Case Reports  |   October 1995
Severe Neurologic Deficit after Nitrous Oxide Anesthesia
Author Notes
  • (Hadzic) Chief Resident in Anesthesiology.
  • (Glab) CA-2 Resident in Anesthesiology.
  • (Sanborn) Associate Director of Anesthesia; Associate Clinical Professor of Anesthesiology.
  • (Thys) Director of Anesthesia; Professor of Clinical Anesthesiology.
  • Received from the Department of Anesthesiology, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York. Submitted for publication January 27, 1995. Accepted for publication May 10, 1995.
  • Department of Anesthesiology, St. Luke's-Roosevelt Hospital Center, Amsterdam Avenue at 114th Street, New York, New York 10025.
Article Information
Case Reports
Case Reports   |   October 1995
Severe Neurologic Deficit after Nitrous Oxide Anesthesia
Anesthesiology 10 1995, Vol.83, 863-866.. doi:
Anesthesiology 10 1995, Vol.83, 863-866.. doi:
Key words: Anesthesia: adverse effects. Anesthetics. gases: nitrous oxide. Anemia: pernicious anemia. Complications: neurologic; paralysis. Spinal cord: paraplegia. Vitamins: B12.
THE interaction of nitrous oxide and vitamin B12is well known from experimental studies in animals and anecdotal clinical reports. [1-4] Nitrous oxide oxidizes cobalamin in vitamin B12and disrupts several pathways involved in one-carbon chemistry. The result is an irreversible inactivation of the enzyme methionine synthase, which requires vitamin B12in the +1 oxidation state to act as its coenzyme. The clinical syndrome associated with oxidation of vitamin B12develops after prolonged exposure to nitrous oxide and consists of megaloblastic erythropoiesis and subacute combined degeneration of the spinal cord. [2-4] We present the case of a patient who developed a severe neurologic deficit 6 weeks after anesthesia with nitrous oxide.
Case Report
A 47-yr-old previously healthy former ballet dancer underwent elective cosmetic surgery of the face and scalp. Her preanesthesia assessment disclosed a history of thyroidectomy at age 16 and a remote history of anemia. The patient did not remember the exact indications for the operation or the type of anesthesia that she received in her home country (Russia) but denied any difficulties perioperatively. She denied smoking or alcoholism and claimed to be an occasional vegetarian. There was no history of intake of vitamins or other medications. Her hematocrit was 41% with a mean corpuscular volume of 99 femtoliters (fl; normal 81-99 fl). The surgical procedure lasted 8 h, during which the patient was anesthetized with fentanyl (200 micro gram) and isoflurane (0.27-0.7%) in a mixture of oxygen and 70% N2O. lntraoperative blood loss was less than 100 ml. Her intraoperative and immediate postoperative course was uneventful, and she was discharged home in good condition. Six weeks later, the patient was readmitted to the hospital with complaints of paresthesia in the extremities and unsteady gait. On admission, she gave a history of loss of balance, frequent falling, and worsening numbness and weakness in her lower back, suprapubic region, and lower extremities. A neurologic examination disclosed weakness and decreased muscle tone in both lower extremities. The patient walked with a broad base. The complete blood count on admission included hematocrit of 34% and mean corpuscular volume of 105 fl. Results of magnetic resonance imaging of her head and spine were normal. Analysis results of her cerebrospinal fluid were normal except for slightly increased proteins. The serum vitamin B12concentration was 8.0 pg/ml (normal 130-770 pg/ml) and folate concentration 19.5 ng/ml (normal 1.5-20.6 ng/ml). An electrophysiologic study was suggestive of a generalized demyelinating polyneuropathy, whereas a Schilling test was diagnostic of pernicious anemia. Her neurologic condition gradually improved with monthly injections of cobalamin. Sixteen weeks after the initiation of therapy, her only complaint was mild fatigue.
A case of severe neurologic deficit after nitrous oxide anesthesia in a patient with unsuspected pernicious anemia is described. To date, there are three reports of the development of subacute combined degeneration of the spinal cord after routine nitrous oxide anesthesia in five patients. [5-7] All of these patients, including the one in our report, had unrecognized subclinical vitamin B12deficiency and underwent routine surgery under nitrous oxide anesthesia in duration of at least 90 min. After an uneventful immediate perioperative period, several weeks later they presented with severe neurologic deficits. They all had hematologic features of megaloblastic anemia at some time, decreased vitamin B12concentrations, and a favorable but slow response to B12therapy (Table 1).
