Is Nitrous Oxide Associated With Outcome?

INTRODUCTION

Nitrous oxide is the venerable elder statesman of anesthesia. Its use has been characterized by peaks and troughs of enthusiasm and controversy from its first use to the present day. The first documented synthesis of nitrous oxide is generally attributed to the clergyman scientist Joseph Priestly in 1772, although some have attributed its first isolation to a physician, Joseph Black, in 1767. Humphry Davy, a chemist, made important advances in the production of nitrous oxide and suggested in 1800 that nitrous oxide may have a role as an analgesic during surgical procedures. Although there was much interest in the recreational effects of “laughing gas” during this period, the medical use of nitrous oxide did not gain traction. Horace Wells, an American dentist, however, appreciated the potential of nitrous oxide after watching a demonstration by Gardner Quincy Colton (a medical school dropout and showman) in 1844. ^, ^, He subsequently used it for his own dental extraction and briefly introduced it to his dental practice. ^, In an attempt to demonstrate the utility of nitrous oxide to a wider audience, Wells conducted a demonstration at the Massachusetts General Hospital in Boston. The demonstration was a failure, and Wells subsequently left dentistry and later committed suicide with the assistance of chloroform. After the failed demonstration, and with the introduction of ether, interest in nitrous oxide waned, until Colton “revived” the use of nitrous oxide for dental anesthesia in 1863. ^, Edmund Andrews subsequently pioneered the use of nitrous oxide and oxygen for surgical anesthesia from 1868, and nitrous oxide has remained (to greater or lesser degrees) a part of the anesthetist's armamentarium to the present day. ^,

Nitrous oxide (N ₂ O), correctly termed dinitrogen monoxide, is an inorganic compound composed of two nitrogen atoms and one oxygen atom and has a molecular weight of 44 g/mol. It has a boiling point of -88.5°C at standard pressure, and at standard temperature and pressure, it is a colorless gas with a sweetish odor. It has a critical temperature of 36.5°C and is 1.53 times as dense as air. Although nonflammable at room temperature, it does support combustion and may form explosive mixtures similar to oxygen.

Nitrous oxide has a low blood/gas partition coefficient of 0.47 (only desflurane has a lower coefficient of 0.42, although this may be as high as 0.57 depending on the methodology used) and has the lowest brain/blood, muscle/blood, and fat/blood partition coefficients of the inhalational agents currently used in routine clinical practice. ^, These pharmacokinetic characteristics result in a rapid onset and offset of clinical effect as alveolar, blood, and central nervous system concentrations rapidly approach equilibrium with little tissue accumulation. Nitrous oxide is much more soluble in blood than nitrogen is. This has been used to explain the concentration and second gas effects: during induction the relatively rapid uptake of nitrous oxide from the alveolus leads to a rapid rise in the alveolar concentration of both nitrous oxide and other coadministered anesthetic agents. This explanation and the existence of these phenomena have, however, been questioned. During emergence, the reverse process may lead to rapid inflow of nitrous oxide from blood to alveolus, diluting other gases (including oxygen) in the alveolus and potentially resulting in diffusion hypoxia. Nitrous oxide may also enter air-filled spaces more rapidly than nitrogen can diffuse from these spaces, resulting in an increased pressure within the space or an increase in volume of the structure. Nitrous oxide does not undergo any metabolism.

Nitrous oxide has analgesic, anxiolytic, and hypnotic effects. The anesthetic effects of nitrous oxide are mediated via antagonism of the NMDA (N-methyl-D-aspartate) receptor, thus inhibiting the effects of the excitatory neurotransmitter glutamate. ^, This contrasts with the volatile anesthetic agents and most intravenous (IV) agents (except ketamine) whose major mechanism of action is via GABA _A agonism. Other mechanisms of action include inhibition of AMPA receptors, the TREK-1 two-pore-domain potassium channel, neuronal nicotinic receptors, and voltage-gate calcium channels. The analgesic effect of nitrous oxide appears to be mediated by the release of opioid peptides in the periaqueductal gray, which result in noradrenaline release and stimulation of α-2 adrenoreceptors in the spinal cord. The minimum alveolar concentration (MAC) of nitrous oxide is 104%, and thus it cannot be used as a sole anesthetic agent for general anesthesia; however, significant analgesic and anxiolytic effects are noted at lower concentrations.

