Current Status of Nitrous Oxide
Release Date: March 2007
Expiration Date: March 31, 2008
FA CULT Y
Edmond I Eger II, MD
ACCREDITATION STATEMENT(S)
Physician: This activity has been planned and implemented in accordance with the Essential
Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME)
through the joint sponsorship of AKH Inc. and Applied Clinical Education. AKH Inc. is accredited
by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this
educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should
only claim credit commensurate with the extent of their participation in the activity.
Pharmacy: AKH Inc. is accredited by the Accreditation Council for Pharmacy Education
(ACPE) as a provider of continuing pharmacy education. This program has been assigned
the Universal Program Number 077-999-07-009-H01 and is acceptable for 1.0 contact hour(s)
(0.1 CEU(s)).
Nurse Anesthetist: This program has been prior approved by the American Association of Nurse
Anesthetists for 1.0 CE credits; Code Number 29525; Expiration Date March 31, 2008.
TARGET AUDIENCE
This activity is intended for physicians, pharmacists, and nurse anesthetists.
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It is the policy of AKH Inc. to ensure independence, balance, objectivity, scientific rigor, and
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significant relationships with commercial interests whose products or devices may be mentioned
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ESTIMATED TIME OF COMPLETION
This activity should take approximately 60 minutes to complete.
METHOD OF PARTICIPATION
There are no fees for participating and receiving credit for this activity. The participant should, in
order, read the objectives and monograph, answer the multiple-choice post-test and complete the
registration and evaluation form. Participation is available online at CMEZone.com (availability may
be delayed from original print date). Enter the project number “SR650” in the keyword field to
directly access this activity and receive instantaneous participation. Or, complete the answer
sheet with registration and evaluation on page 8 and mail to: AKH Inc., P.O. Box 2187, Orange
Park, FL 32067-2187; or fax to (904) 215-0534. Statements of participation will be mailed/emailed in approximately 4 weeks after receipt of the mailed or faxed submissions. A score of at
least 80% is required to successfully complete this program. Retests are NOT available for
CRNAs. Other participants are allowed one retake. The corrected answer sheet will be provided
for comparison with course information. Credit is available through March 31, 2008.
This activity is made possible by an educational
grant from Baxter.
Jointly sponsored by AKH Inc. and Applied
Clinical Education.
Copyright © AKH Inc. 2007
Department of Anesthesia and
Perioperative Care
University of California at San
Francisco School of Medicine
San Francisco, California
Dr. Eger is a paid product consultant
and speaker for Baxter Healthcare
Corp.
Kirk Hogan, MD, JD
Department of Anesthesiology
University of Wisconsin Medical
School
Madison, Wisconsin
Dr. Hogan is a paid product consultant for Third Wave Technologies, Inc.
LEARNING OBJECTIVES
At the completion of this activity, participants should be able to:
1 List noxious effects of nitrous oxide
(N2O) anesthesia.
2 Discuss risks and benefits of N2O
compared with other inhaled anesthetics.
3 Review safety concerns, including
effects of N2O on vitamin B12 and
folate metabolism and the implications of these effects for selected
patients.
4 Relate N2O use patterns to the introduction of other inhaled anesthetics.
5 Identify clinical scenarios in which
N2O use is contraindicated.
DISCLAIMER
This course is designed solely to provide the
healthcare professional with information to
assist in his/her practice and professional
development and is not to be considered a diagnostic tool to replace professional advice or
treatment. The course serves as a general
guide to the healthcare professional, and therefore, cannot be considered as giving legal,
nursing, medical, or other professional advice in
specific cases. AKH Inc., the author(s), and the
publisher specifically disclaim responsibility for
any adverse consequences resulting directly or
indirectly from information in the course, undetected error, or reader’s misunderstanding of
the content.
Distribution Via:
Introduction
Newer anesthetics can supply most of the desirable properties of
nitrous oxide (N2O), properties previously considered to be unique. The
availability of these newer anesthetics combined with the limitations and
toxicities of N2O, may indicate that the use of N2O should be curtailed or
discontinued.
Several advantages of N2O prompted its continued use for more than
a century and a half. These included an absence of pungency, minimal
cardiorespiratory depression, low solubility and rapid kinetic changes,
low cost, minimal metabolism, and apparent freedom from toxicity after
routine clinical exposure. But several factors have decreased its use in
clinical practice (Figure 1), particularly an understanding of its negative
attributes and the capacity of newer potent inhaled anesthetics to provide its advantageous but not its deleterious effects. Some negative
attributes have long been known: a limited potency and a potential for
hypoxia at higher concentrations; untoward kinetics (expansion of internal gas spaces; diffusion hypoxia); and possible production of abortions.
