We reviewed the evidence about the harmful effects of nitrous oxide on people undergoing general anaesthesia.
Nitrous oxide is an anaesthetic gas which has been used for more than 160 years for inducing anaesthesia and keeping patients anaesthetized throughout an operation. It is also known as 'laughing gas'. It is a colourless non-flammable gas with a pleasant, faint sweet odour and taste. Its low cost and low toxicity have made nitrous oxide by far the most commonly used general anaesthetic. However, some studies have reported that adding nitrous oxide may lead to harmful effects. This has led many anaesthetists to question its continued routine use in a variety of operating room settings.
We wanted to discover whether using nitrous oxide in general anaesthesia was better or worse than not using nitrous oxide.
We examined the evidence available up to 17 October 2014. We included 35 trials involving 13,872 adult participants, all of whom were randomized to either receive nitrous oxide or no nitrous oxide. The trials covered a variety of situations during general anaesthesia.
We found that general anaesthesia with nitrous oxide increased the risk of pulmonary atelectasis (i.e. failure of the lungs to expand fully). When we restricted the results to the highest quality studies only, we found evidence that nitrous oxide may potentially increase the risk of pneumonia and severe nausea and vomiting. However, nitrous oxide had no effect on the patients' survival, the incidence of heart attack, stroke, wound infection, the occurrence of blood clots within veins, the length of hospital stay, or the length of intensive care unit stay.
Quality of the evidence
The evidence related to survival of participants was of moderate quality because we did not have enough data. The evidence related to some harmful effects, such as failure of the lungs to expand fully and heart attack, was of high quality, while for other harmful effects, such as stroke and the occurrence of blood clots within veins, the evidence was of moderate quality. For others, such as pneumonia, severe nausea and vomiting, and wound infection, the evidence was of low quality. The evidence related to the length of time spend in hospital was of moderate quality.
The avoidance of nitrous oxide may be reasonable in participants with pre-existing poor pulmonary function or at high risk of postoperative nausea and vomiting.
Given the evidence from this Cochrane review, the avoidance of nitrous oxide may be reasonable in participants with pre-existing poor pulmonary function or at high risk of postoperative nausea and vomiting. Since there are eight studies awaiting classification, selection bias may exist in our systematic review.
Nitrous oxide has been used for over 160 years for the induction and maintenance of general anaesthesia. It has been used as a sole agent but is most often employed as part of a technique using other anaesthetic gases, intravenous agents, or both. Its low tissue solubility (and therefore rapid kinetics), low cost, and low rate of cardiorespiratory complications have made nitrous oxide by far the most commonly used general anaesthetic. The accumulating evidence regarding adverse effects of nitrous oxide administration has led many anaesthetists to question its continued routine use in a variety of operating room settings. Adverse events may result from both the biological actions of nitrous oxide and the fact that to deliver an effective dose, nitrous oxide, which is a relatively weak anaesthetic agent, needs to be given in high concentrations that restrict oxygen delivery (for example, a common mixture is 30% oxygen with 70% nitrous oxide). As well as the risk of low blood oxygen levels, concerns have also been raised regarding the risk of compromising the immune system, impaired cognition, postoperative cardiovascular complications, bowel obstruction from distention, and possible respiratory compromise.
To determine if nitrous oxide-based anaesthesia results in similar outcomes to nitrous oxide-free anaesthesia in adults undergoing surgery.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014 Issue 10); MEDLINE (1966 to 17 October 2014); EMBASE (1974 to 17 October 2014); and ISI Web of Science (1974 to 17 October 2014). We also searched the reference lists of relevant articles, conference proceedings, and ongoing trials up to 17 October 2014 on specific websites (http://clinicaltrials.gov/, http://controlled-trials.com/, and http://www.centerwatch.com).
We included randomized controlled trials (RCTs) comparing general anaesthesia where nitrous oxide was part of the anaesthetic technique used for the induction or maintenance of general anaesthesia (or both) with any general anaesthesia using a volatile anaesthetic or propofol-based maintenance of anaesthesia but no nitrous oxide for adults undergoing surgery. Our primary outcome was inhospital case fatality rate. Secondary outcomes were complications and length of stay.
Two review authors independently assessed trial quality and extracted the outcome data. We used meta-analysis for data synthesis. Heterogeneity was examined with the Chi² test and by calculating the I² statistic. We used a fixed-effect model if the measure of inconsistency was low for all comparisons (I² statistic < 50%); otherwise we used a random-effects model for measures with high inconsistency. We undertook subgroup analyses to explore inconsistency and sensitivity analyses to evaluate whether the results were robust. We assessed the quality of evidence of the main outcomes using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.
We included 35 trials (13,872 adult participants). Seven included studies were at low risk of bias. We identified eight studies as awaiting classification since we could not obtain the full texts, and had insufficient information to include or exclude them. We included data from 24 trials for quantitative synthesis. The results of meta-analyses showed that nitrous oxide-based techniques increased the incidence of pulmonary atelectasis (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.18 to 2.10, P = 0.002), but had no effects on the inhospital case fatality rate, the incidence of pneumonia, myocardial infarction, stroke, severe nausea and vomiting, venous thromboembolism, wound infection, or the length of hospital stay. The sensitivity analyses suggested that the results of the meta-analyses were all robust except for the outcomes of pneumonia, and severe nausea and vomiting. Two trials reported length of intensive care unit (ICU) stay but the data were skewed so were not pooled. Both trials reported that nitrous oxide-based techniques had no effects on the length of ICU stay. We rated the quality of evidence for two outcomes (pulmonary atelectasis, myocardial infarction) as high, four outcomes (inhospital case fatality rate, stroke, venous thromboembolism, length of hospital stay) as moderate, and three (pneumonia, severe nausea and vomiting, wound infection rate) as low.