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International Society for Anaesthetic Pharmacology

Preclinical Pharmacology Section Editor: Markus W. Hollmann


Anesthetic Clinical Pharmacology Section Editor: Ken B. Johnson

Xenon Anesthesia: A Systematic Review and


Meta-Analysis of Randomized Controlled Trials
Lawrence Siu-Chun Law, MD,* Elaine Ah-Gi Lo, PharmD, BCPS,
and Tong Joo Gan, MD, FRCA, MHS, LiAc*

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 differ-
ence=6 min1 [99% confidence interval {99% CI} 10.0 to 2.3]; mean difference=9 mm Hg
[99% CI 3.114.4]) and propofol anesthesia (mean difference=10 min1 [99% CI 12.4 to
6.6]; mean difference=7 mm Hg [99% CI 0.8513.2]). Compared with baseline, intraopera-
tive 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 1.102.69], risk difference=0.19 [99% CI 0.040.33]).
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. (Anesth Analg 2016;122:67897)

X
enon anesthesia has been studied for decades. The theoretically, is not metabolized to toxic metabolites, does
anesthetic property of xenon is mainly conferred by not react with absorbent, and does not deplete vitamin B12,
the inhibition of N-methyl-d-aspartate receptors in as opposed to other inhaled agents. The blood-gas (0.115)
the central nervous system.1 The minimal alveolar concen- and brain-blood (0.23) coefficients of xenon are the lowest
tration (MAC) of xenon is 71%.2 Xenon is an inert gas and, 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
From the *Department of Anesthesiology, Duke University Medical Center, than other volatile agents.4 Some reviews suggest that xenon
Durham, North Carolina; and Faculty of Pharmaceutical Sciences, the
University of British Columbia, Vancouver, British Columbia, Canada.
facilitates stable hemodynamics5 and may be neuroprotec-
Lawrence Siu-Chun Law, MD, is currently affiliated with Center for Quanti
tive.1,6 Xenon is not associated with malignant hyperther-
tative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore. mia,7 diffusion hypoxemia,3 or coagulopathy.8 Some animal
Tong Joo Gan, MD, FRCA, MHS, LiAc, is currently affiliated with the studies9 showed that xenon has no hepatic or renal toxicity,
Department of Anesthesiology, Stony Brook Medicine, Stony Brook, New York. although some other studies10 showed that it may reduce
Accepted for publication May 8, 2015. portal venous flow and compromise hepatic perfusion.
Funding: None. Xenon has many properties of an ideal anesthetic.
The authors declare no conflicts of interest. Clinically, there are certain disadvantages to xenon anes-
Reprints will not be available from the authors. thesia. Similar to N2O, but to a lesser extent, xenon may
Address correspondence to Tong Joo Gan, MD, FRCA, MHS, LiAc, Depart- accumulate in closed spaces.3,11 Although it is not pungent,12
ment of Anesthesiology, Stony Brook Medicine, HSC Level 4, Rm 060, Stony
Brook, NY 11794. Address e-mail to tong.gan@stonybrookmedicine.edu. the high MAC of xenon limits the oxygen concentration
Copyright 2015 International Anesthesia Research Society
and prevents it from being a sole agent safe for induc-
DOI: 10.1213/ANE.0000000000000914 tion.13 Xenon may also increase the risk of postoperative

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nausea and vomiting (PONV).14 Because of its high den- immediately before the incisions (the latest reading in the
sity (approximately 4.56 times of air), xenon was found to period between induction and incision) or measured at 10
increase airway resistance and work of breathing in an ani- to 15 minutes after induction (whenever applicable) for
mal study.15 Nevertheless, it may be a good choice for high- analyses. Systolic blood pressure and diastolic blood pres-
risk patients with unstable hemodynamics, cardiovascular sure were converted into MAP with the following equation:
diseases, expected prolonged recovery from anesthesia, or MAP=systolic blood pressure/3 + 2 diastolic blood pres-
advanced age.1619 sure/3. The intraoperative HR and MAP were compared
The number of randomized controlled trials (RCTs) com- with their baseline values (preinduction) if these were avail-
paring the clinical outcomes between xenon and other anes- able. A change of 20% from the baseline was considered
thetics for general anesthesia is increasing. However, no as clinically significant. We also compared central venous
meta-analysis of these RCTs has been conducted. The aim of pressure (CVP) between xenon and propofol.
this study was to systematically review all available evidence We compared the time (minutes) to eye opening, tracheal
from RCTs and to conduct meta-analysis on the results from extubation, spatial orientation, countdown, and react on
RCTs. Primary outcomes included intraoperative hemody- demand of xenon anesthesia with volatile agents. We ana-
namic variables, recovery outcomes, and PONV. Our meta- lyzed sevoflurane, isoflurane, and desflurane individually,
analysis attempted to quantify the effects of xenon anesthesia because their recovery times were expected to be different.
on these primary outcomes in relation to other anesthetics. We Aldrete scores21,22 at 5, 15, and 30 minutes were compared
also analyzed secondary outcomes: opioid consumption, inci- between xenon anesthesia and volatile anesthesia. A patient
dence of other adverse events, and length of stay in the postan- with an Aldrete score (ranged 010) 8 is usually considered
esthesia care unit (PACU), the hospital, and the intensive care fit for discharge from PACU. We also reviewed the recovery
unit (ICU). We compared xenon anesthesia with other inhaled data for xenon versus propofol.
anesthesia and total IV anesthesia (TIVA) with propofol. We assessed the incidence of adverse events, length of
hospital stay, length of PACU stay, and length of ICU stay of
METHODS xenon anesthesia against other forms of anesthesia. Adverse
events reported included PONV, hypertension, hypotension,
Search Strategy
Our study conforms to the Preferred Reporting Items bradycardia, shivering, mortality, and delirium. For opi-
for Systematic Reviews and Meta-analyses statement for oid consumption, conversion to morphine equivalent was
reporting systematic reviews and meta-analyses.20 We unnecessary, because we natural-log-transformed the data
searched PubMed, MEDLINE, CENTRAL, EMBASE, and and compared the percentage change of opioid consumption
CINAHL for RCTs comparing xenon with any other agents instead of the absolute difference for statistical reasons. We
for general anesthesia. We used the search term xenon AND also compared the duration of anesthesia (minutes).
(anesthesia OR anaesthesia), with no restriction on the year For postoperative cognitive dysfunction, the outcome
of publication. The latest search was done in January 2015. variables were heterogeneous. Thus, we opted to report the
results descriptively.
Selection of Included Studies
Two authors (Lawrence S.C. Law and Elaine A.G. Lo) Statistical Analyses
searched independently and assessed eligibility based on Meta-analysis was conducted with Review Manager 5.3
the title and abstract ( = 0.90). We limited our inclusion (Cochrane Collaboration, Copenhagen, Denmark). Random
effects model was used for all analyses. Standard error of
criteria to RCTs performed on humans and publications in
means (SEMs) and 95% confidence intervals (95% CI) were
English, because the quality of studies in other languages
converted into SD with the following formulas: SEM=(95%
could not be adequately assessed. Conference abstracts >3
CI)/1.96 and SD = SEM N . Otherwise, mean and SD
years old and studies on healthy human subjects (i.e., no
were estimated from reported P values. If SD could not be
surgery) were excluded. We imposed no limitation on out-
obtained with the above means, we substituted the miss-
come variables or anesthetic.
ing SD with the pooled SD of other studies within the same

Data Extraction comparison by: ( N SD ) N .


