INTRODUCTION-
Nitrous oxide , better known as ‘ laughing gas ‘ was first used to put patients to sleep more than 160 years ago. It has been used routinely in different anesthetic techniques worldwide. However , nowadays ,concerns and criticism regarding the safety profile of the world’s oldest general anesthetic have come up and today a raging debate on the propensity of nitrous oxide to cause post operative  complications and death is going on. Nevertheless, I vehemently say that nitrous oxide does not  increase the risk of complications and death in the patient after surgery. This lecture puts forth several points of scientific evidence to support this notion. The evidence was collected after doing an electronic search through various scientific data bases, journals and textbooks.
EVIDENCE AGAINST THE  OCCURRENCE OF COMPLICATIONS/ ADVERSE EFFECTS OF NITROUS OXIDE  IN THE PATIENT  AFTER SURGERY-

1. CARDIOVASCULAR CONCERNS-

Nitrous oxide may increase the risk of myocardial ischemia by  increasing plasma homocysteine concentrations and causing  endothelial dysfunctions after surgery. It can increase the risk of post operative stroke and thrombosis.
Evidence against this-

1. Recent studies have questioned whether the association between homocysteine elevation and cardiovascular  risk truly exists and even if it does, if it is causal, or merely an association , as recent studies using folate/ B- vitamins to reduce homocysteine levels failed to reduce cardiovascular adverse effects.[1]
2. Elevations in plasma homocysteine from pre operative  levels are also seen after surgery in patients not exposed to nitrous oxide. [2]
3. Kosmary and colleagues had found a trend towards a reduction in intra and post operative myocardial ischemia / infarction in patients undergoing carotid surgery who received nitrous oxide.[3]
4. The GALA trial showed no association between nitrous oxide and an increased risk of the composite primary end point of stroke , death or myocardial infarction within 30 days of carotid endarterectomy. [4]
5. In the POISE  study, cardiac complications, intraoperative arterial blood pressure , heart rate and consumption of vasoactive drugs were all comparable inpatients who were or were not given nitrous oxide.[5]
6. ADVERSENEUROLOGICAL CONCERNS- These include myelinopathies, neurotoxicity/hypoxic-ischaemic injury, neurodevelopmental disturbances, postoperative cognitive dysfunction(POCD) and alterations in intracranial dynamics, expansion of venous air emboli(VAE) and conversion of a pneumocephalus into a tension pneumocephalus.

Evidence against this-

1. The complication of myelinopathy is limited to case reports and usually involves prolonged exposure, either occupationally or as a result of nitrous oxide abuse that exceeds clinical anaesthetic exposure.[6]
2. SACD develops only after several months of daily exposure to nitrous oxide [7]
3. Animal studies have reported a smaller cortical infarct volume in ischaemic stroke with the use of nitrous oxide thus showing a possibility of neuroprotective effect of nitrous oxide.[8]
4. A posthoc analysis by McGregor and colleagues found no difference in early or late neurological deficits between those who had received nitrous oxide and those who had not in patients who had undergone intracranial aneurysm surgery.[8]
5. Nitrous oxide by itself does not cause apoptosis in neonatal rat brains at concentrations less than or equal to 75%.[9]
6. No human clinical trials have linked nitrous oxide exposure specifically to adverse neurodevelopmental outcomes.[8]
7. Current human data suggest that the aetiology of POCD seen after cases given nitrous oxide is multifactorial, including varied risk factors with little evidence to suggest a role for nitrous oxide.[8]
8. The global effect  of nitrous oxide on human cerebral metabolic rate may be dependent on depth of anaesthesia and the agent co-administered with nitrous oxide.[8]
9. The effects of nitrous oxide on intracranial dynamics are highly dependent on the anaesthetic milieu. Adverse effects are seen when nitrous oxide is added to other agents to achieve deep anaesthesia, >1.5 MAC, or when the subjects are too lightly anaesthetised.[8]
10. Good surgical conditions have been reported with the use of nitrous oxide based regimes in brain tumour surgery despite many of these patients having a significant mass effect before operation.[10]
11. It has been reported that patients who received nitrous oxide during dural closure in craniotomy had lower ICPs than those who did not receive nitrous oxide. The rapid washout of nitrous oxide may actually decrease the pneumocephalus.[8]
12. Lossaso and colleagues found no evidence that nitrous oxide increased the risk, volume or clinical consequences of VAE.[8]
13.  The N-methyl-D-aspartic acid antagonist action of nitrous oxide has been shown to be neuroprotective in a number of models, similar in potency to xenon.[11]

3. ADVERSE PULMONARY CONSEQUENCES
Diffusion hypoxia, lung atelectasis, pneumonia, risk of delivery of hypoxic gas mixtures at low fresh gas flow rates.
Evidence against this-

1. Turan et al in their study found that intraoperative administration of nitrous oxide was associated with a 40% reduction in the risk of major  lung and breathing related complications. [12]
2. Turan et al suggested that high inspired oxygen concentrations contribute to postoperative atelectasis and hint at the possibility that inclusion of nitrous oxide is protective despite a modest (46% versus 55%) difference in the inspired oxygen concentrations in the two matched groups. [13]
3. Although elimination of nitrous oxide can result in diffusion hypoxia, it is now recognised that this phenomenon has been overrated and is actually of minimal clinical significance. [14]