Concern has heightened in the past decade regarding other diverse
effects: toxicity consequent to inactivation of methionine synthase combined with genetic, age, and nutritional factors promoting a deficit of
methionine synthase; a tendency to increase postoperative nausea; poor
amnestic properties; and a contribution to greenhouse gases. Replacing
N2O with newer, potent inhaled anesthetics of reduced solubility (ie, desflurane and sevoflurane) that supply most of the desirable attributes of
N2O, may also decrease equipment costs associated with anesthesia–but will require additional delivery of more expensive potent
inhaled anesthetics to compensate for the omission of the anesthetic
contribution by N2O.
Neutral Properties of N2O
Metabolism. N2O is the least metabolized inhaled anesthetic. Intestinal
bacteria degrade it trivially,1 and interaction of N2O with methionine synthase destroys an equally miniscule amount. However, although desflurane2 and sevoflurane3 undergo metabolic degradation (desflurane
0.02%; sevoflurane 5%), with one exception the metabolites (eg, inorganic fluoride, trifluoroacetic acid, and hexafluoroisoprpanol) are not toxic.
On rare occasions, trifluoroacetate from desflurane can produce an
immune hepatotoxic response.4
Degradation by Carbon Dioxide Absorbents. Carbon dioxide (CO2)
absorbents do not degrade N2O. Desiccated CO2 absorbents can
degrade potent inhaled anesthetics (particularly desflurane) to clinically
relevant concentrations of carbon monoxide (CO).5 Sevoflurane degradation by moist or desiccated CO2 absorbents produces a nephrotoxin,
compound A.6 Although this can cause renal injury in humans,7 such
injury is minimal and exceedingly rare. New CO2 absorbents that minimally degrade sevoflurane (or desflurane) eliminate this rare problem,8
even when the absorbents are desiccated.9
Desirable Properties of N2O
Cost. N2O is inexpensive and decreases the need for more expensive
anesthetics.10 Because MAC (the minimum alveolar concentration of
anesthetic that produces immobility in response to noxious stimulation in
50% of subjects) decreases with increasing age,11 the contribution of a
constant N2O concentration (eg, 50% to 60%) to the total required anesthetic increases with increasing patient age. For children, the contribution provides only a quarter of the anesthetic requirement but this rises
to over half in the elderly.11
Respiratory Irritation. Because N2O has no pungency, its use for induction of anesthesia minimizes coughing, breath holding, laryngospasm
or increased secretions. Accordingly, it is used with pungent anesthetics (desflurane, isoflurane) to smooth anesthetic induction. But sevoflurane also is nonpungent,12 and anesthetizing concentrations produce
minimal or no undesirable respiratory responses.13
Solubility. Relative to the solubilities of potent inhaled anesthetics,14 the
poor solubility of N2O in blood15 and tissues15 makes it useful for induction of and recovery from anesthesia. It enters and leaves the body
faster than potent inhaled anesthetics, and the second gas effect from
N2O enhances the entrance of anesthetics given concurrently.16 The
concentration effect accelerates its own entrance into the body.16 However, where the rapid entrance and exit of N2O clearly exceeds that
found with older anesthetics such as isoflurane, ingress and egress differ but slightly from that with desflurane17 and sevoflurane.10
Cardiorespiratory Effects. Like potent inhaled anesthetics, N2O can profoundly decrease the ventilatory response to imposed increases in
CO2 and to hypoxia.18 Unlike potent inhaled anesthetics, N2O partial
pressures of up to 1.5 MAC (approximately 1.6 atmospheres of N2O)
do not increase the partial pressure (tension) of arterial carbon dioxide
(PaCO2),19 nor does N2O appear to increase the depression produced
by potent inhaled anesthetics.20 Substitution of, say, 50% N2O for a
comparable MAC contribution of a potent anesthetic may decrease
cardiovascular depression (one can argue whether depression is good
or bad). N2O minimally affects blood pressure and heart rate.
Neuromuscular Effects. N2O minimally, if at all, triggers malignant hyperthermia.21 Thus, one indication for the use of N2O is a finding of a personal or familial history of the disorder
Undesirable Properties of N2O
Potency. A drawback to N2O is its limited potency; its MAC in 30 to 60
% of General Anesthetics
with N2O
40
30
20
10
Audit of operating room
anesthesia in US hospitals
0
1998 2000 2002 2004
Year
F i g u re 1 . O pe ra t i n g u s a ge o f N 2 O in the past
dec ade. Ext rapolat ion of these results sug gests
that N 2 O use will approach z e ro in 2-3 years.
Data were gathered by Hospital Research Associates for Baxter Healthcare
Corp., and privately communicated to EIE
2
year-old patients exceeds one atmosphere. Alone it cannot produce
anesthesia, even in the elderly.11 Thus, it lacks the flexibility of potent
inhaled anesthetics. Its use, perforce decreases the O2 concentration
presented to the patient and increases the risk of hypoxia. Impaired
pulmonary function may further decrease the N2O contribution by
requiring greater O2 concentrations to secure adequate oxyhemoglobin saturation.