2

We conducted meta-analysis if 2 or more studies were For continuous and ordinal variables, mean differences
available for a particular outcome. Results were reported were compared with the inverse variance method. For
descriptively if only 1 study was available. dichotomous variables, risk ratios were computed with the
We compared heart rate (HR, min1), mean arterial pres- Mantel-Haenszel method. Risk difference was calculated
sure (MAP, mm Hg), cardiac index/output, incidence of when the absolute change of risk was deemed important or
PONV, and perioperative opioid consumption of xenon when risk ratio was not applicable (zero incidence in both
anesthesia with both inhaled agents (sevoflurane, isoflu- xenon and control groups).
rane, desflurane, and N2O) and TIVA using propofol. Data Percentage change was reported if the continuous vari-
were analyzed separately for inhaled agents and propofol ables were expected to be log-normal, namely, the emergence
groups. Subgroup analyses for each inhaled agent (xenon outcomes: time to eye opening and tracheal extubation, and
versus sevoflurane, xenon versus isoflurane, xenon opioid consumption.2327 Natural log- transformation was
versus desflurane, and xenon versus N2O-only) were
adopted according to the method by Higgins et al.28: z=ln(x)
also conducted. If 2 or more values were reported for the
intraoperative HR or MAP, we chose the values measured ln(s2/x2 + 1)/2 and sz = ln ( s 2 / x 2 + 1) , whereas x and

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Table 1.Characteristics of Included Studies
n Inclusion criteria
ASA physical

680
Author/year Xenon Control End-tidal xenona Anesthesia in the control groupa Type(s) of surgeryb Age status Special remarks
Abramo et al. (2010)56 10 10 60%65% (0.9 MAC) 1 MAC sev Roux-en-Y 1860 IIII Patients with obesity
Abramo et al. (2012)57 10 10 60%65% (0.9 MAC) 1 MAC sev Roux-en-Y 1860 IIII Patients with obesity
10 propofol 5 mgkg1h1
Barakat et al. (2008)48 45 30 70% (1.0 MAC) 70% N2O (0.7 MAC) Breast, body surface 1770 IIII
Baumert et al. (2008)19 20 20 62%68% (0.9 MAC) propofol 5 mgkg1h1 Noncardiac 40 IIIIV Patients with known CAD
or angina pectoris with
cardiovascular risk factors
Baumert et al. (2007)18 13 13 60% (0.8 MAC) propofol 5 mgkg1h1 Noncardiac 65 IIIIV Patients with known or
Meta-Analysis on Xenon Anesthesia

suspected CAD
Baumert et al. (2005)59 12 14 60%65% (0.9 MAC) propofol 3 mgkg1h1 Installation of implantable 18 IIIIV Patients with heart failure,
cardiac devices LVEF <50%
Bein et al. (2005)64 20 19 55%60% (0.8 MAC) Propofol 38 mgkg1h1 Aortic ? III Patients with 3 of 4

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cardiovascular risk factors:
HT, HC, chronic smoking,
age 65
Bein et al. (2004)60 20 19 60% (0.8 MAC) Propofol TIVA Abdominal aortic aneurism ? III Patients with sinus cardiac
repair rhythm
Boomsma et al. (1990)41 16 16 70% (1.0 MAC) 70% N2O (0.7 MAC) Gynecologic, plastic, ? III
orthopedic
Bronco et al. (2010)53 29 30 60% (0.8 MAC) 1.4% sev (0.8 MAC) General, ENT, orthopedic, Adult III
urologic, gynecologic
Coburn et al. (2008)63 71 71 60% (0.8 MAC) Propofol 0.1 mgkg1min1 ENT, urologic, gynecologic, 1860 III
plastic, orthopedic
Coburn et al. (2007)4 17 19 60% (0.8 MAC) 5.2%5.5% des (0.8 MAC) ENT, trauma, gynecologic, 6575 IIII
urologic
Coburn et al. (2005)62 63 53 60% (0.8 MAC) Propofol Any 1860 III
Coburn et al. (2005)61 80 80 60% (0.8 MAC) Propofol 0.10.12 mgkg1min1 Any 1860 III
Cremer et al. (2011)40 19 20 60% (0.8 MAC) 1.1%1.4% sev (0.7 MAC) Urology, gynecology, 6575 IIII
trauma, ENT, orthopedic,
abdominal, neurosurgery
(spine only)
Cutolo et al. (2012)31 20 20 ? Sev Abdominal 4085 III
Fahlenkamp et al. (2014)52 22 20 60% (0.8 MAC) 2% sev (1.1 MAC) Abdominal 1875 IIII
Fahlenkamp et al. (2010)50 19 20 55%65% (0.8 MAC) 1.4%1.6% sev (0.8 MAC) Noncardiac 6575 IIII
Fahlenkamp et al. (2010)51 28 28 60% (0.8 MAC) 2% sev (1.1 MAC) Abdominal, gynecologic, 1875 III
urologic
Goto et al. (2004)39 10 10 60% (0.8 MAC) 60% N2O (0.6 MAC) CABG 4776 ? (likely IIIIV) Exclude patients with heart
failure
Goto et al. (2001)38 15 15 56% (0.8 MAC) 1.0%1.5% iso (1.1 MAC) Hysterectomy 3264 III
15 70% N2O (0.7 MAC)
15 1.2%2.5% sev (1.0 MAC)
Goto et al. (2000)37 11 9 56% (0.8 MAC) 1%1.5% iso (1.1 MAC) Total abdominal or vaginal 3856 III
hysterectomy
Goto et al. (1997)34 18 18 60% (0.8 MAC) 0.5% iso + 60% N2O (1.0 MAC) Lower abdominal 3264 III
18 0.7% sev + 60% N2O (1.0 MAC)
(Continued)

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Table 1.Continued
n Inclusion criteria
ASA physical
Author/year Xenon Control End-tidal xenona Anesthesia in the control groupa Type(s) of surgeryb Age status Special remarks
35
Goto et al. (1997) 10 10 60% (0.8 MAC) 0.5% iso + 60% N2O (1.0 MAC) Abdominal hysterectomy 3559 III
10 0.7% sev + 60% N2O (1.0 MAC)
Goto et al. (1999)36 5 5 43% Xe + 0.5% iso 1.2% iso (1.0 MAC) Abdominal 3265 III
5 (1.0 MAC) 60% N2O + 0.5% iso (1.0 MAC)
Hanss et al. (2006)65 22 22 60% (0.8 MAC) Propofol 36 mgkg1h1 Abdominal vascular ? IIIV Patients with cardiovascular
risk factors
Ishiguro et al. (2000)47 13 13 56% (0.8 MAC) 0.94% iso (0.8 MAC) ? 1560 III
13 0.15% iso + 70% N2O (0.8 MAC)
Kunitz et al. (2005)58 21 21 60% (0.8 MAC) propofol 0.090.13 mgkg1min1 ? 1860 III
Lachmann et al. (1990)42 20 20 70% (1.0 MAC) 70% N2O (0.7 MAC) Plastic, breast, genital, 2159 III

