesthetics
Nitrous Oxide
Since the introduction of general anesthesia, a number of nonhalogenated
agents have been used as anesthetics (e.g., diethyl ether, ethylene, cyclopropane),
but only nitrous oxide (N2
O) remains in clinical use. This drug is not
metabolized in human tissue. However, in a physicochemical reaction of N2
O
with vitamin B12
, N2
O is reductively metabolized by rat and
human intestinal bacteria to molecular nitrogen (N2
).[28]
[29]
N2
O reduction in bacteria may occur
through a single electron transfer process that results in the formation of nitrogen
gas (N2
) and free radicals. The reaction between vitamin B12
and N2
O was first reported in 1968, but its clinical relevance was not
realized for 10 years.[30]
N2
O can oxidize
vitamin B12
and inhibit its coenzyme function. For example, this reaction
could affect the activity of methionine synthase, which catalyses the transmethylation
from methyltetrahydrofolate and homocysteine to produce tetrahydrofolate and methionine.
The inhibition of methionine synthase can lead to decreased levels of tetrahydrofolate
and methionine and subsequent impairment of DNA synthesis and "carbon 1" metabolic
reactions, including methylations. However,
such an effect on the activity of vitamin B12
probably is inconsequential
with the short courses of anesthesia using N2
O.
N2
O can induce hepatic enzyme after prolonged exposure
to unspecified concentrations of the drug.[31]
Conversely, continuous exposure of rats to 20% N2
O for 14 to 35 days inhibited
hepatic drug metabolism and induced pulmonary and testicular metabolism.[32]
Exposure of mice to as much as 50% N2
O for 4 hours per day for 14 weeks
did not affect hepatic content of cytochrome P450 or the defluorination of enflurane
or methoxyflurane.[33]
In another study, hexobarbital
sleeping time in rats, used as an indicator of drug metabolism, was unchanged after
exposure to 50% N2
O for 7 hours per day for 5 days.[34]
Xenon
The noble gases xenon, krypton, and argon are all chemically inert
under most circumstances, and all have anesthetic properties. Xenon is of particular
interest because it is the only inert gas that is an anesthetic under normobaric
conditions. Xenon was first identified as an anesthetic agent in 1951.[35]
Although not approved for clinical use, xenon has been submitted for regulatory
medical approval in Europe. Xenon is a normal constituent in atmospheric air at
a concentration no greater than 0.086 ppm and, unlike all other inhaled anesthetics,
is not an environmental pollutant. The gas cannot be manufactured but is recovered
in the process of fractional distillation of liquefied air, and after several separation
steps, a purity of more than 99.99% can be obtained. The cost of xenon is about
$10.00 (U.S.) per liter (i.e., 100 times more expensive than N2
O), and
it may be unlikely to enjoy widespread use due to the expense associated with its
extraction from air. If this problem could be overcome, xenon would be the most
ideal inhaled anesthetic agent, because xenon (minimum alveolar concentration [MAC]
= 71%) is more potent than N2
O, can provide surgical anesthesia in 30%
oxygen, is very insoluble (blood-gas partition coefficient = 0.14), and has positive
medical and environmental effects ( Table
8-1
). Xenon exhibits minimal cardiovascular and hemodynamic side effects,
is not known to be metabolized in the liver or kidney, is not teratogenic, and does
not trigger malignant hyperthermia in susceptible swine.[36]
Environmental positives are that xenon does not deplete stratospheric ozone nor
contribute to global warming and the greenhouse effect. The unique combination of
analgesia, hypnosis, and lack of cardiovascular depression in this one agent makes
xenon a very attractive choice for patients with limited cardiovascular reserve.
Xenon has a density of 5.887 g/L, whereas N2
O and air have densities
of 1.53 g/L and 1.00 g/L, respectively. Because of its greater density, xenon does
increase
pulmonary resistance,[37]
which increases the work
of breathing.[38]
Xenon should be used with caution
in patients with moderate to severe chronic obstructive pulmonary disease, the morbidly
obese, premature infants, and any other patient for whom an increase in the work
of breathing may have adverse effects.
Xenon was first used successfully for general anesthesia in human
volunteers and patients in the 1950s,[35]
[39]
was largely forgotten for 40 years, and rediscovered in 1990.[40]
Over the past decade, xenon has been intensely studied in Europe and Japan in a
number of clinical trials, with very promising results.[41]
[42]
[43]
Lachmann
and colleagues[40]
showed that patients anesthetized
with 70% xenon and 30% oxygen required 80% less supplemental fentanyl than a similar
group anesthetized with 70% N2
O and 30% oxygen. In a comparison of 30
American Society of Anesthesiologists (ASA) class I and class II patients undergoing
total abdominal hysterectomy and receiving 60% xenon, 60% N2
O with 0.5%
isoflurane, or 60% N2
O with 0.7% sevoflurane (all patients had epidurals
and received mepivacaine to control heart rate and blood pressure to within 20% of
baseline), Goto and coworkers[44]
found emergence
from xenon anesthesia was two to three times faster than either comparison group.
In a randomized, controlled, multicenter trial, a total of 224 patients from six
centers received 60% xenon in 40% oxygen or 60% N2
O in 0.5% isoflurane,
with 1 µg sufentanil given if indicated by defined criteria.[45]
This study demonstrated a significantly faster recovery from xenon anesthesia compared
with isoflurane-N2
O anesthesia. It is too early to know whether xenon
anesthesia improves clinical outcomes, particularly in high-risk patients, and justifies
the additional costs associated with its use in clinical anesthesia.
During xenon anesthesia, nitrogen released from the patient's
body accumulates in the anesthesia circuit. Consequently, it is necessary to perform
a prolonged denitrogenation before starting xenon to reduce the risk of hypoxia.
Another technical challenge lies in the transition from denitrogenation to closed-circuit
xenon anesthesia. The anesthesiologist could increase fresh gas flows (too expensive)
or add xenon to the circuit as oxygen is consumed by the patient. This second method
is too slow because patients typically consume only 200 to 250 mL of oxygen per minute.
Several investigators use a second anesthesia machine already primed with 4 L of
xenon. Xenon must be given using a rebreathing system, low fresh gas flow, or a
closed-circuit system. A closed-circuit system is the most economical technique
for the clinical use of xenon. In the study by Goto and coworkers[44]
from Japan, the estimated costs of providing anesthesia per patient were $170.00
for xenon ($17.00/L), $57.00 for isoflurane, and $60.00 for sevoflurane. These differences
in cost would be different in the United States (xenon = $10.00/L) and would become
progressively smaller with longer duration of anesthesia because the rate of xenon
consumption declines exponentially as body tissues become saturated in a closed rebreathing
system. The total yearly production of xenon is approximately 6 million liters or
enough for about 400,000 anesthetic procedures. If delivery systems become available
that allow for recycling of anesthetic gases, xenon anesthesia may become more economical
and available for selected patients who may benefit from its lack of adverse systemic
effects.
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