4. Inhalational Agents: Nitrous Oxide Flashcards
Anaesthesia
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
Dopamine receptors
. 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.
Analgesia
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.
Physical properties:
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.
Advantages in Clinical Practice
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.
Disadvantages in Clinical Practice
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).
Disadvantages in Clinical Practice
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.)
Bone marrow toxicity and neurotoxicity.
— 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
Teratogenicity
— 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.
Outcome after Major Surgery: ENIGMA and ENIGMA II
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
Outcome after Major Surgery: ENIGMA and ENIGMA II
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
