Nitrous Oxide:
Neurotoxicity
Claudia Praetel
Case Synopsis
Two weeks after surgery for prostate adenoma, a 69-year-old man developed ascending
paresthesia of the limbs, severe ataxia, tactile sensory loss in the limbs and trunk, and
absent tendon reflexes. After a second surgical intervention, the patient became confused.
Four months after onset, the patient demonstrated paraplegia, severe weakness of the
upper limbs, cutaneous anesthesia sparing the head, and confusion.
PROBLEM ANALYSIS
Definition
Nitrous oxide (N2O) has been safely used for anesthesia
for almost 140 years, since it first became available in com-
pressed gas cylinders in 1868. However, there are increasing
reports of the neurotoxic potential of N2O associated with
recreational use, with chronic occupational exposure in unscav-
enged environments, and after exposure during general
anesthesia. A small subset of patients routinely seen during
preoperative anesthetic assessment may indeed be at high
risk for postoperative neurologic deterioration if exposed
to N2O. Schilling postulated that N2O may precipitate neu-
rologic disease in patients with unrecognized vitamin B12
deficiency.
The patient described in the case synopsis was diagnosed
with previously unrecognized pernicious anemia with sub-
acute combined degeneration of the spinal cord after exposure
to N2O anesthesia. Marié and coworkers published this case
report in 2000. During the past 20 years, numerous well-
documented case reports have substantiated this potentially
devastating complication. Table 18-1 highlights recent reports
of neurologic complications after N2O in both children and
adults.
Recognition
N2O is a potent oxidant. It irreversibly oxidizes methylcobal-
amin through inhibition of the methionine synthesis path-
way, thereby inactivating the active form of vitamin B12. The
latter is essential for methionine synthase, the key enzyme for
converting homocysteine to methionine (an essential amino
acid) using tetrahydrofolate (the bioactive form of folate) as
the methyl source. Therefore, insufficient availability of either
cobalamin1 or folate results in a decrease of methionine, with
the accumulation of homocysteine. N2O also directly inacti-
vates methionine synthase, possibly due to the production
of free radicals. Inhibition of methionine synthase activity
has deleterious consequences for DNA synthesis, leading to
megaloblastic changes in all rapidly dividing cells, macrocy-
tosis in erythroid precursors, and ineffective erythropoiesis.
18
Lack of methionine can also result in defective myel
nation and demyelination. Neurologic sequelae includ
paresthesias, peripheral neuropathy, and subacute combine
degeneration of both the posterior and lateral columns of th
spinal cord. Subacute combined degeneration is reversible
diagnosed and treated early with cobalamin. Psychologic
symptoms such as memory loss, disorientation, and depre
sion have been described. These conditions may be observe
with or without macrocytic changes in erythrocytes.
Risk Assessment
Inhibition of methionine synthase by N2O anesthesia do
not cause a problem in healthy individuals with sufficien
vitamin B12 stores. However, any patient with even sub
clinical deficits of vitamin B12 is at increased risk for th
development of myeloneuropathy because occult cobalami
deficiency, combined with subsequent N2O exposure, com
pounds inhibition of the methionine synthesis pathwa
Insufficient availability of cobalamin may have the followin
causes:
● Inadequate intake (e.g., alcoholics, long-term stri
vegetarians, breast-fed infants of vitamin B12-deficien
mothers)
● Impaired absorption (e.g., gastric atrophy, long-term use o
drugs that interfere with acid production, Crohn’s diseas
lack of intrinsic factor due to autoimmune destructio
of parietal cells or after surgery such as gastrectomy an
gastric bypass)
● Rare congenital disorders (e.g., deficiencies of transcoba
amin II, familial selective vitamin B12 malabsorption)
Folate deficiency is very rare due to the dietary fort
fication of wheat and corn grains with folic acid. Inherite
defects in folate metabolism (5,10-methylenetetrahydro
folate reductase deficiency) are a contraindication to N2
exposure.
1
The terms cobalamin and vitamin B12 are used interchangeably as gener
terms for all the cobalamides active in human beings. Preparations of vit
min B12 for therapeutic use contain either cyanocobalamin or hydroxo-
cobalamin, because only these derivatives remain active following storage