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Xenon Anesthesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Law, Lawrence Siu-Chun MD; Lo, Elaine Ah-Gi PharmD, BCPS; Gan, Tong Joo MD, FRCA, MHS, LiAc

doi: 10.1213/ANE.0000000000000914
Anesthetic Pharmacology: Research Report

BACKGROUND: Xenon anesthesia has been studied for decades. However, no meta-analysis of randomized controlled trials (RCTs) on xenon anesthesia has been conducted. The aim of this study was to systematically review all available evidence from RCTs comparing xenon and other inhaled and IV anesthetics on anesthetic outcomes. Our meta-analysis attempted to quantify the effects of xenon anesthesia on clinical outcomes in relation to other anesthetics.

METHODS: We found 43 RCTs from PubMed, MEDLINE, CENTRAL, EMBASE, and CINAHL (until January 2015). A total of 31 studies comparing xenon (841 patients) with other inhaled agents (836 patients) and 12 studies comparing xenon (373 patients) with propofol (360 patients) were found. We evaluated clinical outcomes, such as intraoperative hemodynamics, emergence, and postoperative nausea and vomiting (PONV).

RESULTS: Patients undergoing xenon anesthesia had a lower heart rate and higher mean arterial pressure (MAP) intraoperatively than those receiving volatile anesthesia (mean difference = −6 min−1 [99% confidence interval {99% CI} −10.0 to −2.3]; mean difference = 9 mm Hg [99% CI 3.1–14.4]) and propofol anesthesia (mean difference = −10 min−1 [99% CI −12.4 to −6.6]; mean difference = 7 mm Hg [99% CI 0.85–13.2]). Compared with baseline, intraoperative MAP remained relatively stable (change < 5.5%, 99% CI within ±20% of the baseline) under xenon anesthesia, but MAP decreased by ≥15% under volatile (mean difference = −17 mm Hg [99% CI −29.5 to − 4.9], percentage change = −17.5%) and propofol (mean difference = −14 mm Hg [99% CI −26.1 to −2.5], percentage change = −15.0%) anesthesia. Patients had faster emergence from xenon than from volatile anesthesia: eyes opening (versus all volatile agents: mean 4 vs 7 minutes, percentage change = −49.8% [99% CI −55.1% to −44.0%]), tracheal extubation (versus all volatile agents: mean 4 vs 8 minutes percentage change = −44.6% [99% CI −57.3% to −28.1%]), orientation (versus sevoflurane: mean 5 vs 10 minutes, percentage change = −45.1% [99% CI −58.5% to −28.1%]), countdown (versus sevoflurane: mean 6 vs 10 minutes, percentage change = −41.7% [99% CI −50.3% to −31.6%]; versus isoflurane: mean 6 vs 14 minutes, percentage change = −57.7% [99% CI −65.7% to −48.3%]), and reaction on demand (versus sevoflurane: mean 4 vs 8 minutes, percentage change = −53.2% [99% CI −65.7% to −35.6%]). However, xenon anesthesia increased the risks of PONV (incidence 34.4% vs 19.9%; risk ratio = 1.72 [99% CI 1.10–2.69], risk difference = 0.19 [99% CI 0.04–0.33]).

CONCLUSIONS: Xenon anesthesia provides relatively more stable intraoperative blood pressure, lower heart rate, and faster emergence from anesthesia than volatile and propofol anesthesia. However, xenon is associated with a higher incidence of PONV.

Published ahead of print August 13, 2015

From the *Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; and Faculty of Pharmaceutical Sciences, the University of British Columbia, Vancouver, British Columbia, Canada.

Lawrence Siu-Chun Law, MD, is currently affiliated with Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore.

Tong Joo Gan, MD, FRCA, MHS, LiAc, is currently affiliated with the Department of Anesthesiology, Stony Brook Medicine, Stony Brook, New York.

Accepted for publication May 8, 2015.

Published ahead of print August 13, 2015

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Tong Joo Gan, MD, FRCA, MHS, LiAc, Department of Anesthesiology, Stony Brook Medicine, HSC Level 4, Rm 060, Stony Brook, NY 11794. Address e-mail to tong.gan@stonybrookmedicine.edu.