Nitrous oxide has traditionally been used as a mainstay of general anesthesia, dental sedoanalgesia, and labor sedoanalgesia. In the past, it has been used for long-term sedation in the intensive care unit (ICU), but this is no longer practiced because of clear evidence of harm from long-term nitrous oxide use. The use of nitrous oxide has also been explored as procedural sedoanalgesia in diverse settings such as prehospital settings, emergency departments, burn units, endoscopy, and termination of pregnancy, and it may have a role in the treatment of depression and posttraumatic stress disorders. In recent decades, the availability of short-acting anesthetic agents and analgesics (sevoflurane, desflurane, and remifentanil), total IV anesthesia, and labor epidural analgesia have emerged to challenge the traditional unique selling propositions of nitrous oxide. ^, ^, Furthermore, concerns regarding potential adverse effects of nitrous oxide on both patients and the environment have grown, most notably after the publication of the ENIGMA (Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia) trial in 2007. In Scandinavian countries, a survey on the changing utilization of nitrous oxide in the 20 years up to 2011 showed wide variability in the use of nitrous oxide in general anesthesia among different countries, ranging from 0.6% to 38.6% of general anesthetics. Ninety-six percent of hospitals reported either a decrease in the use of nitrous oxide (62%) or had stopped using it altogether (34%). Reasons for the change included a perception that other agents were better, the risk for postoperative nausea and vomiting (PONV), and concerns regarding environmental effects and pollution of the operating room. In a survey of anesthetists in the UK published in 2002, 82% of respondents used nitrous oxide frequently, but 49% reported that their use of N ₂ O had declined in the preceding 5 years. In a subsequent survey from 2011, 85% of UK anesthetists used nitrous oxide in obstetric general anesthesia. A survey of anesthetists (predominantly from European countries but including respondents from all continents except Africa) published in 2009 reported that 64.3% still use nitrous oxide. In a 2005 survey of Indian anesthetists, 84% reported using nitrous oxide frequently, although 27% reported that their use had declined over the preceding 5 years, whereas 93% reported using nitrous oxide regularly in a 2014 study, and 54.8% reported a preference for nitrous oxide as a carrier gas in a survey on low-flow anesthesia that was published in 2016. Among anesthetists from Australia and New Zealand, nitrous oxide was used uncommonly (in <20% of cases) by 66% of anesthetists and only 11% used nitrous oxide commonly (in >60% of general anesthetics). In a Canadian survey published in 2018, 48% of anesthetists used nitrous oxide at least once a month, with only 16.5% using it daily. Of note, 46.5% of respondents used N ₂ O only a few times a year or did not use it at all. Most respondents were not influenced by the results of the ENIGMA-II trial, which countered some of the safety concerns raised in the original ENIGMA trial. The aforementioned data illustrate significant personal and regional variability in the usage of nitrous oxide; however, there is a clear trend toward reduced usage of this agent. Despite the concerns regarding nitrous oxide and a trend to reduced use, nitrous oxide is still used in modern anesthetic practice and there is significant debate and research about its role in anesthesia in the 21st century.

OPTIONS/THERAPIES

Nitrous oxide is stored in cylinders either as pure nitrous oxide or as a 50:50 mixture with oxygen (commonly referred to by one of its trade names, Entonox). Nitrous oxide cylinders have a blue shoulder, with either a blue or white body. As nitrous oxide is usually stored below its critical temperature, it exists as a liquid in equilibrium with the vapor above. The pressure in a nitrous oxide cylinder is between 4400 and 5200 kPa, with the pressure gauge reflecting the vapor pressure. This only reflects the quantity of nitrous oxide in the cylinder once all the liquid has vaporized, and thus nitrous oxide cylinders must be weighed to determine the amount of nitrous oxide remaining in a cylinder. Nitrous oxide is supplied to anesthesia machines via a pipeline supplied by a cylinder bank or via nitrous oxide cylinders mounted on the anesthetic machine.

Entonox is usually supplied in cylinders connected to a demand valve system. The cylinders have a blue and white shoulder and a cylinder pressure of 13,700 kPa. Less commonly, Entonox may be supplied via pipeline. The pseudocritical temperature of Entonox is approximately −7°C. Below this temperature nitrous oxide converts to the liquid phase, with an increasing concentration of oxygen in the gaseous phase. As the oxygen is consumed, the oxygen concentration will eventually drop and a hypoxic gas mixture may develop. Cylinders should be stored well above the pseudocritical temperature or rewarmed appropriately before use if exposed to suitably cold temperatures.

