Introduction
No anesthetic agent has been administered more often than nitrous oxide. Since its first demonstration in 1845, nitrous oxide has been administered to billions of patients for general anesthesia, sedation for diagnostic and therapeutic procedures, labor analgesia, and the pain of trauma. It remains one of the most widely available and widely used anesthetic agents worldwide.
Nitrous oxide is one of the simplest and smallest of anesthetic molecules (N≡N–O). Its anesthetic actions occur via noncompetitive inhibition of the N -methyl-D-aspartate (NMDA) subtype of glutamate receptors, as well as at additional targets. Although nitrous oxide is not very potent (minimum alveolar concentration [MAC], 104%) and is not used alone to produce general anesthesia, it significantly reduces the doses of potent anesthetic agents required to produce hypnosis. NMDA receptor antagonism may also lead to hypothalamic release of corticotropin-releasing hormone and activation of opioidergic neurons in the periaqueductal gray matter. Nitrous oxide’s analgesic action has been attributed to this mode of action, and inhalation of nitrous oxide is favored when rapidly reversible analgesia is required.
Many of the unwanted effects of nitrous oxide are attributed to its inhibition of methionine synthetase, via its oxidation of the cobalt atom on vitamin B 12 (a cofactor for methionine synthetase). The result is impaired conversion of homocysteine to methionine and hyperhomocysteinemia. Because methionine synthetase also catalyzes the conversion of 5-methyltetrahydrofolate to tetrahydrofolate, deoxyribonucleic acid (DNA) synthesis is disrupted after administration of nitrous oxide ( Figure 31-1 ). Significant inhibition of methionine synthetase by nitrous oxide occurs after about 1 hour of administration and may persist for some time after administration has ceased. Other unwanted effects of nitrous oxide result from its physical characteristics and its ability to increase the volume, pressure, or both in gas-filled spaces.
The host of mechanistic studies on the physiologic and pathologic effects of nitrous oxide administration has added greatly to our understanding of nitrous oxide pharmacology. However, it is the study of real endpoints that are most meaningful and important to patients. In particular, patients want to know who will be at risk of important complications, not just what those complications are. Recent large randomized trials and systematic reviews provide this kind of evidence and have provoked a re-evaluation of nitrous oxide use. This chapter reviews the evidence regarding the safety of nitrous oxide as part of the gas mixture for general anesthesia in adult nonobstetric patients and suggests a more selective evidence-based approach to its administration.
Options/Therapies
Nitrous oxide is commonly administered as 50% to 75% of the gas mixture for anesthesia. If nitrous oxide is omitted, three decisions must be made.
What Gases Will Make Up the Gas Mixture?
When nitrous oxide is omitted, the inhaled gas mixture chosen is usually oxygen (25% to 100%) with the balance, where required, composed of nitrogen. The percentage of inhaled oxygen has significant implications for patients, and the benefits and risks of higher inspired concentrations are currently hotly debated.
How Will Hypnosis Be Achieved?
Nitrous oxide significantly reduces propofol and the volatile anesthetic agent requirement for hypnosis. Doses of these agents therefore need to be increased if nitrous oxide is omitted, and those practitioners unfamiliar with the increased doses required could put their patients at risk of awareness.
How Will Intraoperative Analgesia Be Achieved?
The relatively mild analgesic action of nitrous oxide will need to be replaced with other antinociceptive agents intraoperatively, and additional early postoperative analgesics may be necessary. Even though more volatile anesthetic and opioid medication may be administered, omission of nitrous oxide should result in the requirement for fewer antiemetic agents.
Evidence
Cardiovascular Outcomes
One of the most active areas of research in recent years has been the effect of nitrous oxide on cardiovascular outcomes after surgery. As mentioned previously, nitrous oxide administration increases plasma homocysteine concentrations. In a study of 394 noncardiac surgery patients randomly assigned to nitrous oxide–based or nitrous oxide–free anesthesia, plasma homocysteine concentrations were increased postoperatively in patients receiving nitrous oxide (11.1 [standard deviation, 3.8] versus 8.5 [4.0] mmol/L; p = 0.0005), and there was a significant association between the duration of nitrous oxide administration and the relative change in plasma homocysteine concentration ( r = 0.42; p = 0.001). Small studies suggest that 1 week of preoperative oral treatment with vitamin B 12 may ameliorate nitrous oxide’s effect on homocysteine concentrations, whereas an infusion of vitamin B 12 immediately before induction of anesthesia may not.
Some patients are more likely to develop hyperhomocysteinemia after nitrous oxide exposure than others. Patients who are homozygous for polymorphisms in the methylenetetrahydrofolate reductase gene develop higher plasma homocysteine concentrations than patients with the wild-type or heterozygous allele and may reach homocysteine concentrations considered abnormal (>15 micromoles) during nitrous oxide administration. Pre-existing elevated homocysteine concentrations, which are common in elderly patients and those with cardiovascular disease, may cause frank hyperhomocysteinemia after exposure to nitrous oxide.