Xenon anesthesia has been studied for decades. The anesthetic property of xenon is mainly conferred by the inhibition of N-methyl-D-aspartate receptors in the central nervous system.1 The minimal alveolar concentration (MAC) of xenon is 71%.2 Xenon is an inert gas and, theoretically, is not metabolized to toxic metabolites, does not react with absorbent, and does not deplete vitamin B12, as opposed to other inhaled agents. The blood-gas (0.115) and brain-blood (0.23) coefficients of xenon are the lowest among all inhaled agents (e.g., nitrous oxide [N2O]: blood-gas 0.47, brain-blood 1.1; desflurane: blood-gas 0.42, brain-blood 1.3).3 Xenon provides faster recovery from anesthesia than other volatile agents.4 Some reviews suggest that xenon facilitates stable hemodynamics5 and may be neuroprotective.1,6 Xenon is not associated with malignant hyperthermia,7 diffusion hypoxemia,3 or coagulopathy.8 Some animal studies9 showed that xenon has no hepatic or renal toxicity, although some other studies10 showed that it may reduce portal venous flow and compromise hepatic perfusion. Xenon has many properties of an ideal anesthetic.

Clinically, there are certain disadvantages to xenon anesthesia. Similar to N2O, but to a lesser extent, xenon may accumulate in closed spaces.3,11 Although it is not pungent,12 the high MAC of xenon limits the oxygen concentration and prevents it from being a sole agent safe for induction.13 Xenon may also increase the risk of postoperative nausea and vomiting (PONV).14 Because of its high density (approximately 4.56 times of air), xenon was found to increase airway resistance and work of breathing in an animal study.15 Nevertheless, it may be a good choice for high-risk patients with unstable hemodynamics, cardiovascular diseases, expected prolonged recovery from anesthesia, or advanced age.16–19

The number of randomized controlled trials (RCTs) comparing the clinical outcomes between xenon and other anesthetics for general anesthesia is increasing. However, no meta-analysis of these RCTs has been conducted. The aim of this study was to systematically review all available evidence from RCTs and to conduct meta-analysis on the results from RCTs. Primary outcomes included intraoperative hemodynamic variables, recovery outcomes, and PONV. Our meta-analysis attempted to quantify the effects of xenon anesthesia on these primary outcomes in relation to other anesthetics. We also analyzed secondary outcomes: opioid consumption, incidence of other adverse events, and length of stay in the postanesthesia care unit (PACU), the hospital, and the intensive care unit (ICU). We compared xenon anesthesia with other inhaled anesthesia and total IV anesthesia (TIVA) with propofol.

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METHODS

Search Strategy

Our study conforms to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for reporting systematic reviews and meta-analyses.20 We searched PubMed, MEDLINE, CENTRAL, EMBASE, and CINAHL for RCTs comparing xenon with any other agents for general anesthesia. We used the search term “xenon AND (anesthesia OR anaesthesia),” with no restriction on the year of publication. The latest search was done in January 2015.

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Selection of Included Studies

Two authors (Lawrence S.C. Law and Elaine A.G. Lo) searched independently and assessed eligibility based on the title and abstract (κ = 0.90). We limited our inclusion criteria to RCTs performed on humans and publications in English, because the quality of studies in other languages could not be adequately assessed. Conference abstracts >3 years old and studies on healthy human subjects (i.e., no surgery) were excluded. We imposed no limitation on outcome variables or anesthetic.

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Data Extraction

We conducted meta-analysis if 2 or more studies were available for a particular outcome. Results were reported descriptively if only 1 study was available.

We compared heart rate (HR, min−1), mean arterial pressure (MAP, mm Hg), cardiac index/output, incidence of PONV, and perioperative opioid consumption of xenon anesthesia with both inhaled agents (sevoflurane, isoflurane, desflurane, and N2O) and TIVA using propofol. Data were analyzed separately for inhaled agents and propofol groups. Subgroup analyses for each inhaled agent (“xenon versus sevoflurane,” “xenon versus isoflurane,” “xenon versus desflurane,” and “xenon versus N2O-only”) were also conducted. If 2 or more values were reported for the intraoperative HR or MAP, we chose the values measured immediately before the incisions (the latest reading in the period between induction and incision) or measured at 10 to 15 minutes after induction (whenever applicable) for analyses. Systolic blood pressure and diastolic blood pressure were converted into MAP with the following equation: MAP = systolic blood pressure/3 + 2 diastolic blood pressure/3. The intraoperative HR and MAP were compared with their baseline values (preinduction) if these were available. A change of ±20% from the baseline was considered as clinically significant. We also compared central venous pressure (CVP) between xenon and propofol.