Kinetics Issues and Potency. N2O15 is a poorly soluble anesthetic compared to potent inhaled anesthetics such as isoflurane.14 But N2O is
much more soluble than N2 and O2 (blood/gas partition coefficients of
approximately 0.02). This solubility and the need to supply high concentrations of N2O lead to unique kinetic issues. Larger volumes of
N2O than N2 (and other poorly soluble gases) move to and from gas
spaces enclosed within the body. The cause is the greater capacity of
blood to hold N2O as opposed to N2: more N2O is available. N2O
administration can expand bowel gases,22 the gas within a pneumothorax,22 an air embolism,23 and cuffs filled with air [tracheal tube or a
laryngeal mask airway (LMA)].24,25 Anesthetists often avoid using N2O
in patients with abnormal closed gas spaces or devices that may create gas spaces (eg, cardiopulmonary bypass devices).
One study finds that N2O administration delays recovery of bowel
function after surgery on the colon,26 while other studies find no such
effect.27,28 One study finds no clinically significant bowel gas expansion
during bariatric surgery.29 This result is not surprising given the limited
amount of bowel gas (ie, there is little gas to expand). The study also
finds that any expansion of CO2 instilled for laparoscopy does not
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affect the conduct of the procedure, but another study notes that
administration of N2O during laparoscopy may unduly increase intraabdominal pressure if gas is not periodically vented.30
N2O movement into closed gas spaces may increase pressure and
compromise regional blood flow in the skull,31 sinuses, middle ear,32 or
eye.33 Increased pressure in the eye can cause permanent blindness,34
and tympanic membrane rupture has been reported.35 Increased pressure in the middle ear correlates with increased postoperative nausea
and vomiting.36 These effects may also be used to advantage. For
example, N2O used to expand a joint space during arthroscopy is
rapidly reabsorbed,37 and, unlike CO2, N2O does not produce pain
from a local acidosis. Substitution of N2O for CO2 in laparoscopic procedures decreases end-tidal CO2, ventilatory demand, and postoperative pain.38 However, the respiratory acidosis from CO2 insufflation may
better preserve blood pressure and cardiac output.39
N2O also may transiently affect variable-bypass vaporizers because
the solution (absorption) of N2O in the liquid anesthetic in the vaporizer sump decreases effective flow through the sump and thereby
decreases potent anesthetic output from the vaporizer.40 The reverse,
a greater than dialed output, occurs when the carrier gas change from
N2O to O2.41
MACawake. MACawake is the minimum alveolar concentration of
inhaled anesthetic that prevents an appropriate response to command
in 50% of subjects.42 It is a measure of the anesthetic concentration
that suppresses awareness but not necessarily of the concentration
that suppresses recall (ie, produces amnesia); that concentration may
be smaller than MACawake.43 MACawake for N2O is approximately
two-thirds of MAC, a value nearly twice that for desflurane, isoflurane,
and sevoflurane.11 This higher fraction means that relatively less N2O
must be eliminated to permit awakening and thus may expedite patient
transit through the operating room and the post-anesthesia care unit.
But MACawake correlates with what might be called MACamnesia.43
Thus patients primarily anesthetized with N2O may remember events
during anesthesia, whereas those only given potent inhaled anesthetics may be less apt to remember.
Analgesia. The greater MACawake/MAC ratio for N2O may underlie
part of its claim as an analgesic. MAC-fractions that allow a report of
pain/no pain (because the patient is still awake) can be reached with
N2O but not with potent inhaled anesthetics. Parenthetically, concentrations of approximately 0.1 MAC of both N2O and potent inhaled anesthetics have anti-analgesic (hyperalgesic) effects,44 and thereby can
increase the perception of pain. Passing rapidly below these concentrations may be advantageous.
Unlike potent inhaled anesthetics, N2O may increase release of
enkephalins, naturally occurring opioid-like substances,45 through
actions on GABAergic neurons,46,47 and spinal cord alpha1 adrenoceptors.48 GABAergic interneurons at both supraspinal and spinal levels
influence antinociception.49 This effect on naturally occurring opioids
may underlie part of the greater postoperative nausea and vomiting
seen with N2O. Naloxone antagonizes the analgesia produced by
nitrous oxide.50 As with opioids, tolerance to analgesia with N2O develops rapidly.51 Acute tolerance may restore wakefulness and account for
part of awareness during anesthesia that relies heavily on N2O.52
Respiratory Effects. The liter or more per minute of N2O eliminated during the initial portion of recovery dilutes alveolar O2 and CO2. The
smaller concentration of CO2 decreases respiratory drive, and that,
along with the decrease in O2 can slightly decrease oxyhemoglobin
saturation (diffusion hypoxia).53,54 Diffusion hypoxia is only of concern
in patients who have compromised respiratory function, and even in
these patients it may be minimized by administration of O2 during the
first several minutes of recovery.