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abdominal, orthopedic
Luginbhl et al. (2005)33 15 15 70% (1.0 MAC) 70% N2O + 2% des (1.0 MAC) Orthopedic ? III
Mattucci et al. (2012)17 15 15 ? Des Sleeve gastrectomy 1865 IIIII Patients with obesity
Nakata et al. (1998)43 12 15 57% (0.8 MAC) 1.6% sev (0.9 MAC) General, ENT, orthopedic, Adult III
urologic, gynecologic
Nakata et al. (1998)44 11 17 57% (0.8 MAC) 1.6% sev (0.9 MAC) General, ENT, orthopedic, Adult III
urologic, gynecologic
Nakata et al. (1999)45 15 15 0.7 MAC 0.7 MAC N2O Abdominal, breast 2860 III
11 1 MAC
Nakata et al. (1999)46 10 10 1 MAC Xe+ 0.3 MAC 0.7 MAC N2O + 0.6 MAC sev Abdominal Adult III
10 sev 1.3 MAC sev
Rasmussen et al. (2006)66 21 18 50%70% (0.8 MAC) Propofol 35 mgkg1h1 Knee replacement 60 III
Rossaint et al. (2003)32 112 112 60% (0.8 MAC) 0.5% iso + 60% N2O (1.0 MAC) ? 18 IIII
Sabba et al. (2012)16 20 20 ? Des Cardiovascular (aortic/ 7386 III Elderly patients
peripheral aneurism/
stenosis repair, femoral/
iliac crossover)
Stoppe et al. (2013)55 15 15 45%50% (0.7 MAC) 1%1.4% sev (0.7 MAC) CABG 50 IIIV LEVF 50%, EuroSCORE 8
Stoppe et al. (2012)54 20 20 53%56% (0.8 MAC) 1%1.4% sev (0.7 MAC) Gynecologic, urologic 2080 IIII
Stuttmann et al. (2010)49 31 30 58%63% (0.8 MAC) 0.6% iso (0.5 MAC) ENT, breast, liposuction, knee 18 III
arthroscopy
Wappler et al. (2007)14 131 128 60% (0.8 MAC) 1.2% iso (1.0 MAC) Gynecologic, urologic, 18 III
trauma, orthopedic
Xe = xenon; iso = isoflurane; sev = sevoflurane; des = desflurane; N2O = nitrous oxide; MAC = minimum alveolar concentration; TIVA = total IV anesthesia; TCI = target-controlled infusion; ENT = otolaryngology-head and
neck; CABG = coronary artery bypass graft; CAD = coronary artery disease; LVEF = left ventricle ejection fraction; HT = hypertension; HC = hypercholesterolemia.
a
MAC conversion: 1 MAC Xe = 72%, iso = 1.17%, sev = 1.8%, des = 6.6%, N2O = 104%; based on 40-year-old men.29
b
All study included elective surgery only.

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Meta-Analysis on Xenon Anesthesia

s were the mean and SD of raw scale; z and sz were the mean Hg [99% CI 3.114.4]) than those who underwent general
and SD of the natural-log-transformed scale. Percentage anesthesia with other inhaled agents. We compared the
change = (ed 1) 100%, d =zxenon zcontrol, where d is the intraoperative HR and MAP with the baseline values in 7
mean difference in the natural-log-transformed scale. The studies14,32,35,51,53,54,56 (Figs. 4 and 5). With xenon anesthesia,
SEs of d were computed by the Taylor series approxima- HR fell by a mean of 17 min1, which was a 22.3% change
tion28 (Appendix). The arithmetic means and their differ- (mean difference=17 min1 [99% CI 21.4 to 11.7]). The
ences were biased in log-normally distributed data. For change of MAP was not statistically significant, and the 99%
better interpretation of the percentage changes, the geomet- CI was within 20% from the baseline (mean difference=4
ric means (ewz/w, w=the weight of study in comparison) mm Hg [99% CI 17.3 to 9.3], percentage change=4.1%).
of both xenon and control groups were reported. With volatile anesthetics, HR and MAP dropped by means
For comparing HR and MAP with the baseline, percent- of 8 min1 and 17 mm Hg, respectively, which were 11.2%
age change was computed as percentage change=mean dif- and 17.5% changes from baseline (mean difference for
ference/baseline 100%. Because the distributions of HR HR=8 min1 [99% CI 15.1 to 1.6] and mean difference
and MAP were expected to be normal, HR and MAP were for MAP=17 mm Hg [99% CI 29.5 to 4.9]; Table4).
reported on the raw scale without log-transformation. To Subgroup analyses demonstrated similar results for
clarify, all reported means and mean differences were arith- xenon versus sevoflurane31,35,45,51,5356 (HR: mean differ-
metic, unless otherwise specified to be geometric. ence = 7 min1 [99% CI 12.2 to 2.3], MAP: mean dif-
Our preliminary analyses showed that the percentage ference = 12 mm Hg [99% CI 1.7 to 22.9]). No statistical
change of time to eye opening and tracheal extubation was difference was found for HR, and the 99% CI was within
similar (about 50% less) for xenon when compared with sevo- 20% from the baseline (mean difference = 4 min1 [99%
flurane, isoflurane, and desflurane, so these comparisons were CI 17.0 to 9.8]). MAP in the xenon group was significantly
combined. Test for subgroup difference of these 3 compari- higher than the isoflurane group14,32,35,36,47 (mean differ-
sons was conducted. Furthermore, we performed subgroup ence=11 mm Hg [99% CI 2.519.6]). HR and MAP were not
analyses to compare (1) the effect of reduction to MAC 0.5 at significantly different between xenon and N2O-only39,41,45,46
10 minutes before the anticipated end of surgery, (2) volatile- anesthesia (99% CI within 8 mm Hg).
only or volatile + N2O in the control groups, and (3) the use To compare xenon with propofol, we examined 8 stud-
of intraoperative remifentanil infusion or opioid bolus. We ies18,19,58,60,61,6466 for HR (Fig.6) and MAP (Fig.7). Similarly,
also conducted sensitivity analyses for studies when MAC patients undergoing xenon anesthesia had lower HR (mean
between the 2 comparator groups differed by 0.2 or less. MAC difference = 9 min1 [99% CI 12.4 to 6.6]) and higher
values of each group in all studies were estimated according MAP (mean difference=7 mm Hg [99% CI 0.8513.2]) than
to the iso-MAC chart for 40-year-old men29 (Table1). those who underwent TIVA with propofol. We compared
For all comparisons, statistical significance was set at the intraoperative HR and MAP with the baseline values in
P < 0.01 (2-sided) and 99% CIs were reported. For tests 4 studies18,19,61,65 (Figs.8 and 9). With xenon anesthesia, HR
for subgroup differences, statistical significance was set at fell by a mean of 10 min1, which was a 16.2% change (mean
P < 0.05. Egger regression30 was used to assess publication difference=10 min1 [99% CI 17.3 to 3.3]). The change
biases for comparisons with 3 or more studies, and the sta- of MAP was not statistically significant, and the 99% CI
tistical significance was set at P < 0.05. was within 20% from the baseline (mean difference=5
mm Hg [99% CI 18.3 to 7.9], percentage change=5.5%).
RESULTS With propofol anesthesia, the change of HR was not statisti-
Study Selection cally significant and the 99% CI was within 20% from the
Of the 936 studies found, 43 met the inclusion criteria for baseline (mean difference=4 min1 [99% CI 11.0 to 2.8],
meta-analysis (Fig. 1). A total of 31 studies4,14,16,17,3157 com- percentage change = 6.1%), whereas MAP dropped by a
pared xenon with other inhaled agents (n = 841 vs 836). mean of 14 mm Hg, which was a 15.0% change (mean differ-
Within the group of other inhaled agents (total n = 836), ence=14 mm Hg [99% CI 29.0 to 2.5]; Table4).
the sample sizes were 288 (sevoflurane), 358 (isoflurane),
69 (desflurane), and 121 (N2O-only). Twelve studies18,19,5766 Advanced Intraoperative Hemodynamics
compared xenon with TIVA using propofol (n = 373 vs Three studies31,39,55 examined cardiac indices of xenon ver-
360). Two studies67,68 comparing xenon and propofol were sus other inhaled agents (mean difference=0.17 Lmin1m2
retracted and, therefore, excluded from our analysis. [99% CI 0.12 to 0.45]). Another 360,64,65 analyzed cardiac
Characteristics and the risk of bias assessment of included outputs of xenon versus propofol (mean difference=0.46
studies are presented in Tables1 and 2, respectively. All sta- Lmin1[99% CI 1.33 to 0.41]). All studies used transesoph-
tistical results (n, mean difference, risk ratio, risk difference, ageal echocardiography to calculate cardiac indices or out-
percentage change, 99% CI, I2, 2, P) are shown in Table3. puts. No significant difference was found for both analyses.
For xenon versus propofol, one study58 investigated
Basic Intraoperative Hemodynamics the changes (before versus after induction) in cardiac out-
For the comparison of xenon with other inhaled agents, we put and systemic vascular resistance among patients with
examined 16 studies14,32,33,35,36,39,41,4547,51,5356 for HR (Fig. 2), heart failure. Cardiac output did not change significantly for
as well as the same 16 studies with an additional study31 both xenon and propofol anesthesia. However, systematic
for MAP (Fig. 3). Patients undergoing xenon anesthe- vascular resistance increased significantly with xenon anes-
sia had a lower HR (mean difference = 6 min1 [99% CI thesia by 13.8%, whereas it dropped by 5.3% with propofol
10.0 to 2.3]) and a higher MAP (mean difference=9 mm anesthesia (P < 0.05). Another study39 compared xenon and