We compared the time (minutes) to eye opening, tracheal extubation, spatial orientation, countdown, and react on demand of xenon anesthesia with volatile agents. We analyzed sevoflurane, isoflurane, and desflurane individually, because their recovery times were expected to be different.

Aldrete scores21,22 at 5, 15, and 30 minutes were compared between xenon anesthesia and volatile anesthesia. A patient with an Aldrete score (ranged 0–10) ≥8 is usually considered fit for discharge from PACU. We also reviewed the recovery data for xenon versus propofol.

We assessed the incidence of adverse events, length of hospital stay, length of PACU stay, and length of ICU stay of xenon anesthesia against other forms of anesthesia. Adverse events reported included PONV, hypertension, hypotension, bradycardia, shivering, mortality, and delirium. For opioid consumption, conversion to morphine equivalent was unnecessary, because we natural-log-transformed the data and compared the percentage change of opioid consumption instead of the absolute difference for statistical reasons. We also compared the duration of anesthesia (minutes).

For postoperative cognitive dysfunction, the outcome variables were heterogeneous. Thus, we opted to report the results descriptively.

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Statistical Analyses

Meta-analysis was conducted with Review Manager 5.3 (Cochrane Collaboration, Copenhagen, Denmark). Random effects model was used for all analyses. Standard error of means (SEMs) and 95% confidence intervals (95% CI) were converted into SD with the following formulas: SEM = (95% CI)/1.96 and

CV

CV

. Otherwise, mean and SD were estimated from reported P values. If SD could not be obtained with the above means, we substituted the missing SD with the pooled SD of other studies within the same comparison by:

CV

CV

.

For continuous and ordinal variables, mean differences were compared with the inverse variance method. For dichotomous variables, risk ratios were computed with the Mantel-Haenszel method. Risk difference was calculated when the absolute change of risk was deemed important or when risk ratio was not applicable (zero incidence in both xenon and control groups).

Percentage change was reported if the continuous variables were expected to be log-normal, namely, the emergence outcomes: time to eye opening and tracheal extubation, and opioid consumption.23–27 Natural log- transformation was adopted according to the method by Higgins et al.28: z = ln(x) – ln(s2/x2 + 1)/2 and

CV

CV

, whereas x and s were the mean and SD of raw scale; z and sz were the mean and SD of the natural-log-transformed scale. Percentage change = (ed – 1) × 100%, d = zxenonzcontrol, where d is the mean difference in the natural-log-transformed scale. The SEs of d were computed by the Taylor series approximation28 (Appendix). The arithmetic means and their differences were biased in log-normally distributed data. For better interpretation of the percentage changes, the geometric means (e∑wz/∑w, w = the weight of study in comparison) of both xenon and control groups were reported.

For comparing HR and MAP with the baseline, percentage change was computed as percentage change = mean difference/baseline × 100%. Because the distributions of HR and MAP were expected to be normal, HR and MAP were reported on the raw scale without log-transformation. To clarify, all reported means and mean differences were arithmetic, unless otherwise specified to be geometric.

Our preliminary analyses showed that the percentage change of time to eye opening and tracheal extubation was similar (about 50% less) for xenon when compared with sevoflurane, isoflurane, and desflurane, so these comparisons were combined. Test for subgroup difference of these 3 comparisons was conducted. Furthermore, we performed subgroup analyses to compare (1) the effect of reduction to MAC 0.5 at 10 minutes before the anticipated end of surgery, (2) volatile-only or volatile + N2O in the control groups, and (3) the use of intraoperative remifentanil infusion or opioid bolus. We also conducted sensitivity analyses for studies when MAC between the 2 comparator groups differed by 0.2 or less. MAC values of each group in all studies were estimated according to the iso-MAC chart for 40-year-old men29 (Table 1).

Table 1

Table 1

For all comparisons, statistical significance was set at P< 0.01 (2-sided) and 99% CIs were reported. For tests for subgroup differences, statistical significance was set at P < 0.05. Egger regression30 was used to assess publication biases for comparisons with 3 or more studies, and the statistical significance was set at P < 0.05.