Cardiovascular Effects. N2O55 may not supply anesthetic preconditioning and therefore may not protect the heart against the ischemia that
may occur during coronary artery bypass graft placement. In contrast,
desflurane and sevoflurane provide protection.56 N2O may increase
pulmonary vascular resistance.57
Neuromuscular Effects. Potent inhaled anesthetics cause muscle relaxation, and augment the effects of neuromuscular blocking drugs.58 In
contrast, N2O increases muscle tone when used alone,19 and increases the rigidity seen with opioid administration.59 Unlike potent inhaled
anesthetics, N2O minimally augments the effect of neuromuscular
blocking drugs60 and can antagonize such effects.61
Effects on the Central Nervous System. In association with concentrationrelated decreases in electrical activity,62 potent inhaled anesthetics
decrease cerebral metabolic rate,63 and protect against periods of
hypoxia.64,65 In contrast, N2O can increase cerebral metabolic rate,63
cerebral blood flow,63 and intracranial pressure.66 One study finds that
desflurane and isoflurane, but not N2O, protect against cerebral hypoxia.64 However, another study finds that N2O provides protection.67 Studies comparing the relative protection provided by N2O versus potent
inhaled anesthetics against cerebral hypoxia have not been conducted
in primates, and such data would be helpful. N2O depresses sensoryevoked potentials, particularly in combination with potent inhaled anesthetics,68 and its use may be precluded if such potentials are needed
to evaluate the integrity of the central nervous system.
N2O increases postoperative nausea and vomiting more than potent
inhaled anesthetics.69 An elevated middle ear pressure correlates with
this increase in postoperative nausea and vomiting,36 and an enhanced
release of naturally occurring opioids may add to the predisposition to
postoperative nausea and vomiting. Concentrations of N2O (given alone)
exceeding 50% are more likely to produce nausea and vomiting.43
Potent inhaled anesthetics such as desflurane affect electroencephalographic activity more than does N2O.62 In some studies, N2O
minimally affects the values obtained with the bispectral index (BIS)
monitor,70,71 while others show the expected decrease in the value.72 In
regard to these contrasting data, the BIS monitor is an empiricallybased device with limitations. This difference may be important if the
anesthetic community is pressed to routinely use the BIS as a measure
of awareness.
Contribution of N2O to the Greenhouse Effect. Like CO2, N2O absorbs
infrared light and contributes to the greenhouse effect. N2O also adds
to depletion of the oxone layer.73 The atmospheric concentration of
N2O is 0.3 ppm.74 This small concentration is important because the
global warming potential from one molecule of N2O is 200 to 300 times
that of CO2.75 However, most atmospheric N2O comes from microbial
processes of nitrification (the oxidation of ammonia to nitrate) and denitrification (the reduction of nitrates or nitrites to gaseous nitrogen),76
The contribution of N2O from anesthetic sources is small to trivial.
Support of Combustion. Although N2O, itself, does not burn, it supports
combustion. Therefore it can promote explosions during laparoscopy.77 Administration of O2 does not present a comparable hazard
because tissue partial pressures of oxygen rarely exceed 40 mmHg to
50 mmHg (ie, 6%-7% atmospheres), even when a patient breathes
100% O2, whereas tissue partial pressures of N2O can equal those
being respired (eg, 50%-70% atmospheres.) While not specific to N2O,
clinicians should remain current on the Joint Commission on Accreditation of Healthcare Organizations’ educational and competency standards related to staff training in fire prevention and management.
Toxicity of N2O. N2O can produce one specific toxicity in humans and a
second toxicity in rats that may apply to humans. First is the long-known
inactivation of methionine synthase and associated human pathology.
Second, N2O antagonism of the N-methyl-D-aspartate (NMDA) receptor
may produce neuronal death in developing, adult, and aged brains of
rats–with presently unknown human implications. Advocates of N2O
might argue that potent inhaled anesthetics such as isoflurane can also
produce toxicities, particularly those affecting the central nervous system.78,79 N2O may share some of the bases (eg, NMDA blockade)
underlying these capacities to produce injury, but N2O differs from
anesthetics such as isoflurane in that it has an additional basis for its
capacity to produce injury, inactivation of methionine synthase.
Inactivation of Methionine Synthase
Mechanism of Inactivation. Historically, investigators reported adverse
outcomes in patients who received N2O for several days. Such prolonged use does not occur in contemporary practice. However,
adverse hematologic, neurologic and cardiovascular outcomes have
recently been observed after routine clinical exposure, and are discussed below.80-82
N2O irreversibly oxidizes the cobalt moiety of vitamin B12, consequently inactivating the cobalamin-dependent enzyme methionine synthase.81 Methionine synthase catalyzes remethylation of
5-methyltetrahydrofolate to tetrahydrofolate and homocysteine to
methionine. S-adenosylmethionine (SAM), the activated form of methionine, is the universal donor for methylation in protein and nucleotide
synthesis in proliferating tissues. In the methyl donor reaction, SAM is
demethylated to S-adenosylhomocysteine, which is converted to
3
homocysteine either to reenter the methionine cycle, or to be removed
by conversion to cystathionine via vitamin-B6-dependent cystathionine
β-synthase. Steps in the folate-cobalamin-methylation pathway are
enzymatically catalyzed, with the genes encoding each enzyme
expressing multiple polymorphisms (ie, multiple alleles, or DNA
sequence variations of genes within a population). Some polymorphisms can alone be causal of disability and death, but these are rare.