682
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Figure 1. Flow chart for included studies.

N2O-only anesthesia and found no difference in systemic geometric means were 4 minutes for xenon and 8 minutes
vascular resistance. for sevoflurane. The percentage change of time to spatial
CVP was higher in xenon anesthesia than propofol anes- orientation was 45.1% (99% CI 58.5% to 28.1%), and the
thesia in 2 studies60,64 (mean difference = 3 mm Hg [99% geometric means were 5 minutes for xenon and 10 minutes
CI 0.34.9]). However, no difference in CVP was found for sevoflurane. The percentage change of time to countdown
between xenon and N2O-only anesthesia in another study.39 was 41.7% (99% CI 50.3% to 31.6%), and the geometric
means were 6 minutes for xenon and 10 minutes for sevoflu-
Emergence from Anesthesia rane. The percentage change of time to react on demand was
Most of the included studies4,34,35,40,4951,54 reported that the 53.2% (99% CI 65.7% to 35.6%), and the geometric means
emergence end points were tested in regular intervals of 20 were 4 minutes for xenon and 8 minutes for sevoflurane.
to 60 seconds, starting from termination of inhaled agents Four studies32,34,35,49 compared xenon with isoflurane
and administration of high-flow oxygen (Table5). However, (Figs. 10 and 11). Patients undergoing xenon anesthe-
some studies16,17,32,56 did not mention the intervals of testing sia opened eyes, were tracheally extubated, and counted
emergence end points. down faster than those who underwent isoflurane anesthe-
Seven studies34,35,40,50,51,54,56 compared xenon with sevoflu- sia, but no significant effect was found for time to spatial
rane (Figs.10 and 11). Patients undergoing xenon anesthesia orientation. The percentage change of time to open eyes
opened eyes, extubated, oriented spatially, counted down, was 48.8% (99% CI 60.1% to 33.6%), and the geometric
and reacted on demand faster than those who underwent means were 4 minutes for xenon and 7 minutes for isoflu-
sevoflurane anesthesia. The percentage change of time to rane. The percentage change of time to tracheal extubation
open eyes was 52.8% (99% CI 61.2% to 41.4%), and the was 50.3% (99% CI 60.5% to 36.9%), and the geomet-
geometric means were 3 minutes for xenon and 7 minutes ric means were 4 minutes for xenon and 8 minutes for
for sevoflurane. The percentage change of time to tracheal isoflurane. The percentage change of time to countdown
extubation was 48.3% (99% CI 54.6% to 40.5%), and the was 57.7% (99% CI 65.7% to 48.3%), and the geometric

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Table 2.Risk of Biases Table

684
Risk of biases Jadad score
Adequate Blinding of Blinding of Incomplete
sequence Allocation participants and outcome outcome Selective
Author generation concealment personnel assessment data reporting Total Randomization Blinding Attrition
Abramo et al. (2010)56 Unclear Unclear High High Low Low 1 1 0 0
Abramo et al. (2012)57 Unclear Unclear High Low Low Low 1 1 0 0
Barakat et al. (2008)48 Unclear Unclear Low Low Low Low 4 2 2 0
Baumert et al. (2008)19 Unclear Unclear High Low High High 4 1 2 1
Baumert et al. (2007)18 Unclear Unclear High Low Low High 3 1 2 0
Baumert et al. (2005)59 Unclear Unclear High Low High High 4 1 2 1
Meta-Analysis on Xenon Anesthesia

Bein et al. (2005)64 Unclear Unclear High Low Low Low 3 1 2 0


Bein et al. (2004)60 Low Unclear High Low Low Low 4 2 2 0
Boomsma et al. (1990)41 Unclear Unclear Low Low Low Low 1 1 0 0

www.anesthesia-analgesia.org
Bronco et al. (2010)53 Low High High Low Low Low 5 2 2 1
Coburn et al. (2008)63 Low Low High Low Low Low 4 2 2 0
Coburn et al. (2007)4 Low Unclear High Low High Low 5 2 2 1
Coburn et al. (2005)62 Low Low High Low High High 5 2 2 1
Coburn et al. (2005)61 Unclear Unclear High High Low Low 3 2 0 1
Cremer et al. (2011)40 Low Unclear High Low High High 5 2 2 1
Cutolo et al. (2012)31 Unclear Unclear Unclear Unclear Unclear Unclear 1 1 0 0
Fahlenkamp et al. (2014)52 Low Unclear Unclear Low High Low 4 2 1 1
Fahlenkamp et al. (2010)50 Low Unclear Low Low Low Low 5 2 2 1
Fahlenkamp et al. (2010)51 Low Unclear Unclear Unclear Low Low 4 2 1 1
Goto et al. (2004)39 Unclear Unclear Unclear Low Low Low 1 1 0 0
Goto et al. (2001)38 Unclear Unclear Unclear Low High Low 2 1 0 1
Goto et al. (2000)37 Unclear Unclear Unclear Low Low Low 1 1 0 0
Goto et al. (1997)34 Unclear Unclear Unclear Low Low Low 1 1 0 0
Goto et al. (1997)35 Unclear Unclear Unclear Low Low Low 1 1 0 0
Goto et al. (1999)36 Unclear Unclear Unclear Unclear Low Low 2 1 0 1
Hanss et al. (2006)65 Low Unclear Unclear Low Low Low 5 2 2 1
Ishiguro et al. (2000)47 Low Unclear High Low Low Low 2 2 0 0
Kunitz et al. (2005)58 Low Low High High Low High 2 2 0 0
Lachmann et al. (1990)42 Unclear Unclear High Low Low High 3 1 2 0
Luginbhl et al. (2005)33 Unclear Unclear High High Low Low 2 1 0 1
Mattucci et al. (2012)17 Unclear Unclear Unclear Unclear Unclear Unclear 0 0 0 0
Nakata et al. (1998)43 Unclear Unclear High High Low Low 2 1 0 1
Nakata et al. (1998)44 Low Unclear Low Low Low Low 2 2 0 0
Nakata et al. (1999)45 Low Unclear High Low Low Low 3 2 0 1
Nakata et al. (1999)46 Low Unclear High Low Low Low 2 2 0 0
Rasmussen et al. (2006)66 High Unclear High Low Low Low 5 2 2 1
Rossaint et al. (2003)32 High Low High Low Low Low 5 2 2 1
Sabba et al. (2012)16 Unclear Unclear Unclear Unclear Unclear Unclear 1 1 0 0
Stoppe et al. (2013)55 Unclear Unclear High Low Low Low 2 1 0 1
Stoppe et al. (2012)54 Unclear Unclear Low Low Low Low 4 1 2 1
Stuttmann et al. (2010)49 Low Unclear High Low Low Low 2 2 0 0
Wappler et al. (2007)14 Low Unclear High Low Low Low 3 2 0 1