Hyperhomocysteinemia promotes endothelial dysfunction and is associated with vascular disease in the nonoperative setting. Endothelial dysfunction may lead to a failure of flow-mediated vasodilation and an impaired response to increased oxygen requirement. In a recent study of 59 noncardiac surgery patients with cardiovascular disease, nitrous oxide administration was associated with an increase in plasma homocysteine concentrations (mean difference, 4.9 micromoles; 95% confidence interval [CI], 2.8 to 7.0 micromoles; p < 0.0005) and a decrease in flow-mediated dilation (mean difference, 3.2%; 95% CI, 0.1 to 5.3%; p = 0.001).
Nitrous oxide-induced hyperhomocysteinemia is also associated with an increased incidence of myocardial ischemia and cardiovascular complications. In 90 patients seen for carotid endarterectomy, hyperhomocysteinemia was reported in patients receiving nitrous oxide, and they experienced a higher incidence of myocardial ischemia on Holter monitoring (46% versus 25%; p < 0.05) and more ischemic events (82 versus 53; p = 0.02) in the first 48 hours postoperatively than patients who did not receive nitrous oxide. In the aforementioned study of 394 noncardiac surgery patients, postoperative hyperhomocysteinemia was associated with an increased risk of cardiovascular events (relative risk, 5.1; 95% CI, 3.1 to 8.5; p < 0.0005), including myocardial infarction, thromboembolism, and stroke. Strategies to reduce plasma homocysteine concentrations, which are not proved to reduce the incidence of cardiac events in nonoperative settings, have not be evaluated for this outcome perioperatively.
The Evaluation of Nitrous oxide in the Gas Mixture for Anaesthesia (ENIGMA) trial randomized 2050 noncardiac surgery patients having surgery of more than 2 hours’ duration to a nitrous oxide–based or nitrous oxide–free general anesthetic. The primary outcome, hospital length of stay, was not significantly different in patients in the nitrous oxide–based group than in the nitrous oxide–free group (7.1 [interquartile range, 4.0 to 11.8] days versus 7.0 [4.0 to 10.9] days; hazard ratio, 1.09; 95% CI, 1.00 to 1.19; p = 0.06). Trends of increased incidence of myocardial infarction (13 versus 7 events) and death (9 versus 3 events) during the 30-day follow-up period were reported in patients who received nitrous oxide. These patients were not enrolled on the basis of their cardiovascular risk profile, although 79% of them had at least one significant pre-existing medical condition. In addition, the inspired oxygen concentration was not equal in the two groups (30% in the nitrous oxide–based group versus 80% in the nitrous oxide–free group), which is a confounding factor that was emphasized in subsequent commentary as an alternative explanation for the results.
In contrast, a trend toward a decreased 30-day risk of major adverse cardiovascular events in patients receiving nitrous oxide intraoperatively was reported in a retrospective analysis of a 49,016-patient administrative database. Propensity-matching was used to adjust for the fact that nitrous oxide was administered to lower risk patients in this institution. The incidence of cardiac events was 1.8% in the nitrous oxide–based group and 2.2% in the nitrous oxide–free group (odds ratio, 0.82; 95% CI, 0.64 to 1.05; p > 0.05).
Long-term follow-up of the ENIGMA trial patients revealed an increased long-term risk of myocardial infarction but not death or stroke in patients who received nitrous oxide. The median follow-up time was 3.5 years (range, 0 to 5.7), during which time 380 patients (19%) had died, 91 (4.5%) had had a myocardial infarction, and 44 (2.2%) had had a stroke. Nitrous oxide did not significantly increase the risk of death (hazard ratio, 0.98; 95% CI, 0.80 to 1.20; p = 0.82) or stroke (odds ratio, 1.01; 95% CI, 0.55 to 1.87; p = 0.97) but did increase the risk of myocardial infarction (odds ratio, 1.59; 95% CI, 1.01 to 2.51; p = 0.04). In patients with myocardial infarction, postoperative plasma homocysteine and folate concentrations were significantly increased when compared with preoperative values, and more of them had postoperative hyperhomocysteinemia. These authors and others called for a specifically designed randomized trial in high-risk patients.
Such a trial is nearly complete at this time (the ENIGMA-II trial, NCT00430989, www.enigma2.org.au ; accessed May 23, 2012). In ENIGMA-II, 7000 patients with or at risk of ischemic heart disease will be randomly assigned to 70% nitrous oxide or 70% nitrogen, both supplemented by 30% oxygen. Cardiac biomarkers and electrocardiographs will be collected in the early postoperative period, and telephone interviews will be conducted at 30 days and 1 year after surgery. Assessors unaware of group assignments will evaluate all events. The primary outcome is a composite of death and major nonfatal events (i.e., myocardial infarction, cardiac arrest, pulmonary embolism, and stroke) at 30 days after surgery.