More prevalent polymorphisms in folate and cobalamin pathways contribute to more frequent but also potentially harmful phenotypes.
Importantly, all bodily tissues except the liver and kidney rely solely on
methionine synthase for methyl substitutions.
In humans, the mean half-time for hepatic methionine synthase
inactivation by 1 atmosphere N2O is approximately 1 hour (or 0.5
atmospheres for 2 hours),83 with less than 20% residual activity after 2
atmosphere-hours of exposure.83 Restoration of methionine synthase
activity requires synthesis of new enzyme and may take several days.
A second exposure during this interval may be especially harmful
because it prolongs the period of diminished methionine synthase
activity. Because methionine synthase integrates folate and cobalamin
metabolism, inactivation by N2O exaggerates the harmful effects of
acquired conditions and inborn errors of metabolism in these pathways. In such settings, adverse outcomes after exposure may arise
from methyl group deficiencies, from homocysteine accumulation to
toxic levels, or from both.
Methylation Deficiency
Bone Marrow Depression. N2O-mediated interference with cell division
leads to megaloblastic anemia, leukopenia, thrombocytopenia and,
ultimately, marrow failure. In healthy patients anesthetized with N2O for
6 hours, stores of maturing cells maintain normal blood counts until
methionione synthesis is re-established.84 Although N2O decreases
proliferation of human peripheral blood mononuclear cells and
depresses chemotactic migration of monocytes,85 exposure to 65%
N2O does not increase the incidence of surgical wound infections.86
No comparative safety data provide thresholds for effects from
exposure to N2O for more than 6 hours, or from N2O administration to
patients with acquired or inborn errors of folate and cobalamin metabolism, or with co-existing marrow failure from other causes. Few young
patients have a cobalamin deficiency, but 10% or more of elderly
patients do.87 In the absence of patient specific data (eg, normal blood
B12, B6, and folic acid levels), N2O should rarely, if ever, be given to
patients with pernicious anemia, malabsorption syndromes (eg, small
bowel dysfunction, Crohn’s disease, blind loop syndrome, postgasterectomy), diets low in animal products (vegetarians, vegans), malnutrition (eg, secondary to alcohol dependency), and any synthetic
feeding. Its use also might best be avoided where preservation of marrow function is critical (eg, bone marrow harvest).88
Myeloneuropathy in Adults. The recreational popularity of N2O (up to
10% of young adults),89 and concurrent reports of myeloneuropathy
appear to be increasing.90 So are reports of neurotoxicity in adults after
clinical use of N2O for anesthesia and analgesia.82,91-96 In a randomized, prospective investigation, neurologic symptoms lasting up to 4
weeks after surgery followed one hour of N2O anesthesia in elderly
patients with abnormal pre-operative folate levels.97 In a patient with
cobalamin deficiency, a single exposure to N2O may have caused subacute combined degeneration of the spinal cord.98 Lacassie et al.
describe a patient with a common polymorphism (C677T) in the
enzyme antecedent to methionine synthase in the folate cycle, ie, 5,10
methylenetetrahydrofolate reductase (MTHFR), who developed diffuse
myelopathy, paraplegia and neurogenic bladder after two exposures to
N2O anesthesia within an interval of two months.99 Between 5% and
15% of patients are homozygous for this mutation, the frequency varying among ethnic groups.100 The common incidence of such polymorphisms in folate and cobalamin pathways, plus the common frequency
of B-vitamin deficiencies, suggests that many patients undergoing
surgery are doubly vulnerable to the risks of N2O exposure.
Neurotoxicity in Childhood. The incidence of specific disorders caused
by mutations in the enzymes catalyzing folate and cobalamin metabolism that could cause syndromes in the absence of other acquired conditions or drug exposures are rare (perhaps 1/100,000 patients or
fewer).101 Although each “single disorder” of folate and cobalamin
metabolism may be rare, many have been recognized, and in aggregate may be an order of magnitude more common. In such patients,
the contraindication to N2O use is obvious, but it is less clear in appar-
4
ently normal first-degree relatives who carry alleles underlying autosomal recessive traits. Early in the course of disease, no antecedent sign
or symptom may denote the presence of an acquired or inborn disorder of single carbon pathways,81,102,103 except, possibly, hypotonia and
developmental delay. Prevalent mutations (eg, MTHFR C677T discussed above) may be expressed in otherwise normal children, dictating that potential risks of N2O to the developing nervous system in
fetuses and infants be balanced against potential benefits. Given the
limited anesthetic contribution of N2O in the young (ie, its low potency),11 anesthetists should use it with caution.