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Table 3.Summary of Results from Meta-Analysis
Number of Mean difference (MD) or relative Random
Number of subjects risk (RR) or percentage change P for 2 of or fixed
Outcome variables studies Xenon Control () (99% confidence interval) Pa
I
2
heterogeneity effects
Xenon versus other inhaled agents (sevoflurane, desflurane, isoflurane, and N2O)
Intraoperative HR (min1) 16 470 495 MD = 6.17 (10.00, 2.34) <0.0001 68% <0.0001 Random
Intraoperative MAP (mm Hg) 17 490 515 MD = 8.77 (3.14, 14.39) <0.0001 82% <0.00001 Random
Cardiac index (Lmin1m2) 3 45 45 MD = 0.17 (0.12, 0.45) 0.13 14% 0.31 Random
Time to open eyes (min) 14 326 330 = 49.8% (55.1%, 44.0%) <0.00001 84% <0.00001 Random
Time to extubation (min) 13 306 310 = 44.6% (57.3%, 28.1%) <0.00001 69% 0.0001 Random
Aldrete score at 5 min 4 77 79 MD = 0.68 (0.10, 1.46) 0.03 77% 0.005 Random
Aldrete score at 15 min 4 96 99 MD = 0.46 (0.06, 0.85) 0.003 0% 0.69 Random
Aldrete score at 30 min 4 96 99 MD = 0.57 (0.18, 0.95) 0.0001 0% 0.97 Random
Intraoperative opioid consumption 13 254 258 = +9.4% (13.1%, +36.3%) 0.80 91% <0.00001 Random
PONV 6 312 336 RR = 1.65 (1.14, 2.39) 0.0005 0% 0.73 Random
Xenon versus sevoflurane with/without N2O
Intraoperative HR (min1) 7 122 123 MD = 7.46 (12.24, 2.68) <0.0001 47% 0.08 Random
Intraoperative MAP (mm Hg) 8 142 143 MD = 12.32 (1.73, 22.92) 0.003 87% <0.00001 Random
Intraoperative opioid consumption 12 172 177 = +15.0% (20.5%, +66.5%) 0.53 77% <0.0001 Random
Time to open eyes (min) 7 124 126 = 52.8% (62.1%, 41.1%) <0.00001 77% 0.0002 Random
Time to extubation (min) 7 124 126 = 48.3% (54.6%, 40.5%) <0.00001 55% 0.04 Random
Time to spatial orientation (min) 6 114 116 = 45.1% (58.5%, 28.1%) <0.00001 91% <0.00001 Random
Time to countdown (min) 2 28 28 = 41.7% (50.3%, 31.6%) <0.00001 0% 0.82 Random
Time to react on demand (min) 4 86 88 = 53.2% (65.7%, 35.6%) <0.00001 84% 0.0002 Random
Xenon versus isoflurane with/without N2O
Intraoperative HR (min1) 5 271 268 MD = 3.60 (16.95, 9.76) 0.49 91% <0.00001 Random
Intraoperative MAP (mm Hg) 5 271 268 MD = 11.03 (2.46, 19.60) 0.0009 58% 0.05 Random
Time to open eyes (min) 4 150 150 = 48.8% (60.1%, 33.6%) <0.00001 65% 0.03 Random
Time to extubation (min) 4 150 150 = 50.3% (60.5%, 36.9%) <0.00001 65% 0.04 Random
Time to spatial orientation (min) 2 28 28 = 36.9% (72.7%, +46.2%) 0.15 0% 0.96 Random
Time to countdown (min) 2 28 28 = 57.7% (65.7%, 48.3%) <0.00001 0% 0.70 Random
Xenon versus desflurane with/without N2O
Time to open eyes (min) 3 52 54 = 55.5% (70.8%, 33.0%) <0.00001 96% <0.00001 Random
Time to extubation (min) 2 32 34 = 53.7% (71.1%, 25.2%) <0.0001 94% <0.0001 Random
Xenon versus N2O-only
Intraoperative HR (min1) 4 72 61 MD = 1.91 (6.71, 2.89) 0.30 0% 0.76 Random
Intraoperative MAP (mm Hg) 4 72 61 MD = 1.42 (4.68, 7.52) 0.55 19% 0.30 Random
Xenon versus total IV anesthesia using propofol
Intraoperative HR (min1) 8 208 205 MD = 9.45 (12.38, 6.63) <0.00001 0% 0.91 Random
Intraoperative MAP (mm Hg) 8 208 205 MD = 7.00 (0.85, 13.15) 0.003 60% 0.01 Random
Cardiac output (Lmin1) 3 62 60 MD = 0.46 (1.33, 0.41) 0.17 0% 0.85 Random
Central venous pressure (mm Hg) 2 40 38 MD = 2.58 (0.25, 4.92) 0.004 0% 0.62 Random
PONV 3 147 137 RR = 2.33 (0.53, 10.30) 0.14 85% 0.001 Random
Xenon versus all other anesthetic agents
PONV 9 459 473 RR = 1.72 (1.10, 2.69) 0.002 50% 0.04 Random
Hypertension 5 353 350 RR = 1.64 (0.95, 2.82) 0.02 0% 0.53 Random
Hypotension 6 368 365 RR = 0.37 (0.06, 2.30) 0.16 83% <0.0001 Random
Bradycardia 5 353 350 RR = 1.47 (0.61, 3.56) 0.26 0% 0.68 Random
Mortality 2 37 37 RDb = 0.02 (0.13, 0.09) 0.59 0% 0.59 Random
Shivering 4 386 373 RR = 0.89 (0.46, 1.72) 0.65 0% 0.97 Random
Duration of anesthesia (min) 13 544 591 MD = 2.47 (11.98, 7.05) 0.50 23% 0.21 Random
PACU stay (min) 4 223 213 MD = 4.77 (23.72, 14.18) 0.52 7% 0.36 Random
ICU stay (min) 2 37 37 MD = 0.30 (39.40, 40.00) 0.98 59% 0.12 Random
Hospital stay (day) 2 144 145 MD = 3.75 (1.51, 9.02) 0.07 0% 0.90 Random
Postoperative opioid consumption 4 137 140 = 7.7% (40.5%, +44.8%) 0.83 74% 0.009 Random
N2O = nitrous oxide; HR = heart rate; MAP = mean arterial pressure; PONV = postoperative nausea and vomiting; BIS = bispectral index; PACU = postanesthesia
care unit; CO2 = carbon dioxide; ICU = intensive care unit.
a
Critical P = 0.01; significant P values were bolded and italicized.
b
One study had zero incidence in both xenon and control groups; risk difference (RD) was used instead of RR.

means were 6 minutes for xenon and 14 minutes for isoflu- opening and tracheal extubation than desflurane anesthe-
rane. The percentage change of time to spatial orientation sia. The percentage change of time to open eyes was 55.5%
was 36.9% (99% CI 72.7% to +46.2%), and the geomet- (99% CI 70.8% to 33.0%), and the geometric means were
ric means were 5 minutes for xenon and 8 minutes for 4 minutes for xenon and 8 minutes for desflurane. The per-
isoflurane. centage change for time to tracheal extubation was 53.7%
Three studies4,16,17 compared xenon with desflurane (99% CI 71.1% to 25.2%), and the geometric means were
(Figs.10 and 11). Xenon anesthesia had a shorter time to eye 4 minutes for xenon and 8 minutes for desflurane. Only one

