Case Reports  |   December 2000
Severe Neurological Impairment in an Infant after Nitrous Oxide Anesthesia
Author Affiliations & Notes
  • James K. McNeely, M.D.
  • Bogdan Buczulinski, M.D.
  • Diane R. Rosner, M.D.
  • *‡Assistant Professor of Anesthesiology, †CA-2 Resident in Anesthesiology.
Article Information
Case Reports
Case Reports   |   December 2000
Severe Neurological Impairment in an Infant after Nitrous Oxide Anesthesia
Anesthesiology 12 2000, Vol.93, 1549-1550. doi:
Anesthesiology 12 2000, Vol.93, 1549-1550. doi:
THE myelodepressant and neurotoxic effects of nitrous oxide have been established. 1–3 Numerous case reports of adult patients have implicated nitrous oxide in the development of postoperative neurologic dysfunction in patients with undiagnosed vitamin B12deficiency. 4–6 Vitamin B12deficiency is a rare condition in infants. 7 To our knowledge, there is no reported case of an infant with nitrous oxide–induced exacerbation of vitamin B12deficiency. We describe a 6-month-old infant in whom severe metabolic acidosis and neurological impairment developed weeks after general anesthesia with nitrous oxide.
Case Report
A 6-month-old girl was seen for preoperative evaluation before scheduled gastrojejunostomy tube placement for correction of oral feeding difficulties secondary to neurologic impairment. The history obtained from the parents revealed a previously healthy infant who underwent uneventful 3-h general anesthesia for elective craniosynostosis repair at 4 months of age. At that time, preoperative findings were significant for scaphocephaly as seen during plain-film radiologic study. No neurologic defect was described, and hemoglobin concentration was 12.8 g/dl, with a mean corpuscular volume of 89 femtoliters (fl). Anesthesia for the sagittal craniotomy was maintained with administration of isoflurane, nitrous oxide, oxygen, rocuronium, and morphine. No blood products were necessary, and the patient was discharged after 2 days. Three weeks after the procedure, the parents noted a decrease in smiling and playfulness of the infant. They also thought she was somewhat “floppy.” During the next 2 weeks, increased hypotonia developed in the infant. Her interest in feeding decreased and she required emergent admission to the hospital for marked tachypnea and lethargy. Examination revealed dehydration with a severe non–anion-gap acidosis, ketosis, and anemia. Arterial blood gas measurement, obtained with use of face mask oxygen in the emergency room showed a pH = 7.14, a carbon dioxide partial pressure of 7, an oxygen partial pressure of 167, and a bicarbonate concentration of 5; hemoglobin concentration was 7.8 g/dl, platelet count was 198 103/μl, and mean corpuscular volume was 93 fl. Results of peripheral blood smear were positive for schistocytes and anisocytosis. The patient was stabilized with administration of intravenous fluids and admitted for further testing. Magnetic resonance imaging showed diffuse cerebral atrophy. Neurologic examination showed staring without tracking, decreased head control, and hypotonia. No evidence of seizures was seen on the electroencephalogram. Serum testing showed increased proline and ethanolines with decreased tryptophan, whereas urine organic acids showed high methylmalonic acid, propionic acid, and cystine–homocysteine levels. The serum vitamin B12concentration was less than 45 pg/ml (normal, 200–1100 pg/ml). Folate concentration was 15 ng/ml (normal, 1.5–20.5 ng/ml) with normal vitamin B12binding capacity.
The patient was diagnosed as being vitamin B12deficient, and treatment with intramuscular injections of vitamin B12was started (1,000 μg/day intramuscularly). Two weeks after the initiation of treatment serum Vitamin B12concentration was found to be moderately low: 170 pg/ml. Her neurologic condition stabilized and she was scheduled for elective gastrojejunostomy tube insertion and skin fibroblast biopsy. Anesthesia was induced and maintained with intravenous medications. Controlled ventilation was maintained with 100% oxygen delivered via  a Mapleson D circuit. No nitrous oxide was present in the radiology procedure room. The patient made an uneventful recovery in the same room and was directly transferred to the nursing ward.
