Introduction
Nitrous oxide is very much a part of traditional anaesthesia for neurosurgery today. This is more as a result of habit as well as comfort. The reason we are not motivated to replace it with medical air is because the harmful effects of nitrous oxide are not obvious to us at a clinical level in most cases. The biochemical and neuronal effects of nitrous oxide has been studied extensively and proved to be harmful. What is also important is that the alternative i.e. medical air is easily available as a part of most modern anaesthesia machines.

If we were to address the advantages of the agent there are certainly a few:

1. It brings down the overall requirement of anaesthetic drugs
2. It is very useful in eliminating awareness during anaesthesia
3. Combined with 33% oxygen it is a safe mixture
4. The side effects of nitrous oxide probably are very theoretical and have no consequence for shorter durations of anaesthesia
5. While in our country it may be considered expensive, in the more affluent West it is considered a cheap agent.
   Let us try to understand nitrous oxide better and to judge the risks of this drug against its alternative, namely medical air
   1. The commonest known disadvantage of nitrous oxide is megaloblastic bone marrow depression in direct proportion to the duration of anaesthesia
      It is due to N2O inactivation of B121 and irreversible inactivation of methionine synthetase and deoxythymidine synthesis and defects in folate metabolism. Effectively it produces a picture like pernicious anaemia. Once the existing B12 + methionine synthetase has been deactivated, physical balance can only be restored by absorption of new vitamin B12 and the synthesis of new methionine synthetase in the body. Physical balance can’t be restored by simply supplementing with additional vitamin B12 because it will not become bioavailable unless the body has enough methionine synthetase enzymes to activate it. Just how much of the enzyme gets knocked out is dependent on length and concentration of the nitrous oxide exposure as well as individual sensitivity. The relatively short exposure during clinical anaesthesia has usually been considered harmless though there is a 50% decrease in methionine synthetase activity even after two hours of exposure.
      In patients with folic acid deficiency, a single exposure to nitrous oxide has caused spinal cord degeneration.2
   2. Diffusion hypoxia is a well documented phenomenon.N2O will diffuse into air-containing cavities within the body faster than nitrogen diffuses out. This results in a temporary increase in either the pressure and/or volume of the cavity depending upon the distensibility of its walls. The magnitude of the effect is proportional to the blood supply of the cavity, the concentration of N2O inhaled and the length of time the patient is exposed to N2O. Significant morbidity or even death (very rare) can result from this phenomenon.
   3. Pneumocephalus is fairly common after intracranial surgery. In most cases it is undiagnosed and probably clinically insignificant. If nitrous oxide has been used the size of pneumocephalus will certainly be larger (N2O is 34 times more expansile than nitrogen in air) and symptoms in proportion. Although the incidence and size of pneumocephali decrease over the subsequent postoperative days, a significant number of patients have an intracranial air collection large enough to put them at risk for complication if nitrous oxide is used during a second anaesthetic in the first 3 weeks after the first procedure. 3
   4. Venous air embolism has been typically described as a complication of neurosurgery It is said to be 10% for cervical laminectomy to 80% of patients undergoing craniotomy in the sitting position.4 It may rarely occur in spinal instrumentation. Nitrous oxide causes the size of the embolus to be significantly larger and this may have serious cardiovascular consequences.
   5. Because of its effects on the pressure and volume characteristics of air-containing spaces, the decision to use nitrous oxide should be considered carefully in patients with bowel obstruction, pneumothorax, middle ear and sinus disease, and following cerebral air-contrast studies.5
   6. In 1938 C.D. Courville 6 published “The pathogenesis of necrosis of the cerebral gray matter following nitrous oxide anaesthesia” — an article which presents photographs of vacuolated cortical neurons from patients who died subsequent to administration of nitrous oxide. Sixty years later, Jevtovi-Todorovi and co-authors published compelling evidence that N2O causes vacuolation of both the endoplasmic reticulum and mitochondria of neurons in the posterior cingulate and retrosplenial cortices of rats.

      Nitrous oxide’s mechanism of action is NMDA receptor antagonism,7,8 and like other NMDA antagonists, N20 has been shown to reduce damage from excessive glutamate release. Unfortunately, however, because NMDA also excites inhibitory neurons, NMDA blockade causes inhibition of GABA release, and thus general disinhibition. This is probably a component of the mechanism by which N20, like other NMDA antagonists (e.g., ketamine, phencyclidine, dextrorphan, MK-801), can cause neural damage.

      The effect that nitrous oxide has on the neuroprotective efficacy of primary anaesthetics has been addressed by several investigations. Multicentric studies (on rat models) have shown that
      1. Co-administration of nitrous oxide virtually eliminates the protective effect of thiopental in the same model.9
      2. That 0.5 MAC nitrous oxide reduces the protective effect of isoflurane by half,10 and
      3. More recently it has been shown that nitrous oxide converts a non-toxic dose of ketamine into a substantially toxic dose in rats.
         
         There are some studies that show that the deleterious effects of nitrous oxide can be alleviated or even by the simultaneous or preadministration of recombinant EPO and pretreatment with methionine.
      4. Less proved is the hypothesis that even brief exposure to nitrous oxide causes a substantial increase in plasma homocysteine which can increase coagulation and decrease flow-mediated vasodilation, either of which could complicate recovery after surgery.11 Prolonged hyperhomocysteinaemia is an independent risk factor for cerebrovascular disease as well as myocardial infarction.
   7. One of the most serious side effects of nitrous oxide is that it can interfere with DNA synthesis.12 This effect has been observed with nitrous oxide exposures of as little as 2 hours (Amos RJ. 1982; Nunn JF. 1986).
   8. There is some proof of theatre and dental room contamination causing neurological impairment and higher abortion rates in the theatre personnel.13
   9. Studies have demonstrated that N20 diffuses into the endotracheal cuff and replaces air giving higher cuff pressures.14 Authors compared the use of saline vs air to inflate the cuff of the endotracheal tube during anaesthesia and found that the incidence of sorethroat, hoarseness, and dysphagia and largyngeal oedema was far less in the saline group
   10. 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.15
   11. The omission of nitrous oxide significantly reduces PONV.16
   12. The use of nitrous oxide as an addictive agent or a psychotropic agent is out of the context of our discussion but we should bear in mind that it should not be used in previously addicted patients particularly those of narcotic abuse. Nitrous oxide is a partial agonist of the mu, kappa, and sigma opioid receptors.17 There is a danger of precipitating myeloneuropathy in these patients.

Conclusion
Despite so much evidence such clinical ill effects are not seen in regular practice to justify against its traditional use. However in critical cases, or in the event of a neurosurgical or anaesthetic mishap or compromise, the use of N2O lead to worsening of outcome.

Today the outcome of neurological surgery is very promising and every effort is taken to prevent the minutest morbidity. Such an expectation needs to be backed by judicious use of drugs/agents which will promote this philosophy.

Modern anaesthesia machines have incorporated air Nitrous oxide today which is only a carrier gas. Medical air serves the same purpose, yet it is not being put into routine use. This is probably just a mindset. The argument is that patients require more analgesia and depth of anaesthesia. This is true. However with modern day IV drugs narcotics and drugs such as propofol this should be very easy and safe. Medical air is 1/6th the cost of N2O and combined with its advantages should be used more regularly particularly in neurosurgical operations of long duration.

References

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2. Hadzic A, Glab K, Sauborn KC, et al. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 1995; 83 : 863-6.
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