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Meta-Analysis on Xenon Anesthesia

Figure 2. Heart rate (min1), xenon versus other inhaled agents. IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

Figure 3. Mean arterial pressure (mm Hg), xenon versus other inhaled agents. IV = inverse variance; random = random effect; 99% CI = 99%
confidence interval.

study4 reported time to react and demand and spatial orien- Readiness for PACU Discharge
tation and showed that xenon anesthesia had a shorter time When Aldrete scores after xenon and volatile anesthesia
to react on demand (5 vs 9 minutes, P=0.001) and to spa- were compared, there was no difference at 5 minutes (mean
tial orientation (7 vs 11 minutes, P=0.007) than desflurane difference = 0.7 [99% CI 0.01 to 1.46]),4,40,49,56 but scores
anesthesia. were higher for xenon anesthesia at 15 minutes (mean
For time to open eyes and tracheal extubation, all per- difference = 0.5 [99% CI 0.060.85])4,40,49,53 and 30 minutes
centage change for xenon versus sevoflurane, xenon ver-
(mean difference=0.6 [99% CI 0.180.95]).4,40,49,53 Only one
sus isoflurane, and xenon versus desflurane were about
study compared xenon with propofol, and no significant
50%, and no difference was found between the percentage
difference was found at all time points (0, 5, 15, 30, 45, 60,
change for these comparisons (eyes opening: 2[2] = 0.74,
P=0.69, I2=0%; tracheal extubation: 2[2]=0.44, P=0.80, and 120 minutes).61 No data were available for xenon versus
I2=0%4,32,34,35,40,4951,54,56; Figs.10 and 11). isoflurane or desflurane.
Only one study66 compared xenon with propofol for
emergence outcomes. The study demonstrated that xenon Length of Stay
anesthesia had faster emergence than propofol anesthesia Lengths of PACU,32,51,54,61 ICU,55,65 and hospital stay55,65 were not
(260 vs 590 seconds, P=0.001). significantly different between xenon and other anesthetics.

686
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Figure 4. Change of heart rate (min1), xenon versus volatile agents. IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

Figure 5. Change of mean arterial pressure (mm Hg), xenon versus other inhaled agents. IV = inverse variance; random = random effect; 99%
CI = 99% confidence interval.

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Meta-Analysis on Xenon Anesthesia

Table 4.Comparing Intraoperative Hemodynamics with Baseline


Number of Number of Intraoperativebaseline Percentage P for 2 of Random or
Outcome variables studies subjects (99% confidence interval) change P I2 heterogeneity fixed effects
Xenon versus volatile agents (sevoflurane, desflurane, and isoflurane with/without N2O)
Xenon: HR (min1) 7 340 16.54 (21.41 to 11.67) 22.3% <0.0001 63% 0.01 Random
Volatile: HR (min1) 7 348 8.31 (15.06 to 1.57) 11.2% 0.002 83% <0.00001 Random
Xenon: MAP (mm Hg) 7 340 4.02 (17.30 to 9.26) 4.1% 0.44 93% <0.00001 Random
Volatile: MAP (mm Hg) 7 348 17.22 (29.50 to 4.94) 17.5% 0.0003 94% <0.00001 Random
Xenon versus total IV anesthesia using propofol
Xenon: HR (min1) 4 135 10.26 (17.25 to 3.27) 16.2% 0.0002 68% 0.03 Random
Propofol: HR (min1) 4 135 4.08 (10.98 to 2.81) 6.1% 0.13 60% 0.06 Random
Xenon: MAP (mm Hg) 4 135 5.23 (18.32 to 7.86) 5.5% 0.30 85% 0.0002 Random
Propofol: MAP (mm Hg) 4 135 14.31 (26.09 to 2.53) 15.0% 0.002 80% 0.002 Random
Critical P = 0.01; significant P values were bolded and italicized.
N2O = nitrous oxide; HR = heart rate; MAP = mean arterial pressure.

Figure 6. Heart rate (min1), xenon versus propofol. IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

Figure 7. Mean arterial pressure (mm Hg), xenon versus propofol. IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

Postoperative Nausea and Vomiting shivering14,32,61,62 were not statistically different between
We analyzed 6 studies comparing xenon with other
14,32,34,35,49,56 xenon and other anesthetic agents.
inhaled agents and 3 studies19,62,63 comparing xenon with pro- Three studies51,54,56 presented data for intraoperative
pofol. The incidence of PONV was higher for xenon anesthe- awareness. No incidence was reported for all groups. Two
sia (158/459, 34.4%) than that for volatile anesthesia and TIVA studies51,54 reported incidence of dreaming for xenon, but
(94/473, 19.9%). The risk ratio was 1.72 (99% CI 1.102.69), and no statistical difference was found comparing with sevoflu-
the risk difference was 0.19 (99% CI 0.040.33). Subgroup anal- rane. One study55 reported similar incidence of postopera-
ysis remained significant for xenon versus volatile agents tive delirium between xenon and sevoflurane.
(risk ratio=1.65 [99% CI 1.142.39]) but not for xenon versus
propofol (risk ratio=2.33 [99% CI 0.5310.30]; Fig.12). Pain and Opioid Consumption
We analyzed 13 studies4,33,41,43,4956 comparing intraoperative
Other Adverse Events opioid consumption for xenon versus other inhaled agents
The incidences of hypertension,14,19,32,56,61 hypoten- and 1 study61 for xenon versus propofol, and 4 studies4,53,54,63
sion,14,19,32,55,56,61 bradycardia,14,19,32,56,61 mortality,55,65 and investigating postoperative opioid consumption. There was no
significant difference in both intraoperative and postoperative

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Figure 8. Change of heart rate (min1), xenon versus propofol. IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

Figure 9. Change of mean arterial pressure (mm Hg), xenon versus propofol. IV = inverse variance; random = random effect; 99% CI = 99%
confidence interval.

opioid consumption. The percentage change in intraoperative 72 hours postoperatively (xenon versus desflurane); while68
opioid consumption was +9.4% (99% CI 13.1% to +36.3%) Rasmussen et al.66 examined visual-verbal learning, atten-
for xenon versus other inhaled agents. For the single study tion, and executive function at 3 to 5 days and 3 months after
comparing xenon and propofol, the intraoperative remifent- surgery (xenon versus propofol). No difference in both short-
anil consumptions were 0.19 (SD 0.09) versus 0.18 (SD 0.08) and medium-term neurocognitive outcomes was found.
gkg1min1. In postoperative opioid consumption, the per-
centage change was 7.7% (99% CI 40.5% to +44.8%). Two Duration of Anesthesia
studies37,53 reported no difference in postoperative pain control The duration of anesthesia was not significantly different
at 0 to 6 hours between xenon and sevoflurane or isoflurane. 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
Postoperative Cognitive Dysfunction
Two studies4,66 investigated postoperative cognitive dys- Subgroup Analyses
function after xenon anesthesia. Coburn et al.4 measured Two studies4,40 reduced MAC to 0.5 at about 10 minutes before
alertness, divided attention, and working memory at 6 to the anticipated end of anesthesia (Table5). We compared the

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Table 5.Clinical Variables Associated with Recovery from Anesthesia (for Studies with Data on Emergence, Aldrete Scores, and PACU Stay)
Anesthetic
reduction