EVIDENCE

Mortality

Given the safety of modern anesthetic practice, it is a matter of debate as to whether mortality is an appropriate outcome with which to compare anesthetic agents. It is, however, the ultimate “hard” outcome, and further discussion about an anesthetic agent would be moot if it resulted in an increased mortality rate.

The ENIGMA and ENIGMA-II trials are seminal randomized controlled trials (RCTs) assessing the safety of nitrous oxide. ^, The ENIGMA trial randomized patients undergoing major surgery (anticipated to last at least 2 hours) to receive nitrous oxide–containing (70% N ₂ O/30% O ₂ ) or nitrous oxide–free (80% O ₂ /20% N ₂ ) anesthesia. The study enrolled 2050 patients from 2003 to 2004. The primary outcome was hospital length of stay, which did not differ between the two groups. Death within 30 days was a prespecified secondary outcome, and this also did not differ between the two groups, with a mortality rate of 0.3% in the nitrous oxide–free group and 0.9% in the nitrous oxide group (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.09–1.25; p = .10). Long-term follow-up of the ENIGMA patients (over a median of 3.5 years) similarly showed no difference in mortality between the two groups (hazard ratio [HR] for death with N ₂ O, 0.98; 95% CI, 0.80–1.20; p = .82). Of interest, there was a lower risk for death in the nitrous oxide group in patients undergoing nonabdominal surgery (OR, 0.64; 95% CI, 0.43–0.96; p = .03), with no difference in those undergoing abdominal surgery. The significance of this subgroup finding is unclear.

The ENIGMA-II trial randomized patients at risk for cardiovascular complications (aged 45 years or older, with coronary artery disease or cardiac risk factors) receiving general anesthesia for major noncardiac surgery to receive nitrous oxide–based (70% N ₂ O/30% O ₂ ) or nitrous oxide–free anesthesia (70% N ₂ /30% O ₂ ). The study enrolled 7112 patients between 2008 and 2013. The mortality rate at 30 days was 1% in the nitrous oxide group and 2% in the nitrous oxide–free group, which was not statistically significant (risk ratio [RR], 0.74; 95% CI, 0.50–1.11; p = .14). Follow-up at 1 year also showed no difference in mortality rate between the two groups (HR, 1.17; 95% CI, 0.97–1.43; p = .10).

The Perioperative Ischemic Evaluation (POISE) trial investigated the role of perioperative B-blockade in patients with cardiac risk factors undergoing noncardiac surgery. A post hoc subanalysis of this study showed no difference in mortality at 30 days between those who received nitrous oxide during their surgery and those who did not (OR, 1.04; 95% CI, 0.6–1.81; p = .88). In a large retrospective cohort analysis of patients who underwent noncardiac surgery between 2005 and 2009, 30-day mortality was compared (following propensity score matching) between 10,746 patients who received nitrous oxide and the same number who received nitrous oxide–free anesthesia. The risk for death at 30 days was significantly lower in the nitrous oxide group (OR, 0.67; 95% CI, 0.46–0.97; p = .02).

A metanalysis conducted before the publication of ENIGMA-II evaluated the effect of nitrous oxide on short-term (until 30 days from operation), and long-term (from 30 days after operation) mortality. Thirteen trials were included for the analysis of short-term mortality, with no significant difference being found between the nitrous oxide and nitrous oxide–free groups (OR, 1.75; 95% CI 0.69–4.40). Only two trials were included in the analyses for long-term mortality, and similarly no significant difference was found between the nitrous oxide and nitrous oxide–free groups (OR 0.94; 95% CI 0.80–1.10). The authors, however, concluded that there was not enough evidence to reach any robust conclusions regarding the effect of nitrous oxide on mortality. A Cochrane review including eight studies (10,148 participants) that were published before October 2014 also found no difference in in-hospital case fatality rate between nitrous oxide–based and nitrous oxide–free anesthesia (OR, 0.87; 95% CI 0.61–1.26; p = .47).

Based on the aforementioned findings, we can now say with reasonable certainty that nitrous oxide is not associated with increased perioperative mortality.

Cardiovascular Effects

The cardiovascular effects of nitrous oxide represent an interplay between the short-term hemodynamic effects of nitrous oxide and possible long-term effects on major adverse cardiac events (MACE).