Table 1. Neurologic Sequelae Associated with Nitrous Oxide Anesthesia in Patients with Unrecognized Vitamin B12 Deficiency
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Table 1. Neurologic Sequelae Associated with Nitrous Oxide Anesthesia in Patients with Unrecognized Vitamin B12 Deficiency
In our patient, the diagnosis of subacute combined degeneration of the spinal cord was made on the basis of the following criteria: (1) recent exposure to nitrous oxide, (2) typical clinical presentation, (3) postoperative anemia unexplained by intraoperative blood loss, (4) increase in mean corpuscular volume, (5) low serum vitamin B12concentration, (6) normal values for folate, (7) slightly increased protein concentration in her cerebrospinal fluid, and (8) the results of the electrophysiologic study. Underlying pernicious anemia is the most likely explanation for our patient's failure to restore her levels of B sub 12 postoperatively. Other neurologic diseases that can be confused with vitamin B12deficiency include multiple sclerosis, cervical spondylosis, spinal cord tumors, and syphilitic meningomyelitis. These were excluded by her clinical course and by the results of the diagnostic tests. However, a coincidental administration of nitrous oxide to a patient who was in the midst of developing neurologic manifestations associated with pernicious anemia cannot be excluded.
The interaction of cobalamin and nitrous oxide was first reported by Lassen et al. [2] in 1956. Patients undergoing treatment for tetany with prolonged sedation with nitrous oxide experienced hematologic changes identical to those produced by vitamin B12deficiency. The neurologic effects of chronic exposure to nitrous oxide were reported in 1978 in several individuals who used nitrous oxide for recreational purposes. [3,4] They presented with a neurologic syndrome consisting of weakness and spasticity of the legs, ataxia, paresthesias of the hands and legs, and mental status changes.
To date, cobalamin is known to be required in two biochemical reactions in humans: the conversion of L-methylmalonyl coenzyme A into succinyl coenzyme A and the formation of methionine by methylation of homocysteine. The transmethylation reaction is essential to DNA synthesis and to the maintenance of the myelin sheath by the methylation of myelin basic protein. Active vitamin B12contains cobalt in its reduced form (Cobalt +). Nitrous oxide irreversibly oxidizes active reduced cob(I)alamin to inactive cob(III)alamin. [1] The inactive cobalamin is excreted so that repetitive exposure to nitrous oxide results in depletion of cobalamin body stores.
The most common causes of vitamin B12deficiency are pernicious anemia, postgastrectomy, intestinal organisms ("blind loops"), and ileal abnormalities. Certain clinical features of vitamin B12deficiency are common to all etiologies. The hematologic manifestations are almost entirely the result of anemia. The gastrointestinal manifestations reflect the effect of cobalamin deficiency on the rapidly proliferating gastrointestinal epithelium. The neurologic complications are the most worrisome, because infrequently, patients may fail to revert to normal with treatment. [8] The most prominent findings are in the peripheral nerves and dorsal and lateral columns of the spinal cord. Fragmentation and spongy degeneration of myelin usually begin in the lower cervical and upper thoracic regions. [9] Patients first complain of paresthesias in the hands or legs. Neurologic symptoms progress if untreated; ataxia and stiffness eventually are followed by paraplegia and dysfunction of bowel and bladder. Occasionally, the neurologic disease occurs in a patient with a normal hematocrit and normal erythrocyte indexes. [8] 
The shortest duration of exposure to nitrous oxide required to produce megaloblastic hematopoiesis varies among patients and may depend on their general health. In healthy patients undergoing general surgery, mild megaloblastic bone marrow changes can be seen after 12 h of exposure to 50% N2O. These changes become marked after 24 h of exposure. [10] Seriously ill patients could be at increased risk of nitrous oxide-related bone marrow changes. [11] Experimental data suggest that the threshold concentration of nitrous oxide below which nitrous oxide has no biochemical effect is 1,000 ppm (0.1%). [12] In one study, 3 of 20 dentists exposed to mean concentrations of nitrous oxide of up to 4,600 ppm had abnormal bone marrow. [13] It has been found that methionine synthase activity is low after several hours of routine anesthesia with nitrous oxide. [14] Recovery of the enzyme activity takes 3-4 days, because the oxidation of cobalamin is irreversible and new enzyme must be synthesized to restore the activity. The incidence of nitrous oxide-related neurologic complications and the minimum duration of exposure to nitrous oxide required to produce neurologic complications are not known. It is possible that nitrous oxide-related neurologic manifestations are mostly mild or transient and thus underreported, because most anesthesiologists are not aware of the progress of their patients several weeks after anesthesia and surgery. We learned about our case after the patient was admitted to the hospital and an anesthesiology consultation was requested by the surgeon.
We conclude that the use of nitrous oxide should be reconsidered in patients who have an increased mean corpuscular volume on their routine preoperative hematology screen, history of unexplained anemia, or vitamin B12deficiency. In a patient who presents with a complex neurologic defect several weeks after anesthesia with nitrous oxide, cobalamin deficiency should be suspected.
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Lassen HCA, Henriksen E, Neukirch F, Kristensen HS: Treatment of tetanus: Severe bone-marrow depression after prolonged nitrous-oxide anesthesia. Lancet 1:527-530, 1956.
Layzer RB: Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 2:1227-1230, 1978.
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Table 1. Neurologic Sequelae Associated with Nitrous Oxide Anesthesia in Patients with Unrecognized Vitamin B12 Deficiency
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Table 1. Neurologic Sequelae Associated with Nitrous Oxide Anesthesia in Patients with Unrecognized Vitamin B12 Deficiency