History of nitrous oxide (N2O)
Nitrous oxide was first produced by the English chemist and Presbyterian minister, Joseph Priestley, in 1772 and further investigated by Humphrey Davy in 1799 at the Pneumatic Medical Institution in Bristol. In his book on nitrous oxide, Davy recorded that breathing the gas helped to relieve toothache - from which he was suffering at the time - and suggested that: 'it may probably be used with advantage in surgical operations'.
It was first used for dental extractions by Wells in 1844 but was superseded by ether and chloroform because they were more potent and convenient to use. N2O was reintroduced by Colton in 1863.
N2O is manufactured by heating ammonium nitrate to 250°C
NH4NO3 » N2O + 2H2O
During this process, a number of contaminants may be produced, unless the temperature is carefully controlled. These include NH3, N2, NO, NO2 and HNO3, and they are actively removed by passage through scrubber, caustic soda and water.
French blue cylinders are used to store N2O in a liquid phase with its vapour on top at a gauge pressure of 4400 kPa at room temperature. As the liquid is less compressible than a gas, the cylinder should be only partially filled.
The filling ratio is the weight of the fluid in the cylinder divided by the weight of water required to fill the cylinder. In the UK, the filling ratio for N2O is 0.75, but in hotter climates the filling ratio needs to be 0.67, to avoid cylinder explosion.
Hospitals store N2O in large cylinders (e.g. size J) in two groups of cylinder manifolds.
Molecular weight 44
Boiling point -88°C
Critical temperature 36.5°C
Critical pressure 72 bar
Partition coefficients Blood/gas 0.47, Oil/gas 1.4
The gas is a powerful analgesic in concentrations above 20%. Despite a MAC of 105%, N2O is a central nervous system depressant and in concentrations of 80% will cause loss of consciousness in most subjects. It increases cerebral blood flow and should be avoided in patients with raised intracranial pressure. During neurosurgery, it may expand and result in an air embolus, causing a pneumoencephalocoele.
Nitrous oxide decreases myocardial contractility in vitro; in vivo, the mean arterial pressure is usually well maintained by a reflex increase in peripheral vascular resistance. However, patients who are unable to increase their sympathetic drive, the direct myocardial depressant effects may significantly reduce cardiac output. It does not sensitise the heart to catecholamines.
N2O is non-irritant and does not cause bronchospasm. It causes a small fall in tidal volume that is offset by an increase in respiratory rate so that the minute volume and CO2 remain unchanged. It may cause diffusion hypoxia at the end of surgery.
It expands air-filled cavities because it is 40 times as soluble as nitrogen; thus, it passes from the blood into the cavity faster than nitrogen can diffuse out. This can double the size of a pneumothorax in 10 minutes at a concentration of 70%. Also expands air embolism and may cause pneumoencephalocoele after neurosurgery.
Nitrous oxide can cause the expansion of gas-containing bowel. It is associated with postoperative nausea and vomiting.
The use of nitrous oxide during general anaesthesia in gas-filled eyes may have disastrous visual results caused by gas expansion and elevated intraocular pressure. The gases SF6 and C3F8 are most commonly used. Patients must be advised of the potentially catastrophic results of undergoing general anaesthesia before their intraocular gas bubble has resorbed. The use of nitrous oxide for patients with intraocular gas should be avoided. It may be prudent for patients with intraocular gas to wear notification bracelets warning anaesthetists about the presence of intraocular gas lest emergency surgery be needed by a patient unable to advise anaesthesia personnel about the potential danger.
[i] Visual Loss after Use of Nitrous Oxide Gas with General Anesthetic in Patients with Intraocular Gas Still Persistent Up to 30 days after Vitrectomy. Anesthesiology: Volume 97(5) November 2002 pp 1305-1308
[ii] Complications of general anesthesia using nitrous oxide in eyes with preexisting gas bubbles. Fu AD, McDonald HR, et al. Retina. 2002 Oct;22(5):569-74.
N2O does not affect renal or hepatic function, or uterine or skeletal muscle tone.
Nitrous oxide is excreted unchanged through the lungs and skin.
Methionine synthetase appears to be directly inhibited by N2O, which also oxidises the cobalt ion present in vitamin B12, so that it is unable to act as a cofactor for methionine synthetase. The result is reduced synthesis of methionine, thymidine, tetrahydrofolate and DNA. Prolonged use of high concentrations of N2O (>6 hours) can result in clinical syndromes akin to pernicious anaemia, megaloblastic anaemia and pancytopenia. Protracted use of the gas may also lead to the development of a peripheral neuropathy or a neurological syndrome that resembles subacute combined degeneration of the cord. Nitrous oxide is teratogenic in animals when administered during early pregnancy. Experimentally, this effect is prevented in rats given folinic acid; however, this has never been demonstrated unequivocally in humans.
Contraindications to Nitrous Oxide
N2O should not be used for patients with bowel obstruction, pneumothorax, middle ear and sinus disease, and following cerebral air-contrast studies. Many anaesthetists feel that use of N2O should be restricted during the first two trimesters of pregnancy because of its effects on DNA production and the experimental and epidemiological evidence that N2O causes undesirable reproductive outcomes. Since N2O affects white blood cell production and function, it has been recommended that N2O not be administered to immunosuppressed patients or to patients requiring multiple general anaesthetics.
[i] Nitrous oxide and the fetus. A review and the results of a retrospective study of 175 cases of anaesthesia for insertion of Shirodkar suture
Aldridge LM, Tunstall ME
Br J Anaesth 1986; 58: 1348-56
[ii] Omitting nitrous oxide in general anaesthesia: meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials
Tramer M, Moore A, McQuay H
Br J Anaesth 1996; 76: 186-93
[iii] Prefixed equimolar nitrous oxide and oxygen mixture reduces discomfort during flexible bronchoscopy in adult patients: a randomized, controlled, double-blind trial.
Atassi K, Mangiapan G, Fuhrman C, Lasry S, Onody P, Housset B.
Chest. 2005 Aug;128(2):863-8
STUDY OBJECTIVES: Flexible bronchoscopy (FB) is an invasive procedure associated with patient discomfort and frequent nose pain. A simple sedation procedure that does not require the intervention of an anesthetist is of interest. The aim of this prospective, randomized, double-blind study was to assess efficiency of nitrous oxide inhalation on the reduction of FB-induced discomfort in adult patients.
DESIGN AND SETTINGS: Two hundred six patients were randomized to receive either a prefixed equimolar nitrous oxide/oxygen mixture (N2O) or a prefixed equimolar nitrogen and oxygen mixture (control). The primary outcome was stress as assessed by pulse rate and systemic BP during the procedure. Secondary outcomes were self-assessed pain using a visual analog scale (VAS) and patient satisfaction based on a questionnaire. Adverse events were recorded.
RESULTS: A significant increase in BP was observed only in the control group (p = 0.003), while pulse rate values did not differ between the two groups. As assessed by the VAS, pain was lower in the N2O group as compared to placebo (p = 0.02). Nose pain and cough were also significantly reduced by N2O. Adverse events, mostly anxiety, were reported in 10 patients.
CONCLUSION: These results indicate that equimolar N2O inhalation is efficient in reducing patient discomfort and may be an alternative to general anesthesia.
[iv] Ceasing routine use of nitrous oxide-a follow up.
Enlund M, Edmark L, Revenas B
Br J Anaesth 2003; 90: 686-8