4. Inhalational Agents: Nitrous Oxide

GABAA (mainly inhibitory) and NMDA (mainly excitatory) receptors in the CNS: N2O appears to have no effect on GABAA receptors but strongly inhibits NMDAactivated currents. There is concern that NMDA antagonists can be neurotoxic, which is a potential problem only if N2O is used alone under hyperbaric conditions (which is a mainly theoretical scenario). If GABAA agonist agents or facilitators (such as benzodiazepines) are used in addition, they may exert a protective effect to offset this damage

. N2O stimulates some dopaminergic neurons; this may mediate release of endogenous opioid peptides and explains why the effects of N2O are partly antagonized by naloxone.

Opioid peptide release: the release of endogenous ligands for opioid receptors occurs in the peri-aqueductal grey matter of the midbrain, stimulates descending inhibitory noradrenergic pathways which modulate pain processing via noradrenaline release. Noradrenaline acts at α2-receptors in the dorsal horn Other theories: N2O may also activate a supraspinal descending pain inhibition system with an increase in encephalinergic interneurons in the substantia gelatinosa of the cord. These endogenous encephalins inhibit transmission via substance P-dependent synapses.

N2O has a rapid onset and equilibration because of its very low blood–gas partition coefficient (0.47). Its boiling point is -88.5 °C; critical temperature 36.5 °C; and MAC 105%. It is manufactured in a simple process of heating ammonium nitrate to a temperature of 240 °C (at higher temperatures the exothermic reaction risks detonation); NH4NO3 → 2H20 + N2O. Metabolism: N2O undergoes a negligible amount of metabolism by gut bacteria (0.004%) so in effect is excreted unchanged.

It is a useful carrier gas for more potent anaesthetic agents.
It has a rapid onset and equilibration (blood–gas partition coefficient of 0.47).
The induction of anaesthesia is accelerated via the second gas effect, in which the rapid uptake of N2O from the alveoli increases the alveolar concentration of other agents. It is a potent analgesic whose effects are usually underestimated. The drug acts partly at opioid receptors and transiently has the potency of morphine. This is not surprising, given survey data showing that Entonox (N2O/O2) affords better pain relief during labour (effective analgesia in around 50% of mothers) than pethidine (effective analgesia in about 35%). It is associated with a significant reduction in chronic post-surgical pain.
It is a weak anaesthetic (MAC50 is 105%), but, in combination with its analgesic actions, it decreases the MAC of other inhalational agents.
It may offer some neuroprotection via the reduction of NMDA-induced glutamate excitatory toxicity.

Effect on air-filled spaces: the diffusing capacity ofN2Orelative tonitrogen is high (25). — In non-compliant air-filled spaces, pressure increases (in the middle ear, in nasal sinuses and in the eye if it has been filled with gas such as SF6 after vitreoretinal surgery). The pressure change is related arithmetically to the alveolar partial pressure of N2O, so that administration of 50% N2O leads to a pressure increase of 0.5 atmospheres. In compliant air-filled spaces, volume increases (significant for pneumothoraces, bullae, bowel, air embolus, cuffs of tracheal tubes). After 4 hours of 66% N2O, the volume of the bowel increases by 200%. The volume change is related geometrically to alveolar partial pressure of N2O; the percentage increase is given by the % N2O divided by (1.0 – FiN2O). So, at 50%, the final percentage volume increase is 50/0.5 = 100%. At 75%, a pneumothorax will triple in size after 30 minutes of N2O administratio Emesis: this is probably caused by a combination of its sympathomimetic and opioid effects, together with the effects of bowel distension.
Second gas effect: this results in diffusion hypoxia (which is of modest clinical relevance; it lasts less than 10 minutes and can be readily overcome by giving supplemental oxygen).

Cardiovascular system: N2O is a direct negative inotrope and chronotrope. Cardiac contractility is decreased if cardiac function is already impaired; its use exacerbating ischaemic change in any situation in which myocardial O2 supply is exceeded by demand. It is an indirect stimulant (via its sympathomimetic action). It increases pulmonary vascular resistance in the presence of pre-existing pulmonary hypertension. Respiratory depression: there is an increase in respiratory rate to offset decreased tidal volume; this is common to all volatile agents. Greenhouse effect: N2O is a greenhouse gas which is some 300 times as potent as CO2 in its potential to trap atmospheric heat; anaesthesia contributes about 1% of the global total. (Bacteria produce nitrous oxide naturally, and it is also generated by nitrate fertilizer use in agriculture.)

— A biochemical lesion in the liver (methionine synthetase inhibition) is demonstrable after only 40 minutes of N2O administration. — N2O oxidizes the cobalt atom in vitamin B12 (cyanocobalamin) from Co++ to Co3+ in a very simple reaction and thereby inactivates it. Vitamin B12 however, is a co-factor for the enzyme methionine synthetase. — Inhibition of methionine synthesis therefore prevents the production of methionine and tetrahydrofolate. — The administration of methionine and folinic acid will provide substrates to allow biosynthesis to continue below the level of the enzyme block

— These mechanisms plus its other actions are believed to contribute to possible teratogenicity; α1-adrenoceptor agonism is associated with disorders of left/right body axis development (such as situs inversus). The association is not strong; almost 25 million administrations of the drug take place in the USA annually without obvious sequelae.

ENIGMA trial recruited more than 2,000 patients who were undergoing major surgery expected to last more than 2 hours N2O than in the group that received 80% O2 in air, and concluded that the routine use of the agent should be questioned. No patients received 30% O2 in air, however, and so it was not possible to determine whether the purported beneficial effects were caused by a high FiO2, the avoidance of N2O, or both Subsequent to these methodological criticisms, the ENIGMA II trial recruited more than 7,000 patients of medium to high cardiovascular risk in a randomized single-blinded study. There were no differences in outcome between the two groups, although there was a 15% incidence of PONV in the nitrous oxide group. This difference too was eliminated by the administration of prophylactic antiemetics

ENIGMA trial recruited more than 2,000 patients who were undergoing major surgery expected to last more than 2 hours N2O than in the group that received 80% O2 in air, and concluded that the routine use of the agent should be questioned. No patients received 30% O2 in air, however, and so it was not possible to determine whether the purported beneficial effects were caused by a high FiO2, the avoidance of N2O, or both Subsequent to these methodological criticisms, the ENIGMA II trial recruited more than 7,000 patients of medium to high cardiovascular risk in a randomized single-blinded study. There were no differences in outcome between the two groups, although there was a 15% incidence of PONV in the nitrous oxide group. This difference too was eliminated by the administration of prophylactic antiemetics