Nitrous oxide is conventionally reported to have a minimal effect on systemic arterial pressure and heart rate, especially in comparison to volatile anesthetic agents. ^, As such, it may be expected to improve hemodynamic stability intraoperatively, compared with other anesthetic agents. This apparent hemodynamic stability results from sympathetic stimulation offsetting the direct myocardial depressant effect of nitrous oxide. In patients with impaired myocardial contractility, or in those who are otherwise reliant on preexisting elevated sympathetic tone to maintain hemodynamic stability, the direct myocardial depressant effect may dominate and lead to hemodynamic compromise. Similarly, the mild vasoconstrictive effects of nitrous oxide may lead to increased pulmonary vascular resistance, which may have deleterious effects in patients at risk for right-ventricular pressure overload. ^,

Research suggests the hemodynamic effects of nitrous oxide are complex and context dependent, varying in different populations and depending on coadministered anesthetic agents. A study on healthy volunteers showed that nitrous oxide induced a dose-dependent increase in stroke volume, cardiac output, and systemic arterial pressure, but that this effect was time-dependent, occurring during the first hour of exposure and returning to baseline by the second hour. In a study evaluating the effect of 50% nitrous oxide in patients with mitral stenosis and pulmonary hypertension, a 34% percent increase in pulmonary vascular resistance was noted, but there were no other associated or downstream hemodynamic consequences from the administration of nitrous oxide. A similar study evaluating the effect of 70% nitrous oxide in patients with mitral valve disease and pulmonary hypertension showed only minor hemodynamic changes with nitrous oxide, but these included a small reduction in mean pulmonary artery pressure.

In a study of the cardiovascular effects of nitrous oxide pre- and postcardiopulmonary bypass, N ₂ O had no effect on global ejection fraction, increased early diastolic relaxation prebypass, and increased regional wall motion abnormalities postbypass. Fifty percent nitrous oxide was also found to decrease mean arterial pressure (MAP), cardiac index, and stroke index and increase pulmonary vascular resistance, mean pulmonary artery pressure, and left ventricular end-diastolic pressure in patients undergoing coronary artery surgery. In a cohort of patients with ischemic heart disease undergoing abdominal vascular surgical procedures, 60% nitrous oxide had minimal effect on hemodynamic parameters; however, significantly more patients in the nitrous oxide group required nitroglycerine to treat hypertension or left ventricular failure and had an increased incidence of myocardial ischemia intraoperatively. As part of the study design, the nitrous oxide group received lower doses of fentanyl than the nonnitrous oxide groups, and although median isoflurane concentrations during surgery were reported to be the same in both groups, it is difficult to assess whether the changes described were because of nitrous oxide per se or because of differences in total anesthetic/analgesic “dose” in the two groups. In contrast to the aforementioned, 50% nitrous oxide reduced peripheral vascular resistance, systemic arterial pressure, pulmonary arterial pressure, left ventricular end-diastolic pressure, and left anterior descending coronary artery (LAD) graft resistance, with no effect on stroke volume, pulmonary artery pressure, or LAD graft flow in patients undergoing coronary artery surgery. The authors concluded that the overall hemodynamic effects of nitrous oxide were mild, did not impair myocardial oxygenation, and were likely to benefit the myocardium. Similarly, a study evaluating the effect of 50% nitrous oxide in patients undergoing cardiac catheterization demonstrated a reduction in systemic pressure-rate product and left ventricular minute work index, suggesting a potentially beneficial reduction in myocardial oxygen demand.

The addition of 70% nitrous oxide did not alter the hemodynamic response to equal doses of propofol at induction of anesthesia, indicating nitrous oxide had no additive effect on the hemodynamic effects of propofol. This study did not, however, evaluate whether the addition of nitrous oxide to propofol at induction would allow for a lower dose of propofol to be used and thus reduce the hypotensive effect of propofol. Jain et al. and Singh et al., however, showed that the addition of 67% nitrous oxide to propofol at induction resulted in a significant reduction in induction time and in the induction dose of propofol with no significant hemodynamic changes. ^, Similarly Shiga et al. showed that the addition of 70% nitrous oxide to propofol target-controlled infusion (TCI) anesthesia did not cause a significant reduction in MAP (versus the nonnitrous oxide control group) until the propofol concentration reached 5 ug/min. Aortic blood flow, peak aortic flow acceleration, and aortic peak velocity (surrogates of myocardial contractility) showed no difference between the two groups at any target concentration, suggesting minimal functional impact on cardiac performance. A study evaluating the effect of the addition of a low concentration of nitrous oxide (20%) to propofol TCI sedation found that nitrous oxide appears to attenuate the hypotensive effect of propofol. Fernandes et al. demonstrated that the addition of 60% nitrous oxide to sevoflurane anesthesia for laparoscopic surgery allowed for a 35% reduction in sevoflurane requirements, with no change in hemodynamic parameters. In elderly patients the hemodynamic effect of 50% nitrous oxide differed depending on whether it was administered with halothane or isoflurane. In the 50% nitrous oxide and isoflurane group mean cardiac index increased by 0.5% from baseline, with a drop in cardiac index seen with equi-MAC concentrations of isoflurane and halothane, and the greatest decrease (20.4%) being seen in the 50% nitrous oxide and halothane group. Systemic vascular resistance decreased in all groups except the 50% nitrous oxide and halothane group. The addition of 70% nitrous oxide to 1% isoflurane in patients with ischemic heart disease, however, led to additive reductions in systemic arterial pressure, and myocardial oxygen consumption and extraction. Inada et al. evaluated the effect of substituting 0.65 MAC of nitrous oxide during 1.5 MAC of anesthesia using sevoflurane or isoflurane. There was no significant difference in MAP between the nitrous oxide and nonnitrous oxide groups with either volatile; however, mean pulmonary artery pressure (MPAP) was elevated in the nitrous oxide arm with both volatile agents. Pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP) increased significantly in the nitrous oxide arm with sevoflurane, with no significant change with isoflurane. The systemic vascular resistance index (SVRI) increased significantly, whereas heart rate decreased significantly in the nitrous oxide group with isoflurane but not with sevoflurane. Additionally, the changes between the nitrous and nonnitrous periods had similar trends in both the isoflurane and sevoflurane groups, with an overall trend to increased vascular resistances and pressures in the nitrous oxide group. Nitrous oxide in combination with sevoflurane or isoflurane was also found to impair cold-induced vasoconstriction less than equi-MAC doses of sevoflurane or isoflurane alone. Beyond the hemodynamic effects, this suggests that nitrous oxidebased anesthesia may impair thermoregulation less than using volatile agents alone.

Although individual study results may appear confusing, overall, the immediate hemodynamic effects of nitrous oxide are mild and relatively benign. Because intraoperative hypotension has been associated with adverse postoperative outcomes, it may be hypothesized that the hemodynamic profile of nitrous oxide would allow for less intraoperative hypotension and thus improve perioperative outcomes. This hypothesis remains unproven, and instead concerns have arisen regarding the potential for nitrous oxide to lead to perioperative adverse cardiac events (ACE).

The aforementioned concern may be related to the direct hemodynamic effects of nitrous oxide and, in particular, a potential to cause vasoconstriction and hypertension and/or elevated heart rates. The metabolic effects of nitrous oxide, however, provide an additional pathway via which it may result in ACE. Nitrous oxide inactivates vitamin B ₁₂ , which inhibits methionine synthase, which prevents the conversion of homocysteine to methionine, resulting in elevated homocysteine levels. Studies consistently support the association between nitrous oxide exposure and elevated homocysteine levels in both adult and pediatric patients. Reported increases vary from 25% to 567% of baseline. ^, The increase in homocysteine levels occurs rapidly, being noted immediately postoperatively or within the first few hours after anesthesia. The duration of this elevation is unclear, with a report of values having returned to normal by 24 hours in a pediatric study. On the whole, however, other studies suggest that homocysteine levels remain elevated for at least 24 to 48 hours. ^, ^, ^, ^, The magnitude of the increase in homocysteine levels is related to the duration of nitrous oxide exposure, suggesting a dose-response effect. ^, Hyperhomocysteinemia has been associated with the development of endothelial dysfunction, thrombophilia, inflammation, and accelerated cardiovascular disease, including coronary artery disease. ^, This provides a biologically plausible mechanism whereby nitrous oxide may increase perioperative ACE.

The clinical impact of the previous associations in the perioperative period has been the subject of much research and has generated much controversy. Badner et al. reported that in patients undergoing carotid endarterectomy, nitrous oxide use was associated with a significant increase in the incidence of perioperative ischemia and in the duration of myocardial ischemia in the first 48 hours postoperatively. In the ENIGMA trial the adjusted OR for myocardial infarction (MI) was 0.58 in the nitrous oxide–free group; however, this was not statistically significant (95% CI, 0.22–1.50). To diagnose MI in the ENIGMA trial, both electrocardiogram (ECG) changes and an increase in cardiac enzymes were required; however, significantly more patients (30 vs. 10, p = .002) in the nitrous oxide group had either an increase in cardiac enzymes or ECG changes suggestive of MI, raising further concerns regarding an increased risk for ACE. Long-term follow-up subsequently showed a statistically significant increase in MI in the nitrous oxide group (adjusted OR, 1.59; 95% CI, 1.01–2.51; p = .04), with patients who had an MI having significantly higher homocysteine levels. Nevertheless, there were a number of methodologic issues with the ENIGMA trial preventing clear conclusions being drawn regarding ACE risk: MI was not the primary study outcome and the study population was not at high risk for ACE and as such had a relatively low event rate; furthermore, the control group received 80% oxygen (as opposed to 70% nitrous oxide), and thus the study was more correctly a comparison of nitrous oxide–based anesthesia versus high supplemental oxygen therapy. The ENIGMA-II trial was designed to address these concerns. Despite the study population being at high risk for ACE, there was no difference in the primary outcome of death or cardiovascular complications within 30 days of surgery between the nitrous oxide and nitrous oxide–free groups (RR, 0.96; 95% CI, 0.83–1.12; p = .64). Specifically, there was no difference in the risk for MI, intraoperative or early postoperative myocardial ischemia, cardiac arrest, stroke, or pulmonary embolism between the two groups. Similarly, at 1-year follow up there was no difference in primary outcome (OR, 1.08; 95% CI, 0.94–1.25; p = .27), risk for MI, or risk for stroke. A secondary analysis of the general anesthesia versus local anesthesia for carotid surgery (GALA) trial evaluated the risk of the combined outcome of death, stroke, or MI within 30 days of carotid surgery in patients who received a nitrous oxide–based anesthetic (671 patients) versus those who had nitrous oxide–free general anesthesia (944 patients). Despite a greater prevalence of cardiac risk factors in the nitrous oxide group, there was no difference in the combined primary outcome (RR, 1.12; 95% CI, 0.73–1.73; p = .63). Results from a post-hoc analysis of the POISE (Perioperative Ischemic Evaluation Study) trial were in keeping with those of ENIGMA-II, showing no difference in primary outcome (a composite of cardiovascular death, nonfatal MI, and nonfatal cardiac arrest within 30 days), MI, stroke, or significant hypotension. Turan et al.’s retrospective cohort analysis also showed no difference in cardiac morbidity or mortality with the use of nitrous oxide (OR, 0.86; 95% CI, 0.64–1.16).

A Cochrane systematic review and meta-analysis, conducted after the publication of ENIGMA-II, showed an OR of 1.01 (95% CI, 0.84–1.22, p = .88) for the occurrence of MI after nitrous oxide–based anesthesia.

Certain patient subgroups may be at elevated risk for ACE after exposure to nitrous oxide. Folate and vitamin B ₁₂ are important for the conversion of homocysteine to methionine. Vitamin B ₁₂ and folate deficiency are associated with elevated homocysteine levels, and patients with either of these deficiencies may be at elevated risk for postoperative hyperhomocysteinemia and adverse outcomes associated with nitrous oxide anesthesia. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate/vitamin B ₁₂ cycle and subsequently in the conversion of methionine to homocysteine. Polymorphisms associated with reduced MTHFR activity (most notably C677T and A1298C MTHFR gene variants) are associated with increased homocysteine levels and an increased risk for vascular complications. Individuals with these polymorphisms may also be at increased risk for nitrous oxide–related adverse effects. Given the important biologic role of folate and vitamin B ₁₂ in methionine synthesis, supplementation with either or both of these agents could theoretically reduce adverse events putatively associated with hyperhomocysteinemia. The outcomes of such studies in the nonoperative setting have been conflicting. A Cochrane review found no effect on MI or death, but a small reduction in stroke, whereas a metanalysis by Li et al. showed a 10% reduction in stroke, with a 4% reduction in all cardiovascular disease overall, but no effect on coronary artery disease. Additionally, a previous meta-analysis found that although B vitamin supplementation significantly lowered homocysteine levels, there was no reduction in major vascular events, major coronary events, or strokes. The Vitamins in Nitrous Oxide (VINO) trial is the only RCT on this topic from the perioperative field. This study randomized 500 patients with cardiac risk factors undergoing major noncardiac surgery with nitrous oxide–based anesthesia to receive either perioperative vitamin B ₁₂ and folate, or placebo. The primary outcome was myocardial injury, as assessed by troponin elevation within 72 hours of surgery. A nitrous oxide–free comparator group of 125 patients was also included in the study. The study showed that although B vitamins significantly reduced the postoperative rise in homocysteine levels, there was no difference in myocardial injury between the two nitrous oxide groups. Furthermore, the study showed that MTHFR gene polymorphisms did not have a significant effect on postoperative homocysteine levels, were not associated with an increased risk for myocardial injury, and did not benefit from vitamin B supplementation. Similarly, there was no increased risk for myocardial injury in the nitrous oxide–free comparator group.

The overwhelming body of evidence thus suggests that nitrous oxide has no significant detrimental cardiovascular effects and may be used safely even in patients with cardiac risk factors. Despite the theoretical benefits of “improved hemodynamic stability,” there is similarly little evidence to suggest any compelling benefit to the use of nitrous oxide from a cardiovascular point of view.

Neurologic Effects

Cerebral Physiology

Despite decades of research, the effects of nitrous oxide on cerebral physiology are controversial and depend on the study design and the influence of coadministered anesthetic agents.

Nitrous oxide increases cerebral blood flow, most likely via cerebral vasodilation. ^, Although both nitrous oxide and volatile anesthetic agents increase cerebral blood flow (CBF) and cerebral blood volume (CBV), data from Lorenz et al. suggest that there are regional differences in this effect. Nitrous oxide tends to increase CBF and CBV in supratentorial gray matter, whereas isoflurane increases these parameters in the infratentorial basal ganglia. The clinical relevance of this finding is uncertain but highlights the fact that the effect of anesthetic agents on cerebral physiology is complex and that focusing just on global changes may mask potentially important regional effects. Kaisti et al. demonstrated that the addition of nitrous oxide to sevoflurane or propofol resulted in increased regional CBF compared with values when either agent was used alone. Regional CBF with nitrous oxide did not exceed awake values, though, and when used with propofol, values were still significantly lower than baseline values. Other data have suggested that the addition of nitrous oxide to propofol anesthesia has little effect on cerebral blood flow velocity and autoregulation. ^, Studies in children have shown that nitrous oxide causes significant increases in CBF velocity when added to propofol or sevoflurane anesthesia but has no effect with desflurane. This further highlights that the specific effects of nitrous oxide on cerebral physiology may differ significantly in different populations and with different coanesthetic agents. Although clearly a complex phenomenon, the concern has long existed that the increase in CBF and CBV potentially seen with nitrous oxide may lead to raised intracranial pressure (ICP) and subsequent adverse effects in patients with intracranial pathology. Although raised ICP may be a valid concern with spontaneously breathing patients, the clinical effect using modern anesthetic techniques appears negligible. ^, Todd et al. studied the effect of propofol/fentanyl, isoflurane/nitrous oxide, and nitrous oxide/fentanyl anesthesia on patients undergoing supratentorial craniotomy. Although there was no difference in mean ICP between the three groups, the isoflurane/nitrous oxide group had significantly more patients with an ICP of at least 24 mm Hg and had significantly lower cerebral perfusion pressures (CPPs) than either of the other groups. This suggests that potentially detrimental effects on intracranial dynamics may be more a factor of the coanesthetic agent than nitrous oxide per se. Furthermore, although an increase in ICP may reduce CPP and lead to cerebral ischemia, the cerebral vasodilation and systemic hemodynamic stability seen with nitrous oxide may actually increase effective CPP and reduce zero-flow pressure, which may improve cerebral oxygen delivery. ^,

Depending on the study design, nitrous oxide has been shown to increase, decrease, or have no effect on cerebral metabolic rate (CMR). Human studies appear to show minimal, if any, increase in CMR and, at least in the healthy brain, the net effect appears to be an increased ratio of oxygen delivery compared with oxygen demand. ^, ^, Nevertheless, the situation is likely to be more complex than global markers of cerebral metabolism indicate. In a study on human volunteers, nitrous oxide had no significant effect on global CMR but increased metabolic rate in the thalamus and basal ganglia. Volatile anesthetic agents and propofol tend to significantly reduce CMR. When nitrous oxide is added to either sevoflurane or propofol, the CMR is generally significantly higher than with sevoflurane or propofol alone; however, it still remains significantly lower than baseline values.

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