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RESULTS

Study Selection

Table 2

Table 2

Table 3

Table 3

Figure 1

Figure 1

Of the 936 studies found, 43 met the inclusion criteria for meta-analysis (Fig. 1). A total of 31 studies4,14,16,17,31–57 compared xenon with other inhaled agents (n = 841 vs 836). Within the group of other inhaled agents (total n = 836), the sample sizes were 288 (sevoflurane), 358 (isoflurane), 69 (desflurane), and 121 (N2O-only). Twelve studies18,19,57–66 compared xenon with TIVA using propofol (n = 373 vs 360). Two studies67,68 comparing xenon and propofol were retracted and, therefore, excluded from our analysis. Characteristics and the risk of bias assessment of included studies are presented in Tables 1 and 2, respectively. All statistical results (n, mean difference, risk ratio, risk difference, percentage change, 99% CI, I2, χ2, P) are shown in Table 3.

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Basic Intraoperative Hemodynamics

For the comparison of xenon with other inhaled agents, we examined 16 studies14,32,33,35,36,39,41,45–47,51,53–56 for HR (Fig. 2), as well as the same 16 studies with an additional study31 for MAP (Fig. 3). Patients undergoing xenon anesthesia had a lower HR (mean difference = −6 min−1 [99% CI −10.0 to −2.3]) and a higher MAP (mean difference = 9 mm Hg [99% CI 3.1–14.4]) than those who underwent general anesthesia with other inhaled agents. We compared the intraoperative HR and MAP with the baseline values in 7 studies14,32,35,51,53,54,56 (Figs. 4 and 5). With xenon anesthesia, HR fell by a mean of 17 min−1, which was a 22.3% change (mean difference = −17 min−1 [99% CI −21.4 to −11.7]). The change of MAP was not statistically significant, and the 99% CI was within ±20% from the baseline (mean difference = −4 mm Hg [99% CI −17.3 to 9.3], percentage change = −4.1%). With volatile anesthetics, HR and MAP dropped by means of 8 min−1 and 17 mm Hg, respectively, which were 11.2% and 17.5% changes from baseline (mean difference for HR = −8 min−1 [99% CI −15.1 to −1.6] and mean difference for MAP = −17 mm Hg [99% CI −29.5 to −4.9]; Table 4).

Table 4

Table 4

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

Subgroup analyses demonstrated similar results for xenon versus sevoflurane31,35,45,51,53–56 (HR: mean difference = −7 min−1 [99% CI −12.2 to −2.3], MAP: mean difference = 12 mm Hg [99% CI 1.7 to 22.9]). No statistical difference was found for HR, and the 99% CI was within ±20% from the baseline (mean difference = −4 min−1 [99% CI −17.0 to 9.8]). MAP in the xenon group was significantly higher than the isoflurane group14,32,35,36,47 (mean difference = 11 mm Hg [99% CI 2.5–19.6]). HR and MAP were not significantly different between xenon and N2O-only39,41,45,46 anesthesia (99% CI within ± 8 mm Hg).

Figure 6

Figure 6

Figure 7

Figure 7

Figure 8

Figure 8

Figure 9

Figure 9

To compare xenon with propofol, we examined 8 studies18,19,58,60,61,64–66 for HR (Fig. 6) and MAP (Fig. 7). Similarly, patients undergoing xenon anesthesia had lower HR (mean difference = −9 min−1 [99% CI −12.4 to −6.6]) and higher MAP (mean difference = 7 mm Hg [99% CI 0.85–13.2]) than those who underwent TIVA with propofol. We compared the intraoperative HR and MAP with the baseline values in 4 studies18,19,61,65 (Figs. 8 and 9). With xenon anesthesia, HR fell by a mean of 10 min−1, which was a 16.2% change (mean difference = −10 min−1 [99% CI −17.3 to −3.3]). The change of MAP was not statistically significant, and the 99% CI was within ±20% from the baseline (mean difference = −5 mm Hg [99% CI −18.3 to 7.9], percentage change = −5.5%). With propofol anesthesia, the change of HR was not statistically significant and the 99% CI was within ±20% from the baseline (mean difference = −4 min−1 [99% CI −11.0 to 2.8], percentage change = −6.1%), whereas MAP dropped by a mean of 14 mm Hg, which was a 15.0% change (mean difference = −14 mm Hg [99% CI −29.0 to −2.5]; Table 4).