Occupational Exposure. The American Society of Anesthesiologists Task
Force on Trace Anesthetic Gases of the Committee on Occupational
Health of Operating Room Personnel found no evidence that waste
anesthetic gases pose a risk to pregnant women (or those contemplating pregnancy) working in a scavenged environment. [Waste Anesthetic
Gases Information for Management in Anesthetizing Areas and the
Postanesthesia Care Unit (PACU). http://www.ASAhq.org/publicationsAndServices/wasteanes.pdf] However, occupational exposures above
the regulatory maximum occur with mask leaks, uncuffed endotracheal
tubes and laryngeal mask airways, and scavenging system defects.104,105
Moreover, N2O use outside the operating room is expanding.106,107 Dental assistants occupationally exposed to N2O may have more spontaneous abortions and decreased fertility.108,109 Occupational exposure
also may increase the incidence of low birth-weight infants.110
Carcinogenesis. Regulation of DNA methylation in the promoter
sequences of genes is a key mechanism of coordinated gene expression, and altered DNA methylation is documented in tumorigenesis.111
Genome-wide hypomethylation correlates with malignancy, and may
cause chromosomal translocations and altered expression of protooncogenes and tumor suppressor genes.112 Presently, data in adults
do not reveal an increased risk of developing cancer after exposure to
N2O. Studies are needed to determine whether exposure to N2O in
early life affects methylation status, and the occurrence of chronic disease later in life.
Homocysteine Accumulation
N2O increases homocysteine levels through its effect on methionine
synthase. Iincreased homocysteine levels can produce various
pathologies. It is tempting to complete this syllogism and argue that
N2O can produce various pathologies, but the direct evidence for or
against the safety of N2O in these settings is limited at present.
Homocysteine Vascular Toxicity. Plasma homocysteine levels can
increase after N2O exposures routinely encountered in anesthesia,113
and may not return to normal for a week or more.114 Short-term elevations of homocysteine can increase platelet aggregation, activate procoagulant factor V, and inhibit anticoagulant protein C.115 Homocysteine is
cytotoxic to endothelial cells, oxidizes low-density lipoproteins, and
inhibits flow-mediated vasodilation of vascular smooth muscle.116 Moderately elevated homocysteine levels (>15 mmol/l) are an independent
risk factor for myocardial infarction, stroke and peripheral vascular disease.117 The MTHFR C677T mutation and others in the folate and cobalamin pathways contribute to hyperhomocysteinemia in some but not all
studies.118 Patients randomized to receive N2O for carotid endarterectomy have a higher incidence and duration of postoperative myocardial
ischemic events.80 Randomized trials with genotyping and dose dependencies remain to be conducted. For now, concern about the vascular
consequences of N2O appears warranted, with particular attention to
disorders associated with preoperative hyperhomocysteinemia (eg,
renal failure), and conditions intolerant of a super-imposed lesion (eg,
thrombophilia from other causes, peripheral vascular, cardiovascular or
cerebrovascular disease).119
Homocysteine Neuronal Toxicity. Acute and chronic hyperhomocysteinemia may contribute to Alzheimer’s disease,120 Parkinson’s disease,121 and stroke.122 Homocysteine damages neurons by impairing
DNA synthesis and triggering apoptosis.123 Two models of adult traumatic injury provide evidence that folate is needed to promote neuronal regeneration, suggesting the avoidance of N2O in settings of
neural trauma.124
Drug Interactions
N2O inactivation of methionine synthase can underlie adverse drug
interactions. For example, severe toxicity with mucositis and myelosup-
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pression may accompany the combined use of N2O and adjuvant
chemotherapy.125 Methotrexate inhibits dihyrofolate reductase and
blocks regeneration of tetrahydrofolate from dihydrofolate.126 Through
depletion of 5-methyl-THF, methothrexate reduces methionine synthase
activity, augmenting the effect of N2O.127 Hyperhomocysteinemia after
methotrexate is marked in patients who are also MTHFR C677T
homozygotes.128 Methotrexate induces leukoencephalopathy in
patients treated intrathecally, intravenously and even orally, who may
be particularly vulnerable to the harmful effects of N2O.129,130 Lipid-lowering drugs, oral hypoglycemics, anticonvulsants, diuretics, ompeprazole, cyclosporine and levodopa are associated with
hyperhomocysteinemia.131 For example, methylation of levopopa and
dopamine by catechol-O-methyltransferase uses SAM as a methyl
donor, and yields S-adenosylhomocysteine, which is rapidly converted
to homocysteine.132 Patients taking levodopa have approximately twice
the concentration of plasma homocysteine as controls and untreated
Parkinsonian patients.121,133
Experimental Neurotoxicity. Interference with cobalamin metabolism
does not appear to underlie a second specific neurotoxicity due to
N2O. NMDA receptor blockade by N2O causes neurotoxicity in 7 dayold developing rats, and adding N2O to isoflurane, or to isoflurane
with midazolam, worsens pro-apoptotic effects during brain growth.78
The aging brain is significantly more sensitive to the neurotoxic
effects of N2O in combination with ketamine (another blocker of
NMDA receptors) than the young adult brain, although both are
equally sensitive to N2O alone.134 The mechanisms of these effects
are not fully understood, nor are the analogous clinical investigations
in humans likely to be forthcoming.135 Homocysteine promotes oxidative stress in neurons and may directly activate NMDA glutamate
receptors rendering neurons vulnerable to excitotoxicity.136,137 N2O
readily crosses the placenta to produce a maternal-fetal concentration ratio of 0.8 within 15 minutes of continuous inhalation.138
Prospective investigations addressing possible neurotoxic effects of
N2O during surgical procedures in pregnant women are lacking.
