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April 3, 2001
Nitrous Oxide and Neurologic
Injury in Childhood*
Felmet K, Robins B, Tilford
D, Hayflick SJ. Acute neurologic decompensation in an infant with cobalamin
deficiency exposed to nitrous oxide. J Pediatr 2000;137:427-428.
McNeely JK, Bucsulinski B, Rosner DR. Severe neurologic impairment in an infant
after nitrous oxide anesthesia. Anesthesiology 2000;93:1549-1550.
Commentary by Kirk Hogan, M.D.
Future historians of our
specialty will characterize anesthetic practice at the turn of the century
as the interval when complications long in the aftermath of surgery were traced
to decisions often made by rote in the operating room. The detrimental sequelae
of careless intra-operative temperature management on myocardial ischemia,
wound healing and other major determinants of outcome have been amply documented
in these pages. So too, the benefits of oxygen supplementation during a procedure
in lowering the risk of post-operative wound infection are now widely recognized
within and beyond the specialty. Two very recent reports, one appearing in
the anesthesiology literature and the other in a major pediatric journal,
suggest that routine use of nitrous oxide in pediatric anesthesia may be the
next to follow suit in undergoing refreshed scrutiny.
The J Pediatr article describes the onset of lethargy, hypotonia, tremor
and athetosis in an 8 month old male 6 days after he was anesthetized
with nitrous oxide for an 80 minute orchiopexy. On admission for acute neurologic
deterioration, he was found to have a weight and head circumference less than
the 5th percentile, anemia (hematocrit of 21%), macrocytosis (MCV 104 fL),
hyperhomocysteinemia (120.7 m mol/L; normal 1.2 -9.m mol/L), and
severe cobalamin deficiency (<20 pg/mL; normal 200 - 950 pg/mL). Ten years
earlier, his mother was treated for anemia with cobalamin injections, but
her subsequent cobalamin deficiency and intrinsic factor defect were undiagnosed
during pregnancy and breast feeding.
The 4 month old girl in the Anesthesiology case report underwent an
elective repair for craniosynostosis and received 180 minutes of inhaled nitrous
oxide. Three weeks after surgery, she was admitted for lethargy, hypotonia,
dehydration and acidosis. Laboratory investigations revealed anemia (hemoglobin
7.8 g/dL), macrocytosis (MCV 93 fL), homocysteinuria, and severe cobalamin
deficiency (< 45 pg/mL). Her mother avoided meat and dairy products while
breast feeding, did not use vitamin supplements, and was herself cobalamin
deficient (<172 pg/mL). A particularly harrowing aspect of both case reports
is the persistence of significant developmental delays even after appropriate
therapy was introduced and serum cobalamin levels restored.
In both instances, the likely pathogenesis of the injury was irreversible
nitrous oxide induced oxidation of residual cobalt in patients with previously
acquired dietary deficiency. Cobalamin is an essential constitutent of the
enzyme methionine synthase which is responsible for the conversion of homocysteine
to methionine, the body's sole methyl donor. Among many other reactions, methyl
moieties are crucial for assembly of the myelin sheath, substitution of neurotransmitters,
and DNA synthesis in proliferating tissues such as the marrow and developing
brain. In turn, elevated homocysteine is toxic to the vascular endothelium.
The two case reports carry a number of important clinical implications. First,
nitrous oxide is now to be considered contraindicated in children with
diagnosed acquired cobalamin deficiency just as it would be in adults with
achlorhydria, ileal resection, pernicious anemia or other cause of untreated
megaloblastosis. Far more worrisome in my opinion is the failure under contemporary
mandates of managed care to routinely screen children with pre-operative complete
blood counts, or to carefully review red cell indices when they are available.
Nor would most of us up to now consider a mother's dietary history to be a
critical feature of an all too hurried pre-anesthetic visit. Because the symptoms
and signs of cobalamin deficiency may be deceptive, it is striking that both
groups of authors advocate avoidance of nitrous oxide in children with unexplained
neurologic impairment or mild developmental delay, representing a fairly large
proportion of otherwise suitable candidates for anesthesia with this agent.
At the very least, it would appear wise to routinely obtain complete blood
counts in this subset of patients, and to assure proper vitamin supplementation
by history, and blood level when necessary, before surgery. When this is impossible,
omission of nitrous oxide may in fact be the safest course. From relevant
laboratory investigations, it can be inferred that serial nitrous oxide anesthetics
close on the heels of one another are particularly deleterious.
Second, the number of children, genes and mutations associated with inborn
errors of folate and cobalamin cycle enzymes has been very rapidly expanding
over the past decade. Not only do specific clinical syndromes arise from mutations
within methionine synthase itself, but patients with genetic alterations in
ancillary pathways are also eligible for harm. This possibility was first
alluded to in a small series by Beckman DR et al. [1] Again, and in tandem
with the acquired disorders, clinical clues to the presence of genetic syndromes
may not be overt. Given the unfortunate long term outcomes of the two
patients described above, heightened awareness of genetic folate and cobalamin
disorders on the part of anesthesiologists appears warranted. An authoritative
and up-to-the-minute reference source is: Rosenblatt DS and Fenton WA. Inherited
disorders of folate and cobalamin transport and metabolism. [2]
Finally, the significance of the two case reports for anesthesia of the normal
child must be considered. The good bill of health that nitrous oxide has enjoyed
for much of the preceding century apparently attests to its safety in routine
use, but do these case reports reflect doubt? Although inactivation of methionine
synthase is uniform and irreversible after nitrous oxide, most patients do
not experience adverse outcomes because of adequate stores of bioactive cobalamin.
Conversely, infants in the first months of life are heavily dependent on a
full array of biosynthetic mechanisms for proper neurogenesis. While those
with severe acquired or inborn errors of folate and cobalamin metabolism may
be particularly vulnerable, their intolerance of nitrous oxide poses the question
whether outwardly normal children are suffering undetected lesions. For example,
it is well established that 10 to 20 percent of us carry mutations in 5,10
methylene tetrathydrofolate reductase associated with moderate elevations
of serum homocysteine and premature vasculopathy. It is is unknown whether
children with these and related prevalent mutations are at risk for subtle
plateaus in the rate of skill acquisition, or a decrement in ultimate
attainable performance levels after receiving nitrous oxide in childhood.
One day it will be routine to stratify particularly susceptible patients by
perioperative genetic testing. Until that time, does the burden of proof fall
on practitioners assuming the safety of nitrous oxide use in childhood, or
on those concerned by broader risk? In keeping with all that has recently
been garnered from large cohort studies aimed at such caregiver basics as
temperature and oxygen management, perhaps all we have to do to find the answer
is to look.
Guest Author:
Kirk Hogan, M.D.
Department of Anesthesiology - University of Wisconsin
Madison, WI
• Editor’s note:
For additional commentary, click here to link to the recent literature
review by Board member Charles
Coté, M.D.
References:
- Beckman, et al. Pathological
findings in 5, 10 methylene tetrahydrofolate reductase deficiency. Birth
Defects: Original Article Series 1987;23:47-64.
- Rosenblatt DS and Fenton
WA. Inherited disorders of folate and cobalamin transport and metabolism.
Scriver CR, et al. (eds). The Metabolic and Molecular Basis of Inherited
Disease, 8th Edition, 2001:3897-3934
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