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Advanced Intraoperative Hemodynamics

Three studies31,39,55 examined cardiac indices of xenon versus other inhaled agents (mean difference = 0.17 L·min−1·m−2 [99% CI −0.12 to 0.45]). Another 360,64,65 analyzed cardiac outputs of xenon versus propofol (mean difference = −0.46 L·min−1·[99% CI −1.33 to 0.41]). All studies used transesophageal echocardiography to calculate cardiac indices or outputs. No significant difference was found for both analyses.

For xenon versus propofol, one study58 investigated the changes (before versus after induction) in cardiac output and systemic vascular resistance among patients with heart failure. Cardiac output did not change significantly for both xenon and propofol anesthesia. However, systematic vascular resistance increased significantly with xenon anesthesia by 13.8%, whereas it dropped by 5.3% with propofol anesthesia (P < 0.05). Another study39 compared xenon and N2O-only anesthesia and found no difference in systemic vascular resistance.

CVP was higher in xenon anesthesia than propofol anesthesia in 2 studies60,64 (mean difference = 3 mm Hg [99% CI 0.3–4.9]). However, no difference in CVP was found between xenon and N2O-only anesthesia in another study.39

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Emergence from Anesthesia

Most of the included studies4,34,35,40,49–51,54 reported that the emergence end points were tested in regular intervals of 20 to 60 seconds, starting from termination of inhaled agents and administration of high-flow oxygen (Table 5). However, some studies16,17,32,56 did not mention the intervals of testing emergence end points.

Table 5

Table 5

Seven studies34,35,40,50,51,54,56 compared xenon with sevoflurane (Figs. 10 and 11). Patients undergoing xenon anesthesia opened eyes, extubated, oriented spatially, counted down, and reacted on demand faster than those who underwent sevoflurane anesthesia. The percentage change of time to open eyes was −52.8% (99% CI −61.2% to −41.4%), and the geometric means were 3 minutes for xenon and 7 minutes for sevoflurane. The percentage change of time to tracheal extubation was −48.3% (99% CI −54.6% to −40.5%), and the geometric means were 4 minutes for xenon and 8 minutes for sevoflurane. The percentage change of time to spatial orientation was −45.1% (99% CI −58.5% to −28.1%), and the geometric means were 5 minutes for xenon and 10 minutes for sevoflurane. The percentage change of time to countdown was −41.7% (99% CI −50.3% to −31.6%), and the geometric means were 6 minutes for xenon and 10 minutes for sevoflurane. The percentage change of time to react on demand was −53.2% (99% CI −65.7% to −35.6%), and the geometric means were 4 minutes for xenon and 8 minutes for sevoflurane.

Figure 10

Figure 10

Figure 11

Figure 11

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[2] = 0.74, P = 0.69, I2 = 0%; tracheal extubation: χ2[2] = 0.44, P = 0.80, I2 = 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).

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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.

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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.

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Postoperative Nausea and Vomiting

Figure 12

Figure 12

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).

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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.

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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.

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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.

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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

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Subgroup Analyses

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[1] = 4.20, P = 0.04, I2 = 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[1] = 2.86, P = 0.09, I2 = 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 [1] = 7.20, P = 0.007, I2 = 86%). No subgroup difference was found for HR (χ2[1] = 3.44, P = 0.06, I2 = 71%), MAP (χ2[1] = 0.69, P = 0.41, I2 = 0%), and time to tracheal extubation (χ2[1] = 2.92, P = 0.09, I2 = 66%).

No subgroup difference for time to open eyes (χ2[1] = 0.01, P = 0.91, I2 = 0%) and time to tracheal extubation (χ2[1] = 0.25, P = 0.62, I2 = 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[1] = 0.67, P = 0.41, I2 = 0%) between studies using continuous remifentanil infusion19,56,61,62 and studies using opioid boluses.14,32,34,49

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Sensitivity Analyses

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).

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Publication Bias

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.

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DISCUSSION

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.

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Intraoperative Hemodynamics

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.

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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.

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Adverse Events

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.

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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.

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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.

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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.

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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.

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Limitations

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.

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CONCLUSIONS

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.

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APPENDIX

CV

CV

where x is the mean of raw scale, s is the SD of raw scale, z is the mean of log-transformed scale, sz 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:

CV

CV

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DISCLOSURES

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.

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RECUSE NOTE

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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