690
Intraoperative opioid toward the Termination of Interval of Criteria for
Author/year maintenance Neuromuscular blockers end of surgery anesthesia assessment extubation
Abramo et al. Remifentanil 0.25 g/kg/min, Induction: cisatracurium 0.2 mg/kg; maintenance: No reduction After surgical field ? Spontaneous breathing,
(2010)56 titrated according to cisatracurium 0.02 mg/kg every 40 min; completed etco2 at 5.36.6 kPa
clinical need termination: no cisatracurium in last 30 min
Bronco et al. Remifentanil 0.15 g/kg/min, Induction: succinylcholine 1 mg/kg; maintenance: No reduction After all surgical Not TOF > 90%
(2010)53 titrated according to cisatracurium 0.03 mg/kg to achieve TOF of 1. intervention, include wound applicable
clinical need Termination: atropine 0.02 mg/kg, neostigmine dressing
0.05 mg/kg before skin closure
Coburn et al. Remifentanil 0.15 g/kg/min, Induction: rocuronium 0.6 mg/kg. 10 min before After all surgical intervention, 20 s Upper airway reflex fully recovered,
Meta-Analysis on Xenon Anesthesia

(2007)4 titrated according to Maintenance/termination? end, reduce including bandaging of the adequate respiratory function
clinical need to 0.5 MAC surgical fields, and complete (RR >8, Sao2 > 95% at Fio2 100%)
neuromuscular recovery and hemodynamically stable

www.anesthesia-analgesia.org
Coburn et al. Remifentanil 0.15 g/kg/min, Induction: mivacurium 0.16 mg/kg or No reduction After all surgical intervention, Not Adequate spontaneous ventilation,
(2005)62 titrated according to cisatracurium 0.1 mg/kg or rocuronium including bandaging of applicable etco2 5.36.6 kPa, and open eyes on
clinical need 0.6 mg/kg or vecuronium (0.1 mg/kg). surgical fields, complete command
Maintenance/termination? neuromuscular recovery
Cremer et al. Remifentanil 0.15 g/kg/min, Induction: rocuronium 0.6 mg/kg. 10 min before After all surgical task, including 20 s Full recovery of upper airway, spontaneous
(2011)40 titrated according to Maintenance/termination? end, reduce bandaging, and complete breathing, RR > 8, Sao2 95% at Fio2
clinical need to 0.5 MAC neuromuscular recovery by TOF 100%, and hemodynamically stable
Fahlenkamp Remifentanil 0.15 g/kg/min, Induction: rocuronium 0.6 mg/kg. No reduction After all surgical intervention, 20 s Full upper airway reflex, RR 8/min, Sao2
etal. titrated according to Maintenance/termination: no muscle including bandage, and full > 95 at Fio2 1.0
(2010)50 clinical need relaxant given after intubation neuromuscular recovery
Fahlenkamp Remifentanil 0.15 g/kg/min, Induction: rocuronium 0.6 mg/kg. No reduction After all surgical intervention, 60 s Upper airway reflex fully recovered,
etal. titrated according to Maintenance/termination? including bandage, and full respiratory function (RR >8/min,
(2010)51 clinical need neuromuscular recovery breathing volume > 6 L/min), and open
eye, swallow, breathing on demand
Goto et al. Epidural-mepivacaine/ Induction: vecuronium 10 mg. Maintenance: No reduction At the end of operation 3060 s Open eyes, squeeze hand, or take deep
(1997)34 epinephrine vecuronium/pancuronium as needed. breath on command, and regular
Termination: neostigmine 2.5 mg, breathing pattern
atropine 1 mg before skin closure
Goto et al. Epidural-mepivacaine/ Induction: vecuronium 10 mg. Maintenance: No reduction At the end of operation 3060 s Open eyes, squeeze hand, or take deep
(1997)35 epinephrine vecuronium as needed. Termination: neostigmine breath on command, and regular
2.5 mg, atropine 1 mg before skin closure breathing pattern
Mattucci et al. Fentanyl Induction/maintenance: rocuronium (xenon ? ? ? ?
(2012)17 group), cisatracurium (desflurane group).
Termination: sugammadex (xenon group),
neostigmine (desflurane group)
Rossaint et al. Sufentanil 10 g/3 min if Induction: cisatracurium 0.10.2 mg/kg. No reduction After all surgical intervention, ? Adequate spontaneous ventilation, etco2
(2003)32 necessary Maintenance? Termination: neostigmine including bandaging of the 4050 mm Hg, and open eyes on
if TOF < 0.7 surgical fields command
Sabba et al. Fentanyl Induction/maintenance: rocuronium ? ? ? ?
(2012)16
Stoppe et al. Remifentanil 0.15 g/kg/min, Induction: recuronium 0.6 mg/kg. No reduction After all surgical procedure 60 s Standard extubation criteria (?)
(2012)54 titrated according to Maintenance/termination?
clinical need
Stuttmann Repeated increments of Induction: rocuronium 0.6 mg/kg. No reduction At end of operation 60 s Eyes open, spontaneous breathing, and
etal. fentanyl 1.5 g/kg Maintenance/termination? otherwise stable
(2010)49

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TOF = train-of-four; etco2 = exhaled carbon dioxide; RR = respiratory rate; Sao2 = arterial oxygen saturation; PACU = postanesthesia care unit.

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Figure 10. Time to open eyes, xenon versus volatile agents (subgroup: sevoflurane, isoflurane and desflurane). d = mean difference in the
natural-log-transformed scale; IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

percentage change for xenon versus volatile agents of these For Aldrete score, no subgroup difference was found at all
2 studies with the other 8 studies32,34,35,4951,54,56 without such time points (5, 15, and 30 minutes) between studies4,40 with
reduction. For the 2 studies with MAC reduction, the percent- anesthetic reduction to MAC 0.5 at 10 minutes before the antic-
age change of time to eye opening was 43.4% (99% CI 49.3% ipated end of surgery and studies49,53,56 without such reduction.
to 36.2%) and the difference of geometric means was 3.6 In the control groups, some studies4,14,16,17,40,45,50,51,5356
minutes; the percentage change of time to tracheal extubation used volatile agents only, while others3235 used volatile
was 44.6% (99% CI 47.8% to 41.1%); and the difference of agents together with N2O; or they had 2 control groups36,47
geometric means was 3.8 minutes. For the 8 studies without (both volatile-only and volatile + N2O). We compared per-
MAC reduction, the percentage change of time to open eyes centage change of xenon versus volatile-only with xenon
was 53.7% (99% CI 63.6% to 41.7%) and the difference of versus volatile + N2O. The percentage change (57.1%) of
geometric means was 3.8 minutes; and the percentage change time to open eyes for xenon versus volatile-only was larger
of time to tracheal extubation was 50.3% (99% CI 57.7% than the percentage change (43.6%) of time to open eyes for
to 41.7%), and the difference of geometric means was 4.1 xenon versus volatile + N2O (percentage change=57.1%
minutes. For time to open eyes, the percentage drop (43.4% [99% CI 67.0% to 48.2%] versus 43.6% [99% CI 52.7%
or 3.6 minutes) among the 2 studies with MAC reduction to 35.7%], difference of geometric means=4.5 versus 2.8
was smaller than the percentage drop (53.7% or 3.8 minutes) minutes; 2 [1]=7.20, P=0.007, I2=86%). No subgroup dif-
among the 8 studies without MAC reduction (2[1] = 4.20, ference was found for HR (2[1]=3.44, P=0.06, I2=71%),
P = 0.04, I2 = 76%). Although the difference was statistically MAP (2[1]=0.69, P=0.41, I2=0%), and time to tracheal
significant, the difference (0.2 minutes) was not clinically sig- extubation (2[1]=2.92, P=0.09, I2=66%).
nificant. Furthermore, no statistically significant difference No subgroup difference for time to open eyes
between MAC reduction and no MAC reduction was found (2[1]=0.01, P=0.91, I2=0%) and time to tracheal extubation
for time to tracheal extubation (2[1]=2.86, P=0.09, I2=65%). (2[1]=0.25, P=0.62, I2=0%) was found between studies

