Nitrous Oxide

Nitrous oxide is an inhaled gas with analgesic, sedative and weak anaesthetic properties, a minimum alveolar concentration above 100%, and very low blood solubility. It is used for analgesia in labour and brief procedures (as a 50% oxygen mixture), and as an adjunct to volatile anaesthesia. It expands closed gas spaces, inactivates vitamin B12 with prolonged exposure, and can cause diffusion hypoxia at the end of anaesthesia.

Class. Inhaled general anaesthetic and analgesic.

Mechanism. NMDA receptor antagonism and opioid-mediated descending pain inhibition, with weak GABA-A effects. It inhibits methionine synthase by oxidising vitamin B12.

Pharmacokinetics. Blood-gas partition coefficient 0.47. Minimum alveolar concentration 104%, so it cannot give surgical anaesthesia alone at normal pressure. Onset of analgesia 2 to 3 minutes, offset within 5 minutes. Not metabolised in significant amounts; excreted unchanged through the lungs. The second gas effect speeds uptake of a coadministered volatile agent.

Indications are analgesia in labour and for short painful procedures, anxiolysis and sedation (including in children and dentistry), and an adjunct to volatile agents in general anaesthesia.

Analgesia (50% nitrous oxide and 50% oxygen mixture)

• Self-administered by demand valve; begin inhalation 30 to 60 seconds before a contraction or painful stimulus.
• No fixed maximum dose; titrate by the patient’s response, with the patient remaining conscious.
• Duration: limit continuous use to a few hours; avoid continuous use beyond 24 hours or repeated courses over several days, and check vitamin B12 in frequent users.
• Cylinders are stored above 10 degrees Celsius for at least 24 hours before use, to prevent separation of the mixture (Poynting effect).

Anaesthesia adjunct

• 50 to 70% nitrous oxide in oxygen, with inspired oxygen of at least 30%, in combination with a volatile agent or intravenous infusion. It lowers volatile requirement by about half at 60%.
• At the end of anaesthesia, give 100% oxygen for 3 to 5 minutes to prevent diffusion hypoxia.

Children

• 50% mixture for cooperative children from about 4 to 5 years, under supervision with continuous monitoring.
• As adjunct to anaesthesia: 50 to 70% nitrous oxide in oxygen, with at least 30% oxygen.

Contraindications. Pneumothorax; bowel obstruction or distension; recent intraocular gas injection (sulphur hexafluoride or perfluoropropane, for up to 3 months); middle ear surgery with tympanoplasty; pneumocephalus or recent neurosurgery with intracranial air; air embolism; decompression sickness; severe pulmonary hypertension or bullous lung disease; vitamin B12 deficiency or neurological disease from it; impaired consciousness or inability to cooperate (50% mixture); first trimester of pregnancy for elective procedures (relative).

Boxed-warning-level risks. Expansion of air-filled spaces (pneumothorax, bowel, middle ear, pneumocephalus); hypoxia if the delivery system fails or the oxygen fraction is less than 30%; megaloblastic anaemia, myeloneuropathy and subacute combined degeneration after prolonged or repeated exposure, especially with vitamin B12 deficiency; occupational exposure (scavenging).

Adverse effects. Common: dizziness, nausea, vomiting, euphoria, dissociation, headache. Serious: diffusion hypoxia, hypoxic mixture delivery, pneumothorax expansion, bone marrow suppression, peripheral neuropathy, myeloneuropathy, raised intracranial pressure and increased pulmonary vascular resistance.

Interactions. Opioids, benzodiazepines and volatile agents add sedation and respiratory depression. Methotrexate toxicity increases through additive folate inhibition. Nitrous oxide reduces the minimum alveolar concentration of volatile agents.

Common prescribing errors. Using in a patient with a pneumothorax or bowel obstruction; omitting 100% oxygen at the end of anaesthesia; prolonged exposure in patients with vitamin B12 deficiency or poor nutrition; failing to check the gas supply connections and oxygen analyser; poor scavenging.

Special groups

• Pregnancy: use in labour is common; avoid in the first trimester for elective procedures.
• Breastfeeding: compatible.
• Older adults: usual doses, with attention to cognition and B12 status.
• Kidney impairment: no adjustment.
• Liver impairment: no adjustment.
• Regional: check cylinder connections, the oxygen failure alarm and an inline oxygen analyser, because hypoxic mixtures from crossed supplies have caused harm; use scavenging to limit staff exposure.

Formulations. Compressed gas cylinders (blue) and pipeline supply; pre-mixed 50% nitrous oxide and 50% oxygen cylinders for demand-valve systems.

Administration. Deliver through an anaesthetic machine with a fail-safe oxygen-nitrous oxide interlock, or a demand valve with mouthpiece or mask. Scavenge exhaled gas. Check connections before use.

Baseline. Indications and contraindications (air spaces), vitamin B12 and folate status in prolonged use, pregnancy, respiratory status, and ability to cooperate.

Monitoring. Oxygen saturation and inspired oxygen fraction; level of consciousness; end-tidal gas concentration in anaesthesia. Complete blood count and vitamin B12 in repeated or prolonged use.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop the gas and give 100% oxygen for hypoxia, new chest pain, abdominal distension, excessive sedation or loss of cooperation. Limit total exposure in vulnerable patients.

Referral and escalation. Suspected pneumothorax needs oxygen and decompression. Prolonged exposure with numbness, weakness, gait disturbance or anaemia needs vitamin B12 testing, vitamin B12 replacement, and neurological review.