Neurologic Outcomes
Speed of Emergence
The inclusion of nitrous oxide with a volatile agent in the gas mixture may speed early recovery from anesthesia. This has been attributed to both the “second gas effect” and the “MAC-sparing effect.” To determine the relative importance of these effects, investigators randomly assigned 20 patients to 33% oxygen and either nitrous oxide or air (the control group). Five minutes after cessation of nitrous oxide administration, arterial sevoflurane partial pressure was 39% higher in the control group than in the nitrous oxide-based group ( p = 0.04). Times to eye opening (8.7 versus 10.1 minutes) and extubation (11.0 versus 13.2 minutes) also were shorter ( p = 0.04). The authors concluded that more than half of the reduction of volatile agent concentration resulted from the diffusion effect, and the remainder was due to the MAC-sparing effect. In contrast, times to eye opening were similar in the nitrous oxide-based and nitrous oxide-free groups in the ENIGMA trial, although propofol-based maintenance was used in 20% of these patients; thus a less dramatic effect of nitrous oxide would be expected.
Awareness
The risk of awareness when nitrous oxide is omitted is controversial. In a systematic review to determine the effect of the omission of nitrous oxide on postoperative nausea and vomiting (PONV), the number needed to treat for intraoperative awareness with nitrous oxide–free anesthetic was 46.2 (95% CI, 24.1 to 581). This was attributed by others to unfamiliarity with nitrous oxide–free techniques. In the ENIGMA-I trial, two cases of awareness were reported in the nitrous oxide–based group and none in the nitrous oxide–free group; however, ENIGMA-I was not powered for this outcome. A comprehensive review of reported cases up to 2009 concluded that avoidance of nitrous oxide did not increase the risk of awareness.
Neurotoxicity
Although numerous cases of neurotoxicity associated with nitrous oxide have been published, especially in folate-deficient or overexposed patients, very few data from randomized controlled trials are available. In 228 elderly patients seen for noncardiac surgery under volatile-based general anesthesia, the omission of nitrous oxide did not alter the incidence of delirium (41.9% versus 43.8%; p = 0.78) or cognitive impairment (14.8% versus 18.6%; p = 0.59) within 48 hours of surgery. Similarly, in post-hoc analyses of the International Hypothermia for Aneurysm Surgery Trial, no difference was demonstrated at 3 months postoperatively between patients who received nitrous oxide and those who did not in terms of any outcome variable. In a further subgroup who were treated with temporary parent artery occlusion during surgery, the use of nitrous oxide was associated with an increased risk of deficits due to vasospasm. However, at 3 months postoperatively, no demonstrable difference was found between the two groups.
Respiratory Outcomes
The high solubility of nitrous oxide may potentially promote absorption atelectasis (when compared with nitrogen but not oxygen), but the importance of this phenomenon to real outcomes for patients is unclear. In the ENIGMA-I trial, pneumonia (1.5% versus 3.0%; odds ratio, 0.51; 95% CI, 0.27 to 0.91; p = 0.04) and atelectasis (7.5% versus 13%; odds ratio, 0.55; 95% CI, 0.40 to 0.75; p = 0.001) were less commonly associated with nitrous oxide–free anesthesia than nitrous oxide–based anesthesia ( Table 31-1 ). However, as mentioned previously, the inspired oxygen concentration was higher in nitrous oxide–free patients. In contrast, the aforementioned retrospective analysis of a 49,016-patient administrative database revealed a lower incidence of pulmonary/respiratory complications in patients receiving nitrous oxide (1.6% versus 2.7%; odds ratio, 0.60; 95% CI, 0.47 to 0.77). In this study, nitrous oxide–free patients also received a higher inspired concentration of oxygen. The ENIGMA-II randomized controlled trial, conducted in higher risk patients and with equal inspired oxygen concentration in each group, may illuminate this issue further.
| Outcome (within 30 days) | N 2 O-free ( n = 997) | N 2 O-based ( n = 997) | Adjusted OR * (95% CI) | p Value |
|---|---|---|---|---|
| Severe PONV | 104 (10%) | 229 (23%) | 0.40 (0.31-0.51) † | <0.001 |
| Wound infection | 77 (7.7%) | 106 (10%) | 0.72 (0.52-0.98) ‡ | 0.036 |
| Fever | 275 (28%) | 345 (34%) | 0.73 (0.60-0.90) | 0.003 |
| Pneumonia | 15 (1.5%) | 30 (3.0%) | 0.51 (0.27-0.97) | 0.04 |
| Atelectasis | 75 (7.5%) | 127 (13%) | 0.55 (0.40-0.75) | <0.001 |
| Myocardial infarction | 7 (0.7%) | 13 (1.3%) | 0.58 (0.22-1.50) | 0.26 |
| Thromboembolism | 16 (1.6%) | 10 (1.0%) | 1.60 (0.72-3.55) | 0.25 |
| Blood transfusion | 188 (19%) | 202 (20%) | 0.96 (0.75-1.21) | 0.71 |
| Death | 3 (0.3%) | 9 (0.9%) | 0.33 (0.09-1.22) | 0.096 |
| Any pulmonary complication | 78 (7.8%) | 132 (13%) | 0.54 (0.40-0.74) | <0.001 |
| Any major complication § | 155 (16%) | 210 (21%) | 0.70 (0.55-0.89) | 0.003 |
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