However, experimental data may argue against fetal exposure in light
of evidence pointing to harmful consequences of N2O exposure.
Summary
The authors propose that eliminating N2O use would lead to simpler
and safer anesthetic delivery devices and installations that could
decrease the potential for hypoxia and decrease cost. The decreased
costs would particularly apply to new hospital construction. Use of N2O
versus oxygen and air requires equipment that must be calibrated,
daily-checked and maintained–hidden but real costs. Pipes, valves,
regulators, flowmeters, and scavenging devices all can and do break;
all require periodic testing. On the other hand, the newer, potent
inhaled anesthetics of reduced solubility (ie, desflurane and sevoflurane) that might substitute for N2O will add to the cost of anesthesia.
A half-century ago, most anesthetists believed that, except for its
limited potency, N2O was the perfect anesthetic. Several factors
obscured the untoward consequences of its use. Many noxious effects
of N2O were subtle (eg, expansion of gas-containing spaces) and only
slowly recognized. Many (eg, bone marrow and central nervous system
toxicity) were delayed in detection, and thus usually were not immediately connected to its administration. Some others (eg, homocysteine
toxicity, NMDA antagonism, interference with DNA methylation) await
further appraisal. Regarding toxicity, although N2O is a relatively impotent anesthetic, it affects single carbon metabolism in concentrations
and durations routinely employed in practice. These harmful and
potentially harmful effects combined with competitive contemporary
alternatives make N2O a less attractive option. No absolute indication,
and few relative indications (eg, malignant hyperthermia) justify its continued widespread application. To the contrary, the number of patients
with absolute and relative contraindications to N2O administration by
procedure, genetic predisposition, or acquired susceptibility is larger
than previously appreciated.
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CE/CME/CPE Post-test
Circle the single-letter response that best answers the question or completes the sentence.
1.
2.
3.
4.
5.
Which of the following is not a desirable attribute of N2O?
a. Low cost
b. A decreased density relative to air, and thus a decreased
respiratory resistance
c. No pungency
d. Low solubility
e. Minimal cardiovascular depressant effects
Which of the following is a desirable attribute of N2O?
a. It does not cause a local or respiratory acidosis
b. The ability to enhance the volume or pressure of
therapeutic gases placed in the body
c. Its low solubility relative to nitrogen
d. Potency sufficient to allow the application of high O2
concentrations
e. During induction of anesthesia, it increases the output of
variable bypass vaporizers
Why does administration of N2O increase the volume of
internal gas spaces?
a. N2O diffuses faster than N2 in blood.
b. N2O diffuses faster than N2 in gas spaces.
c. The solubility of N2O in blood is much greater than the
solubility of N2 in blood, and thus much more N2O can be
brought to the space relative to the amount of N2 that can be
removed.
d. The solubility of N2 in blood is much greater than the solubility
of N2O in blood, and thus much more N2O can be brought to
the space relative to the amount of N2 that can be removed.
e. The specific heat of N2O is less than that of N2 and thus
warming of the space and consequent expansion occurs.
N2O transiently alters the output of variable bypass
vaporizers by
a. altering the temperature of the bimetallic control strip.
b. decreasing flow through the sump holding liquid anesthetic by
dissolving in the anesthetic during a change from N2O
administration to O2 administration.
c. decreasing flow through the sump holding liquid anesthetic
by dissolving in the anesthetic during a change from O2
administration to N2O administration.
d. the difference in density of N2O versus O2.
e. the difference in viscosity of N2O versus O2.
Nitrous oxide decreases which of the following
a. Cerebral metabolic rate.
b. Cerebral blood flow.
c. Intracranial pressure.
d. Sensory-evoked potentials.
e. Postoperative nausea and vomiting (PONV).
6.
