Toxicity after intermittent inhalation of nitrous oxide for analgesia

A mixture of nitrous oxide and oxygen in equal proportions (Entonox or Equanox) is an effective analgesic and is considered safe with minimal side effects. The mixture is ideal for treating short term pain. We report a serious neurological problem in a patient using such a mixture to control pain from the daily packing of a large perineal cavity.

Case report

A 21 year old man presented with a short history of being unable to stand. He had had a series of serious operations for the treatment for inflammatory bowel disease over a four year period—colectomy, ileostomy, and laparotomy with the formation of an ileoanal pouch. He developed pelvic sepsis requiring the laying open of an extensive perineal abscess.

The provision of postoperative analgesia for a perineal abscess proved difficult, during daily changes of packs to the cavity. Doctors gave paracetamol, diclofenac, regular oral slow release opioids, morphine tablets, and a 50:50 mixture of nitrous oxide and oxygen for managing the incident pain while changing dressings.

The hospital gave the man a 300 litre cylinder of the mixture as a short term arrangement over the Christmas period to provide analgesia for dressing changes. The man was to be readmitted after two weeks for review. When he was not readmitted as planned, his family arranged for replacement with larger cylinders. The hospital issued increasing amounts during four months, resulting in the weekly consumption of 1280 litres of nitrous oxide mixture. The district nurses contacted the hospital's pain team to express concern about the amount of mixture that the patient was using.

The man had had progressive severe difficulty in walking for six weeks, so his general practitioner referred him to a neurologist with no reference to the use of nitrous oxide. The neurologist diagnosed him as having a spinal cord disorder and admitted him to hospital for more detailed investigation.

On admission, the patient weighed 60 kg; he had a drain in the rectal pouch and reported severe pain in his perineum. He was unable to hold a cup or put on his glasses owing to severe lack of coordination and was unable to stand independently owing to severe ataxia.

The patient reported that his only drugs at that time were the standard analgesics, vitamin and mineral supplements, iron sulphate, citalopram, zinc, and paracetamol. Neurological examination showed severe pseudo-athetosis of the fingers and arms, and motor examination of his arms and legs, brisk reflexes and bilateral flexor plantar responses was normal. Sensory examination found severe loss of joint position sense in the hands and feet and loss of vibration sense in all four limbs with no spinothalamic sensory loss or trunkal sensory level.

He was diagnosed as having a dorsal column spinal syndrome (probably subacute combined degeneration), and doctors gave 1000 μg hydroxocobalamine (vitamin B-12) after taking blood for vitamin B-12 and other haematological and biochemical estimations.

Concentration of vitamin B-12 was slightly below the normal range (269 ng/l; normal > 300 ng/l). Serum and red cell folate were normal. The patient denied having taken folate or vitamin B-12 antagonists.

A long lesion of the dorsal column, typical of subacute combined degeneration, was evident in a magnetic resonance imaging scan of the cervical spinal cord (figure).

Figure 1.

Magnetic resonance image showing dorsal column lesion (arrow) of the spinal cord

Transverse myelitis was a possible differential radiological diagnosis in view of the normal vitamin B-12 concentration. Viral and atypical bacterial organism serological tests were negative. Because of pelvic sepsis and the man's evident rapid improvement, a lumbar puncture was not done.

After his discharge the neurological team learnt that the man had been taking nitrous oxide, explaining the paradoxical clinical picture of subacute combined degeneration with normal vitamin B-12 and folate concentrations. Appropriate aftercare was arranged with further injections of vitamin B-12 and to provide psychological support to manage his evident addiction.

On follow up at three months the man had no gait ataxia and normal hand function and was independent in all activities of daily living. The case illustrates the need to be aware of adverse effects of all drugs—even those considered to be among the safest.

Discussion

Nitrous oxide can interfere with the metabolism of vitamin B-12 and can cause spinal cord degeneration.¹,² The mechanism of neuropathology with nitrous oxide is due to inactivation of vitamin B-12, which leads to impaired methionine synthesis. The cobalt atom in vitamin B-12 donates two electrons to nitrous oxide¹:

This is followed by the rapid reaction of Co³⁺ with Co⁺ resulting in the failure of methylation of basic proteins in myelin sheaths³:

Polyneuropathy and spinal cord degeneration are the most common neurological manifestations of vitamin B-12 deficiency. The diagnosis is made clinically and by finding a decreased serum vitamin B-12 concentration. (Often there is no macrocytosis on the blood film, as in this case). The typical magnetic resonance imaging findings show a typical dorsal cervical cord lesion.⁴

Reports describing spinal cord degeneration of the cord after treatment with nitrous oxide have generally been attributed it to prolonged exposure to the gas and poor nutrition.⁵,⁶ Toxicity related to the prolonged intermittent exposure of low concentrations of nitrous oxide has been described in experimental animals.⁷,⁸

In this case, nitrous oxide probably complicated longstanding malnutrition, causing neurological complications with intermittent administration of small amounts of nitrous oxide. The good safety record and rapid action of 50:50 nitrous oxide-oxygen mixtures in pain management make it a desirable agent, particularly for pain during medical procedures. It is important, however, that health workers who prescribe nitrous oxide are aware of its potential long term adverse effects, particularly in patients with chronic illness. After this incident, our hospital has put in place appropriate procedures to guard against a repetition.