4.HARMFUL REPRODUCTIVE EFFECTS- INCLUDING TERATOGENECITY IN THE PREGNANT PATIENT:
Evidence against this-

1. Harmful teratogenic and reproductive effects pertain only to chronic exposure; it is presumed that healthy surgical patients could receive nitrous oxide without harm . Animal studies that used intermittent exposure to trace amounts of nitrous oxide have failed to reveal any harmful reproductive effects. [15]
2. In general, nitrous oxide has been shown to be directly teratogenic in experimental animals, but only under experimental conditions that are considered extreme. The teratogenic effects observed in animals exposed to inhaled anaesthetics are caused by physiological changes associated with anaesthesia rather than by inherent teratologic properties of the anaesthetics themselves.[7]
3. Retrospective studies of nearly 6000 general anaesthetics in pregnant patients failed to reveal any adverse outcomes for patient or foetus.[15]

5.POST OPERATIVE NAUSEA AND VOMITING:
Evidence against this:

1. Nitrous oxide does not appear to increase the occurrence of postoperative nausea and vomiting in children when combined with volatile anaesthetics.[16]
2. A meta-analysis of 24 randomised controlled trials concluded that omission of nitrous oxide did reduce the incidence of postoperative vomiting and, to a lesser extent, nausea.[14]
3. Nausea and vomiting were not increased by the use of nitrous oxide in a study on patients undergoing laparoscopic cholecystectomy.[14]

6.INTRAOPERATIVE BOWEL DISTENSION AND DELAY IN RETURN OF BOWEL FUNCTION:
Evidence against this:

1. A recent meta-analysis concluded that though nitrous oxide expands the bowel, this did not inevitably worsen operative conditions and did not delay the return of bowel function. [14]

7.BONE MARROW DEPRESSION AND MEGALOBLASTIC ANAEMIA:
Evidence against this –

1. There is some very limited evidence for significant bone marrow depression after exposure of only a few hours, but this is confined to critically ill patients.[14]
2. Megaloblastic changes in bone marrow are observed following exposure to anaesthetic concentrations for 24 hours, and agranulocytosis is apparent after 4 days of exposure. [15]

8.IMMUNOSUPPRESSION, POSTOPERATIVE POOR WOUND HEALING AND SURGICAL SITE WOUND INFECTION:
Evidence against this:

1. A research study with wound infection as the primary outcome, showed no increase in the risk of wound infection in the nitrous oxide group.[8]
2. A large retrospective cohort analysis showed no difference in wound disruption and infectious complications in general, between the nitrous oxide and nitrous oxide free groups.[8]

OTHER  STRONG SCIENTIFIC  EVIDENCE TO SHOW THAT NITROUS OXIDE DOES NOT INCREASE COMPLICATIONS AND/OR DEATH AFTER SURGERY:

1. Leslie K et al. in their post hoc sub analysis of the Perioperative Ischaemic Evaluation (POISE) trial, sought to determine whether nitrous oxide was associated with the primary composite outcome of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal cardiac arrest within 30 days of randomisation. They found that nitrous oxide was not associated with an increased risk of adverse outcomes in the POISE trial patients. [5]
2. Turan et al. at the Cleveland Clinic evaluated 49,016 patients who had non cardiac surgery between 2005 and 2009. 45% of the patients received nitrous oxide. A propensity score match analysis suggested a significant reduction in the risk of death after surgery for patients receiving nitrous oxide about one third lower than in patients who did not receive nitrous oxide. There was also a significant 17% reduction in the combined rate of major complications & death. [12]
3. Despite associations between anaesthetic doses of nitrous oxide and hyper homocysteinemia and between hyperhomocysteinemia and cardiovascular disease, there is no clear evidence that nitrous oxide increases the risk of dying during or after surgery.[9]
4. New evidence and data suggest potential beneficial effects of nitrous oxide on central nervous system, cardiovascular system, and acute and chronic pain.[8]
5. Nitrous oxide exhibits a superior safety profile with no recorded fatalities or cases of serious morbidity when used within recommended concentrations.[17]

The much awaited results of the ENIGMA II trial are finally out and have been recently published.[18,19]
The ENIGMA IItrial was an international,multicentre, randomised,prospective,assessor blinded trial which enrolled over 7000 patients across 45 hospitals in 10 countries  . It aimed to determine the safety of nitrous oxide as an anaesthetic in patients aged atleast 45 years with known or suspected coronary artery disease having major non-cardiac surgery.  It has shown that nitrous oxide did not increase the risk of death and cardiovascular complications or surgical site infection.It has also interpreted that  the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis. The desired effect of reduced volatile agent use was also seen in the trial results.[19]

     Though ENIGMA - 1 trial showed some adverse perioperative outcomes in patients who received nitrous oxide anaesthesia, there are several fallaciesin this  trial.
FALLACIES OF ENIGMA 1 TRIAL:

1. The excess cardiovascular risk implied by ENIGMA could be because of confounding factors. The trial used 70% nitrous oxide. There is a possibility that the greater depth of anaesthesia experienced by the patients accounted for the adverse cardiovascular events.[8]
2. Many of the variables like standardised use of antibiotics, antiemetics, “propofol maintenance anaesthesia” which could have been influential, in part, for some of the different outcomes observed between the two study groups were not controlled tightly. Also, there was no standardisation of the depth of anaesthesia between the two groups. [20]
3. The ENIGMA study did not achieve its end point. The failure to control for anaesthesia related factors that can influence the incidence of PONV may render the conclusion regarding the effects of nitrous oxide on PONV invalid. [21]
4. The effect of nitrous oxide on surgical site infection is difficult to interpret since the ENIGMA trial compared nitrous oxide to oxygen, and supplemental oxygen per se may or may not reduce wound infection risk.[12]

 

SUMMARY:
A variety of scientific evidence and the results of the ENIGMA II trial, strongly vouch for the fact that the use of nitrous oxide does not increase the risk of complications and death in the patient  after surgery and that NITROUS OXIDE IS SAFE.
REFERENCES:

1. Zhou YH, Tang JY, Wu MJ, et al. Effect of a folic acid supplementation on cardiovascular outcomes: a systemic review and meta analysis. PLosS med 2011;6:e25142
2. Rao LK, Francis AM, Wilcox U, Miller JP. Preoperative vitamin B infusion and prevention of nitrous oxide induced homocysteine increase. Anaesthesia 2010;65:71025
3. Kozmary SV, Lampe GH, Benefiel D et al. No finding of increased myocardial ischaemia during or after carotid endarterectomy under anaesthesia with nitrous oxide. Anesth Analg 1990;71:591-6
4. Sanders RD, Graham C, Lewis SC, Bodenham A, Warlow C. Nitrous oxide exposure does not seem to be associated with increased mortality, stroke and myocardial infarction: a non randomised subgroup analysis of general anaesthesia compared with local anaesthesia for carotid surgery (GALA) trial. Br J Anaesth 2012;109:361-7
5. Leslie K, Miles P et al. Nitrous oxide and serious morbidity and mortality in the POISE trial. Anaesth analog 2013;116:1034-40
6. Hathout,El-Saden S.Nitrous oxide-induced B12 deficiency myelopathy: perspectives on  clinical biochemistry of vitamin B12. J Neurol Sci 2011;301:1-8
7.  Jackie L Martin .Inhaled anesthetics: Metabolism and Toxicity.. Miller’s Anesthesia, 7th Edition; Ronald D Miller.
8. K.de Vasconcellos, Sneyd JR. Nirous Oxide : are we still in equipoise? A qualitative review of current controversies. Br Jr Anaesth 2013; 1-9
9. Rooks JP. Safety and Risks of Nitrous Oxide Labor Analgesia: A Review. J Midwifery Womens Health 2011;56:557-565
10. Todd MM, Warner DS, Sokoll MD, et al. A Prospective , comparative trial of three anaesthetics for elective supretentorial craniotomy. Propofol/fentanyl, isoflurane/nitrous oxide, and fentanyl/ nitrous oxide. Anesthesiology 1993; 78:1005-20
11. Marek AM, Allan.G. Nitrous Oxide and Evidence – Based Medicine: Here We Go Again. Anaesthesiology 2008;3: 108-540
12. Turan A, Mascha JE, Jing U, Curz A, Sheeba A et al. The association between nitrous oxide and postoperative mortality and morbidity after non cardiac surgery. Anesth analg 2013;116:1026-33
13. Kirk Hogan, Paul S Myles. This wonder working gas. Anaesth Analg 2013; 116(5): 955
14. Smith.Nitrous oxide in ambulatory anaesthesia : does it have a place in day surgical anesthesia or is it just a threat for personnel and the global environment? Curr Opin Anesthesiol 2006; 19(6): 592-6
15. Daniel E. Becker and Morton Rosenberg. Nitrous Oxide and the inhalational anesthetics. Anesth Prog 2008; 55:124-131Guide
16. Duarte LTD, Duval Neto, Mendes FF. Nitrous Oxide Use in Children. Rev Bra Anaestiol 2012; 62: 3:451-467
17. Guidelines on Use of Nitrous Oxide for Pediatric Dental Patients 2013; 35(6):13-14
18. Anaesthetic Nitrous oxide no longer an enigma: results of international trial announced. (available at ccsmonash.blogspot.com/…../anaesthetic-nitrous-no-longer.html) (last accessed on 15.09.2014)
19. Myles PS, Chan Matthew TV, Forbes A, Peyton PJ, Paech MJ et al. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery(ENIGMA II): a randomised, single-blind trial.(Available at www.thelancet.com. Published online August 18, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60893-X.)  (last accessed on 17/09/2014.)
20. Dawson SJ, Hardman JG. Nitrous Oxide or Nitrogen Effect. Anesthesiology 2008; 108: 540-1
21.  Paul F White , Ronald H Wender. Nitrous Oxide remains a valuable adjuvant for surgery. Anesthesiology2008;108(3): 541.