During subsequent questioning, the mother revealed that she was not a “strict” vegetarian, but she avoided dairy and meat products while breast-feeding. She did not use vitamin supplements. The mother’s complete blood count and erythrocyte indices were normal; however, her serum vitamin B12concentration was moderately low at 172 pg/ml. At follow-up 3 months after the procedure, the patient was developmentally delayed, but with gradual improvement in activity. No follow-up electroencephalography or magnetic resonance imaging were performed. The patient was prescribed a daily vitamin B12supplementation. The primary cause of the vitamin B12deficiency is unidentified.
We describe a case of severe neurologic impairment after administration of nitrous oxide general anesthesia in an infant. To date, at least nine cases of nitrous oxide–induced exacerbation of vitamin B12deficiency syndrome have been reported. 6 However, none of these case reports involved an infant. As in the adult reports, clinical symptoms of neurologic impairment did not appear until several weeks after uneventful administration of nitrous oxide anesthesia.
Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12such that the activity of two vitamin B12-dependent enzymes, methionine synthetase and thymidylate synthetase, are decreased. 8 Methionine synthetase converts homocysteine to methionine, which is necessary for the maintenance of the myelin sheath. Thymidylate synthetase is important for the formation of DNA. Inhibition of these enzymes can lead to the suppression of bone marrow and neurologic dysfunction. In adults, the earliest sign of vitamin B12deficiency usually is megaloblastic anemia caused by the rapid turnover of hematopoietic cells. However, neurologic involvement may be present in the absence of anemia, particularly if folic acid has been used. 9 The peripheral nerves most commonly are involved, followed by the spinal cord and cerebral cortex, with clinical signs of neurologic dysfunction, such as paresthesia of the hands and legs, ataxia, and loss of memory.
In the pediatric literature, several congenital disorders of vitamin B12-dependent metabolism were reported. 10 These infants will present with failure to thrive, vomiting, unexplained severe metabolic acidosis, hypotonia, and developmental delay. The metabolism of methylmalonic acid usually is affected, with large amounts excreted in the urine. In addition to methylmalonic aciduria, varying degrees of pancytopenia and homocystinuria are found. Serum vitamin B12levels usually are less than 200 pg/ml. Magnetic resonance studies may show brain atrophy, which are signs of retarded myelination, with the frontal and temporal lobes affected most. Culture of skin fibroblasts may show reversible dysregulation of the mitochondrial adenosine triphosphatase synthetase. It has been suggested that the more severe brain changes associated with vitamin B12deficiency during infancy may be a result of the infant’s rapid development of neuronal structures. These disorders usually respond to massive doses of B12(1,000 μg/day intramuscularly), but if undetected, death will usually occur in infancy.
In our case, the acute presentation of unexplained metabolic acidosis and neurologic deterioration, accompanied by an elevated mean corpuscular volume and thrombocytopenia was thought to be caused by nitrous oxide–induced exacerbation of a preexisting vitamin B12deficiency. The diagnosis of preexisting vitamin B12deficiency was supported by the findings of an increased mean corpuscular volume before craniosynosthosis repair, coupled with the finding of a low maternal serum vitamin B12level.
Although adults depend on exogenous vitamin B12, a deficient diet rarely is the cause of a deficiency state. 5 Instead, gastric achlorhydria and decreased gastric secretion secretion of intrinsic factor are more likely causes in adults. Other causes include postgastrectomy, intestinal bacterial overgrowth, and surgical disease or resection of the ileum. In the breast-fed infant the most common cause of low serum vitamin B12is a maternal vitamin B12deficiency, especially in infants of vegan mothers. 11 Deficiency of intrinsic factor, disorders of absorption, inborn errors of transport, and intracellular use of vitamin B12also should be considered. In our case, the cause of the low serum vitamin B12was not established.
Our decision to avoid nitrous oxide for the second procedure was based on the concern that, despite large doses of daily vitamin B12,the patient’s serum levels remained abnormal. Experimental data suggests that the minimum duration and minimum exposure levels of nitrous oxide necessary to produce neurologic complications in humans is not known. 12 Consequently, the procedure was performed with use of an oxygen source, a Mapleson D circuit, and intravenous anesthesia.
We conclude that the use of nitrous oxide in an infant with unexplained neurologic impairment possibly should be avoided, until vitamin B12deficiency can be ruled out. An infant that presents with an unexplained metabolic acidosis and neurologic defect several weeks after nitrous oxide general anesthesia should be evaluated for vitamin B12deficiency.
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