MACawake is _______.
a. the concentration of inhaled anesthetic at which 50% of
subjects do not remember
b. greater (as a fraction of MAC) for potent inhaled anesthetics
than for N2O
c. has no relationship to the concentration of anesthetic that
produces amnesia
d. smaller (as a fraction of MAC) for potent inhaled anesthetics
than for N2O
e. None of the above
7.
The analgesia produced by N2O is _____ .
a. transient
b. produced, at least in part, by the release of enkephalins
c. antagonized by naloxone
d. subject to rapidly developing tolerance
e. all of the above
8.
Which correctly describes the toxic potential of N2O?
a. Although metabolism is small, the metabolites (e.g., nitrous
acid) can injure several organs.
b. Degradation by desiccated CO2 absorbents can produce
volatile products (nitrous dioxide) capable of causing severe
lung injury.
c. Although N2O is minimally degraded, it augments the
metabolism of potent inhaled anesthetics to toxic byproducts.
d. N2O inactivates methionine synthase and thereby lessens the
availability of methionine and folic acid.
9.
Which answer most accurately describes the time course of
N2O inactivation of methionine synthase in humans?
a. Inactivation requires exposure over several days.
b. Recovery after inactivation from several hours of N20 exposure
may take several days.
c. Recovery requires several minutes after N2O administration is
discontinued.
d. Tolerance to N2O inactivation explains rapid recovery after
repeated exposures.
10. All of the following are correct except:
a. N2O is a neurotoxin.
b. N2O is a bone marrow toxin.
c. N2O is an effective contraceptive.
d. N2O is an occupational hazard.
e. N2O is a drug of abuse.
7
Answer Sheet & Evaluation Form
Current Status of Nitrous Oxide
Release Date: March 2007
Expiration Date: March 31, 2008
Directions: Select one answer for each question in the exam and circle the appropriate letter. A minimum score of 80% is required to earn credit.
Retakes are not permitted for CRNAs. Other participants are allowed 2 attempts. Please submit your answers only once through one of the methods listed below. Allow 4 weeks for processing.
Participate online at:
or mail to:
or fax to:
CMEZone.com
AKH Inc.
(904) 215-0534
Type “SR650” in the keyword field.
PO Box 2187
Orange Park, FL 32067-2187
Participant Information (please print)
First Name: _____________________________________ Last Name: ______________________________________________________________
Address: ________________________________________________________________________________________________________________
City: ___________________________________________________________________ State: _______________ ZIP: _______________________
Daytime Phone: ___________________________ Fax: __________________________ E-mail: __________________________________________
License # ___________________________________________________________________________ State of Licensure ____________________
Profession:
❑ Physician: I am claiming ____ (in 0.25 increments) AMA PRA Category 1 Credit(s)™.
❑ Pharmacist
❑ Other (specify): _____________________________________________________________________________
❑ Nurse Anesthetist--AANA number (required): _____________________________________________________________________
CE/CME/CPE Post-test Answers
Current Status of Nitrous Oxide
Select the single-letter response that best answers the question or completes the sentence.
1. a
b
c
d
e
6. a
b
c
d
e
2. a
b
c
d
e
7. a
b
c
d
e
3. a
b
c
d
e
8. a
b
c
d
4. a
b
c
d
e
9. a
b
c
d
5. a
b
c
d
e
10. a
b
c
d
e
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8
SR650
Evaluation Questions
Please answer the following questions by circling the appropriate rating.
4 = Strongly Agree
3 = Agree
2 = Disagree
1 = Strongly Disagree
1. After participating in this activity, I am better prepared to:
4
3
2
1
a. List noxious effects of nitrous oxide (N2O) anesthesia.
b. Discuss risks and benefits of N2O compared with other inhaled
anesthetics.
4
3
2
1
c. Review safety concerns, including effects of N2O on vitamin B12 and
folate metabolism and the implications of these effects for selected patients.
4
3
2
1
d. Relate N2O use patterns to the introduction of other inhaled anesthetics.
4
3
2
1
e. Identify clinical scenarios in which N2O use is contraindicated.
4
3
2
1
2. The information was relevant to my professional needs and practice.
4
3
2
1
3. The educational level of this activity was appropriate.
4
3
2
1
4. The faculty was knowledgeable and effective in presentation
of content.
4
3
2
1
5. The teaching method(s) and learning materials were effective.
4
3
2
1
6. Overall, I was satisfied with this educational activity.
4
3
2
1
7. The content was objective, current, scientifically based, and
free of commercial bias. ❏ Yes ❏ No (please explain): _______________________________________________________________
Based on information presented in this activity, I will:
❏ do nothing as the content was not convincing.
❏ seek additional information on this topic.
❏ change my practice.
❏ do nothing as current practice reflects program’s recommendations.
The most important concept learned during this activity that may effect a change in patient care is:_________________________
What issue(s) related to the therapeutic area discussed in this activity, or other topics, would you like addressed
in future continuing education?_________________________________________________________________________________________
Comments: