Four studies32,34,35,49 compared xenon with isoflurane (Figs. 10 and 11). Patients undergoing xenon anesthesia opened eyes, were tracheally extubated, and counted down faster than those who underwent isoflurane anesthesia, but no significant effect was found for time to spatial orientation. The percentage change of time to open eyes was −48.8% (99% CI −60.1% to −33.6%), and the geometric means were 4 minutes for xenon and 7 minutes for isoflurane. The percentage change of time to tracheal extubation was −50.3% (99% CI −60.5% to −36.9%), and the geometric means were 4 minutes for xenon and 8 minutes for isoflurane. The percentage change of time to countdown was −57.7% (99% CI −65.7% to −48.3%), and the geometric means were 6 minutes for xenon and 14 minutes for isoflurane. The percentage change of time to spatial orientation was −36.9% (99% CI −72.7% to +46.2%), and the geometric means were 5 minutes for xenon and 8 minutes for isoflurane.
Three studies4,16,17 compared xenon with desflurane (Figs. 10 and 11). Xenon anesthesia had a shorter time to eye opening and tracheal extubation than desflurane anesthesia. The percentage change of time to open eyes was −55.5% (99% CI −70.8% to −33.0%), and the geometric means were 4 minutes for xenon and 8 minutes for desflurane. The percentage change for time to tracheal extubation was −53.7% (99% CI −71.1% to −25.2%), and the geometric means were 4 minutes for xenon and 8 minutes for desflurane. Only one study4 reported time to react and demand and spatial orientation and showed that xenon anesthesia had a shorter time to react on demand (5 vs 9 minutes, P = 0.001) and to spatial orientation (7 vs 11 minutes, P = 0.007) than desflurane anesthesia.
For time to open eyes and tracheal extubation, all percentage change for xenon versus sevoflurane, xenon versus isoflurane, and xenon versus desflurane were about −50%, and no difference was found between the percentage change for these comparisons (eyes opening: χ2 = 0.74, P = 0.69, I 2 = 0%; tracheal extubation: χ2 = 0.44, P = 0.80, I 2 = 0%4,32,34,35,40,49–51,54,56; Figs. 10 and 11).
Only one study66 compared xenon with propofol for emergence outcomes. The study demonstrated that xenon anesthesia had faster emergence than propofol anesthesia (260 vs 590 seconds, P = 0.001).
Readiness for PACU Discharge
When Aldrete scores after xenon and volatile anesthesia were compared, there was no difference at 5 minutes (mean difference = 0.7 [99% CI −0.01 to 1.46]),4,40,49,56 but scores were higher for xenon anesthesia at 15 minutes (mean difference = 0.5 [99% CI 0.06–0.85])4,40,49,53 and 30 minutes (mean difference = 0.6 [99% CI 0.18–0.95]).4,40,49,53 Only one study compared xenon with propofol, and no significant difference was found at all time points (0, 5, 15, 30, 45, 60, and 120 minutes).61 No data were available for xenon versus isoflurane or desflurane.
Length of Stay
Lengths of PACU,32,51,54,61 ICU,55,65 and hospital stay55,65 were not significantly different between xenon and other anesthetics.
Postoperative Nausea and Vomiting
We analyzed 6 studies14,32,34,35,49,56 comparing xenon with other inhaled agents and 3 studies19,62,63 comparing xenon with propofol. The incidence of PONV was higher for xenon anesthesia (158/459, 34.4%) than that for volatile anesthesia and TIVA (94/473, 19.9%). The risk ratio was 1.72 (99% CI 1.10–2.69), and the risk difference was 0.19 (99% CI 0.04–0.33). Subgroup analysis remained significant for “xenon versus volatile agents” (risk ratio = 1.65 [99% CI 1.14–2.39]) but not for “xenon versus propofol” (risk ratio = 2.33 [99% CI 0.53–10.30]; Fig. 12).
Other Adverse Events
The incidences of hypertension,14,19,32,56,61 hypotension,14,19,32,55,56,61 bradycardia,14,19,32,56,61 mortality,55,65 and shivering14,32,61,62 were not statistically different between xenon and other anesthetic agents.
Three studies51,54,56 presented data for intraoperative awareness. No incidence was reported for all groups. Two studies51,54 reported incidence of dreaming for xenon, but no statistical difference was found comparing with sevoflurane. One study55 reported similar incidence of postoperative delirium between xenon and sevoflurane.
Pain and Opioid Consumption
We analyzed 13 studies4,33,41,43,49–56 comparing intraoperative opioid consumption for xenon versus other inhaled agents and 1 study61 for xenon versus propofol, and 4 studies4,53,54,63 investigating postoperative opioid consumption. There was no significant difference in both intraoperative and postoperative opioid consumption. The percentage change in intraoperative opioid consumption was +9.4% (99% CI −13.1% to +36.3%) for xenon versus other inhaled agents. For the single study comparing xenon and propofol, the intraoperative remifentanil consumptions were 0.19 (SD 0.09) versus 0.18 (SD 0.08) μg·kg−1·min−1. In postoperative opioid consumption, the percentage change was −7.7% (99% CI −40.5% to +44.8%). Two studies37,53 reported no difference in postoperative pain control at 0 to 6 hours between xenon and sevoflurane or isoflurane.
Postoperative Cognitive Dysfunction
Two studies4,66 investigated postoperative cognitive dysfunction after xenon anesthesia. Coburn et al.4 measured alertness, divided attention, and working memory at 6 to 72 hours postoperatively (xenon versus desflurane); while68 Rasmussen et al.66 examined visual-verbal learning, attention, and executive function at 3 to 5 days and 3 months after surgery (xenon versus propofol). No difference in both short- and medium-term neurocognitive outcomes was found.
Duration of Anesthesia
The duration of anesthesia was not significantly different between xenon and control groups (mean difference = −2 minutes [99% CI −12.0 to 7.1]).4,14,32,34,35,37,38,41,50,51,53,62,63
Two studies4,40 reduced MAC to 0.5 at about 10 minutes before the anticipated end of anesthesia (Table 5). We compared the percentage change for xenon versus volatile agents of these 2 studies with the other 8 studies32,34,35,49–51,54,56 without such reduction. For the 2 studies with MAC reduction, the percentage change of time to eye opening was −43.4% (99% CI −49.3% to −36.2%) and the difference of geometric means was −3.6 minutes; the percentage change of time to tracheal extubation was −44.6% (99% CI −47.8% to −41.1%); and the difference of geometric means was −3.8 minutes. For the 8 studies without MAC reduction, the percentage change of time to open eyes was −53.7% (99% CI −63.6% to −41.7%) and the difference of geometric means was −3.8 minutes; and the percentage change of time to tracheal extubation was −50.3% (99% CI −57.7% to −41.7%), and the difference of geometric means was −4.1 minutes. For time to open eyes, the percentage drop (43.4% or 3.6 minutes) among the 2 studies with MAC reduction was smaller than the percentage drop (53.7% or 3.8 minutes) among the 8 studies without MAC reduction (χ2 = 4.20, P = 0.04, I 2 = 76%). Although the difference was statistically significant, the difference (0.2 minutes) was not clinically significant. Furthermore, no statistically significant difference between MAC reduction and no MAC reduction was found for time to tracheal extubation (χ2 = 2.86, P = 0.09, I 2 = 65%).
For Aldrete score, no subgroup difference was found at all time points (5, 15, and 30 minutes) between studies4,40 with anesthetic reduction to MAC 0.5 at 10 minutes before the anticipated end of surgery and studies49,53,56 without such reduction.
In the control groups, some studies4,14,16,17,40,45,50,51,53–56 used volatile agents only, while others32–35 used volatile agents together with N2O; or they had 2 control groups36,47 (both volatile-only and volatile + N2O). We compared percentage change of “xenon versus volatile-only” with “xenon versus volatile + N2O.” The percentage change (57.1%) of time to open eyes for xenon versus volatile-only was larger than the percentage change (43.6%) of time to open eyes for xenon versus volatile + N2O (percentage change = −57.1% [99% CI −67.0% to −48.2%] versus −43.6% [99% CI −52.7% to −35.7%], difference of geometric means = 4.5 versus 2.8 minutes; χ2  = 7.20, P = 0.007, I 2 = 86%). No subgroup difference was found for HR (χ2 = 3.44, P = 0.06, I 2 = 71%), MAP (χ2 = 0.69, P = 0.41, I 2 = 0%), and time to tracheal extubation (χ2 = 2.92, P = 0.09, I 2 = 66%).
No subgroup difference for time to open eyes (χ2 = 0.01, P = 0.91, I 2 = 0%) and time to tracheal extubation (χ2 = 0.25, P = 0.62, I 2 = 0%) was found between studies using continuous remifentanil infusion4,40,50,51,54,56 and studies using opioid boluses.17,32,34,35,49 Similarly, no subgroup difference for PONV was found (χ2 = 0.67, P = 0.41, I 2 = 0%) between studies using continuous remifentanil infusion19,56,61,62 and studies using opioid boluses.14,32,34,49
The difference of MAC between groups was 0.2 or less in 78% of the included studies (in which MAC applicable to the control group). Excluding those studies in which the difference of MAC was >0.2, we repeated all comparisons on hemodynamic outcomes. The results were similar. For xenon versus other inhaled agents,14,32,33,35,36,39,45,47,53–56,69 mean difference for HR was −6 min−1 (99% CI −11.0 to −1.9) and mean difference for MAP was 10 mm Hg (99% CI 3.5–16.1). For xenon versus sevoflurane,35,46,51,53–56 mean difference for HR was −8 min−1 (99% CI −14.0 to −2.3) and mean difference for MAP was 12 mm Hg (99% CI 0.01–24.6). For xenon versus isoflurane, all studies had an MAC difference 0.2 or less, so sensitivity analysis was unnecessary. For xenon anesthesia comparing with baseline,14,32,34,53,54,56 mean difference for HR was −16 min−1 (99% CI −20.9 to −10.8) and mean difference for MAP was −0.8 mm Hg (99% CI −14.3 to 12.7). For volatile anesthesia comparing with baseline,14,32,34,53,54,56 mean difference for HR was −6 min−1 (99% CI −11.1 to −1.4) and mean difference for MAP was −15 mm Hg (99% CI −28.9 to −1.4).
All Egger intercepts were not significant (indicating a low risk of publication bias), with the exception of the intercept for the length of PACU stay.
From the results of our meta-analysis, we attempted to quantify the effects of xenon anesthesia on intraoperative hemodynamics, recovery outcomes, and PONV. Under xenon anesthesia, HR dropped by about 20% (approximately 14 min−1), whereas MAP dropped by 4% to 5% (approximately 5 mm Hg) and the 99% CI of MAP was within ±20% of the baseline value. Recovery from xenon anesthesia was about 50% (approximately 4 minutes) faster than all types of volatile anesthesia. The incidence of PONV after xenon anesthesia was 72% higher than after volatile and propofol anesthesia (incidence: 34.4% vs 19.9%). No effect was found for all secondary outcomes: intraoperative and postoperative opioid consumption, incidence of adverse events except PONV, and length of stay in PACU, hospital, and ICU.
Our meta-analysis shows that MAP is relatively stable (approximately 5% or approximately 5 mm Hg change from the baseline, and 99% CI within ±20% of the baseline) in xenon anesthesia, whereas it decreases by ≥15% in volatile and propofol anesthesia. Patients undergoing xenon anesthesia have a lower HR, higher MAP, and lower CVP compared with those undergoing volatile and propofol anesthesia. This profile of intraoperative hemodynamics may be explained by a previous human study,58 which found an increase in systematic vascular resistance but no significant change in stroke volume under xenon anesthesia. One animal study70 demonstrated an increase in endogenous vasopressors, including epinephrine, norepinephrine, and vasopressin, under xenon-remifentanil anesthesia compared with isoflurane-remifentanil and isoflurane-N2O anesthesia.
Our systematic review found only one RCT58 recruiting patients with heart failure. Three other studies39,60,64 recruited patients undergoing abdominal aortic surgery or coronary artery bypass graft. More data are needed to establish the safety of xenon among patients with high cardiovascular risk.
Although most skilled anesthesiologists are able to manage the hemodynamic changes effectively with other vasoactive agents, our results may help anesthesiologists who use xenon to anticipate the hemodynamic changes and manage the changes proactively.
Emergence from Anesthesia
Our meta-analysis demonstrates that xenon has an excellent recovery profile in terms of emergence from anesthesia (open eyes and extubated approximately 50% or approximately 4 minutes faster) and readiness of discharge from PACU (Aldrete score 0.5–0.7 point higher) versus isoflurane, sevoflurane, and desflurane. In addition, reducing volatile agents to 0.5 MAC 10 minutes before the anticipated end of surgery offsets some but not all (percentage change from −54% to −43%, or difference of geometric means from −3.8 to −3.6 minutes) of the advantage of xenon anesthesia in emergence outcomes over volatile anesthesia.
Our systematic review shows that emergence from xenon anesthesia is faster than that from propofol anesthesia. The difference is empirical. More studies are required to confirm this finding.
Despite faster emergence and greater readiness for PACU discharge, xenon has not been demonstrated to affect the length of PACU, ICU, or hospital stay. Various factors may affect these outcomes, and the contribution of anesthetic agents could be relatively minimal. Future studies are needed to elucidate the factors predicting the length of PACU, ICU, and hospital stay.
On the basis of our meta-analysis, xenon anesthesia increases the incidence of PONV by 72% (34.4% vs 19.9%) when compared with volatile and propofol anesthesia. The risk difference was 19%, which was equivalent to one risk factor according to the consensus guidelines for the management of PONV.71 The mechanism of PONV with xenon remains unclear. Being an inhibitor of 5-hydroxytryptamine type 3 receptors, which are thought to mediate PONV,63,72,73 xenon is expected to relieve nausea and vomiting. It is possible that only certain subtypes of the receptor contribute to PONV. Future basic studies are required to uncover the mechanism. The increased risk of PONV may be a clinical reason that precludes xenon from routine use.
According to our meta-analysis, the incidence of adverse events under xenon anesthesia is similar to other anesthesia. Nevertheless, the number of studies explicitly reporting adverse events is relatively small.
Pain and Perioperative Opioid Consumption
Xenon is believed to be an N-methyl-D-aspartate receptor antagonist, like ketamine. Intraoperative ketamine infusion reduces both intraoperative and postoperative pain and analgesic requirements.74–76 Previous research showed that xenon has antihyperalgesic properties and an analgesic effect similar to N2O.77,78 However, our meta-analysis failed to demonstrate the superiority of xenon in terms of reducing intraoperative and postoperative opioid consumption or short-term postoperative pain. Many of the included studies used continuous remifentanil infusion; thus, intraoperative opioid consumption might not reflect the analgesic effect of xenon. Furthermore, xenon wears off quickly. Unless xenon is administered intranasally after surgery,79 reduction of postoperative opioid consumption or short-term pain is not expected.
Postoperative Cognitive Dysfunction
Although xenon is thought to be neuroprotective via various mechanisms,80–84 our systematic review found 2 studies4,66 that did not support such a notion. With <40 patients in both studies, the insignificant finding may reflect a lack of statistical power (type II error) rather than a true negative outcome. We were unable to conduct a meta-analysis because the studies used different parameters for neurocognitive assessment. The mechanism of postoperative cognitive dysfunction remains unclear and seems to be independent of the type of anesthesia, general versus regional.85,86 This is an important topic for future research.
Other Clinical Issues to Consider
None of the included RCTs suggested an association of xenon anesthesia with malignant hyperthermia and diffusion hypoxemia. One RCT55 reported no significant difference in creatinine clearance or blood nitrogen level between xenon and sevoflurane anesthesia. There is no RCT studying xenon in patients with impaired renal function, coagulopathy, or preexisting pulmonary diseases. We were thus unable to assess the use of xenon among these patients.
Cost of Xenon Anesthesia
The major obstacle of using xenon for general anesthesia is cost. A study69 in 1999 revealed that the cost of using xenon is about 4.2 to 9.7 times higher than N2O-isoflurane for a 60- to 420-minute closed-circuit anesthesia. In 2009, the cost of xenon for a 2-hour anesthesia is about 30 times more than volatile anesthesia or 15 times more than propofol anesthesia.87 More than half of the cost is for priming and flushing. Methods for saving xenon include using closed-circuit low-flow anesthesia, setting up separate circuits for induction and maintenance (and only prime the maintenance circuit with xenon), denitrogenating patients before switching from the induction circuit to maintenance circuit, prefilling the maintenance circuit with pure oxygen, and priming the maintenance circuit with a large syringe.88 Besides cost, the additional equipment required for xenon anesthesia (i.e., end-tidal monitors for xenon concentration) and lack of familiarity also preclude the use of xenon for general anesthesia.
There are several limitations to our meta-analysis. The included studies were heterogeneous, such as, the types of surgery, patient population, discrepancy of MAC between groups, opioid consumption, and schedule of opioid infusion (continuous versus bolus). The heterogeneity could affect some of the outcomes. For example, time to eye opening and tracheal extubation or PONV may be influenced by opioid consumption or the schedule of opioid infusion. Hemodynamic outcomes may be confounded by the discrepancy of MAC between groups. We attempted to explore the effect of such between-studies variables by subgroup analyses or to reduce the effect of heterogeneity by sensitivity analyses.
There was also a potential risk of publication bias, because we only included articles published in English and some comparisons in the meta-analysis had 4 or fewer studies. Egger intercept regression showed that all but one of our results has a low risk of publication bias. It should be noted that, while analyses of some of the end points were based on a great number of studies, for example, hemodynamics, conclusions for some end points were drawn from only a few trials. We tried to discern this by specifying the numbers of trials and participants included for each analysis. The final conclusion was also made taking into account the quality of analysis for each end point.
The results of Aldrete scores should be interpreted with caution. Despite being an ordinal parameter, most studies reported the mean and SD rather than the median and quartile interquartile range. Thus, we analyzed this end point parametrically, although the current statistical approach was less than ideal. In addition, the ideal end point should be the time to meet the criteria for PACU discharge (i.e., time to Aldrete score ≥8), but such data were not available for analysis. Most of the samples were relatively small (approximately 10–30 subjects per group). The CIs of some analyses were wide. Studies with larger sample size are needed.
Xenon anesthesia provides more stable intraoperative blood pressure, lower heart rate, and faster emergence from anesthesia than volatile and propofol anesthesia, but xenon is associated with a higher risk of PONV.
Our results may help anesthesiologists who use xenon to anticipate the hemodynamic changes and manage the changes proactively. Xenon may be a choice of anesthesia if faster emergence from anesthesia is required. The increased risk of PONV may preclude the routine use of xenon.
Furthermore, xenon may increase the readiness for PACU discharge but does not seem to be associated with shorter PACU, ICU, or hospital stays. Xenon seems to have no effect on opioid consumption and postoperative cognitive dysfunction, yet more data are required to draw robust conclusions.
where x is the mean of raw scale, s is the SD of raw scale, z is the mean of log-transformed scale, s z is the SD of log-transformed scale, d is the mean difference of the mean in the log-transformed scale.
The standard error of d is given by the following formulas:
Name: Lawrence Siu-Chun Law, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Lawrence Siu-Chun Law has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Elaine Ah-Gi Lo, PharmD, BCPS.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Elaine Ah-Gi Lo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Tong Joo Gan, MD, FRCA, MHS, LiAc.
Contribution: This author helped write the manuscript.
Attestation: Tong Joo Gan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
Tong Joo Gan is the Section Editor for Ambulatory Anesthesiology and Perioperative Management for Anesthesia & Analgesia. This manuscript was handled by Dr. Ken B. Johnson Section Editor for Anesthetic Clinical Pharmacology and Dr. Gan was not involved in any way with the editorial process or decision.
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