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Meta-Analysis on Xenon Anesthesia

Figure 11. Time to tracheal extubation, xenon versus volatile agents (subgroup: sevoflurane, isoflurane, and desflurane). d = mean difference
in the natural-log-transformed scale; IV = inverse variance; random = random effect; 99% CI = 99% confidence interval.

using continuous remifentanil infusion4,40,50,51,54,56 and stud- 0.8 mm Hg (99% CI 14.3 to 12.7). For volatile anesthe-
ies using opioid boluses.17,32,34,35,49 Similarly, no subgroup sia comparing with baseline,14,32,34,53,54,56 mean difference
difference for PONV was found (2[1] = 0.67, P = 0.41, for HR was 6 min1 (99% CI 11.1 to 1.4) and mean dif-
I2 = 0%) between studies using continuous remifentanil ference for MAP was 15 mmHg (99% CI 28.9 to 1.4).
infusion19,56,61,62 and studies using opioid boluses.14,32,34,49
Publication Bias
Sensitivity Analyses All Egger intercepts were not significant (indicating a low
The difference of MAC between groups was 0.2 or less in risk of publication bias), with the exception of the intercept
78% of the included studies (in which MAC applicable to for the length of PACU stay.
the control group). Excluding those studies in which the
difference of MAC was >0.2, we repeated all comparisons DISCUSSION
on hemodynamic outcomes. The results were similar. For From the results of our meta-analysis, we attempted to quan-
xenon versus other inhaled agents,14,32,33,35,36,39,45,47,5356,69 tify the effects of xenon anesthesia on intraoperative hemo-
mean difference for HR was 6 min1 (99% CI 11.0 to dynamics, recovery outcomes, and PONV. Under xenon
1.9) and mean difference for MAP was 10 mm Hg (99% anesthesia, HR dropped by about 20% (approximately 14
CI 3.516.1). For xenon versus sevoflurane,35,46,51,5356 mean min1), whereas MAP dropped by 4% to 5% (approximately
difference for HR was 8 min1 (99% CI 14.0 to 2.3) 5 mm Hg) and the 99% CI of MAP was within 20% of the
and mean difference for MAP was 12 mm Hg (99% CI baseline value. Recovery from xenon anesthesia was about
0.0124.6). For xenon versus isoflurane, all studies had 50% (approximately 4 minutes) faster than all types of vola-
an MAC difference 0.2 or less, so sensitivity analysis was tile anesthesia. The incidence of PONV after xenon anesthesia
unnecessary. For xenon anesthesia comparing with base- was 72% higher than after volatile and propofol anesthesia
line,14,32,34,53,54,56 mean difference for HR was 16 min1 (incidence: 34.4% vs 19.9%). No effect was found for all sec-
(99% CI 20.9 to 10.8) and mean difference for MAP was ondary outcomes: intraoperative and postoperative opioid

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Figure 12. Incidence of postoperative nausea and vomiting (PONV), xenon versus volatile agents and propofol. MH = Mantel-Haenszel; ran-
dom = random effect; 99% CI = 99% confidence interval.

consumption, incidence of adverse events except PONV, and Emergence from Anesthesia
length of stay in PACU, hospital, and ICU. Our meta-analysis demonstrates that xenon has an excel-
lent recovery profile in terms of emergence from anesthesia
Intraoperative Hemodynamics (open eyes and extubated approximately 50% or approxi-
Our meta-analysis shows that MAP is relatively stable mately 4 minutes faster) and readiness of discharge from
(approximately 5% or approximately 5 mm Hg change PACU (Aldrete score 0.50.7 point higher) versus isoflu-
rane, sevoflurane, and desflurane. In addition, reducing
from the baseline, and 99% CI within 20% of the baseline)
volatile agents to 0.5 MAC 10 minutes before the anticipated
in xenon anesthesia, whereas it decreases by 15% in vola-
end of surgery offsets some but not all (percentage change
tile and propofol anesthesia. Patients undergoing xenon
from 54% to 43%, or difference of geometric means from
anesthesia have a lower HR, higher MAP, and lower CVP 3.8 to 3.6 minutes) of the advantage of xenon anesthesia
compared with those undergoing volatile and propofol in emergence outcomes over volatile anesthesia.
anesthesia. This profile of intraoperative hemodynamics Our systematic review shows that emergence from
may be explained by a previous human study,58 which found xenon anesthesia is faster than that from propofol anesthe-
an increase in systematic vascular resistance but no signifi- sia. The difference is empirical. More studies are required to
cant change in stroke volume under xenon anesthesia. One confirm this finding.
animal study70 demonstrated an increase in endogenous Despite faster emergence and greater readiness for
vasopressors, including epinephrine, norepinephrine, and PACU discharge, xenon has not been demonstrated to affect
vasopressin, under xenon-remifentanil anesthesia compared the length of PACU, ICU, or hospital stay. Various factors
with isoflurane-remifentanil and i soflurane-N2O anesthesia. may affect these outcomes, and the contribution of anes-
Our systematic review found only one RCT58 recruiting thetic agents could be relatively minimal. Future studies
are needed to elucidate the factors predicting the length of
patients with heart failure. Three other studies39,60,64 recruited
PACU, ICU, and hospital stay.
patients undergoing abdominal aortic surgery or coronary
artery bypass graft. More data are needed to establish the
Adverse Events
safety of xenon among patients with high cardiovascular risk. On the basis of our meta-analysis, xenon anesthesia increases
Although most skilled anesthesiologists are able to man- the incidence of PONV by 72% (34.4% vs 19.9%) when com-
age the hemodynamic changes effectively with other vaso- pared with volatile and propofol anesthesia. The risk difference
active agents, our results may help anesthesiologists who was 19%, which was equivalent to one risk factor according to
use xenon to anticipate the hemodynamic changes and the consensus guidelines for the management of PONV.71 The
manage the changes proactively. mechanism of PONV with xenon remains unclear. Being an

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Meta-Analysis on Xenon Anesthesia

inhibitor of 5-hydroxytryptamine type 3 receptors, which are the maintenance circuit with xenon), denitrogenating patients
thought to mediate PONV,63,72,73 xenon is expected to relieve nau- before switching from the induction circuit to maintenance cir-
sea and vomiting. It is possible that only certain subtypes of the cuit, prefilling the maintenance circuit with pure oxygen, and
receptor contribute to PONV. Future basic studies are required priming the maintenance circuit with a large syringe.88 Besides
to uncover the mechanism. The increased risk of PONV may be cost, the additional equipment required for xenon anesthesia
a clinical reason that precludes xenon from routine use. (i.e., end-tidal monitors for xenon concentration) and lack of
According to our meta-analysis, the incidence of adverse familiarity also preclude the use of xenon for general anesthesia.
events under xenon anesthesia is similar to other anesthe-
sia. Nevertheless, the number of studies explicitly reporting Limitations
adverse events is relatively small. There are several limitations to our meta-analysis. The
included studies were heterogeneous, such as, the types of
Pain and Perioperative Opioid Consumption surgery, patient population, discrepancy of MAC between
Xenon is believed to be an N-methyl-d-aspartate receptor groups, opioid consumption, and schedule of opioid infu-
antagonist, like ketamine. Intraoperative ketamine infusion sion (continuous versus bolus). The heterogeneity could
reduces both intraoperative and postoperative pain and affect some of the outcomes. For example, time to eye open-
analgesic requirements.7476 Previous research showed that ing and tracheal extubation or PONV may be influenced
xenon has antihyperalgesic properties and an analgesic effect by opioid consumption or the schedule of opioid infusion.
similar to N2O.77,78 However, our meta-analysis failed to dem- Hemodynamic outcomes may be confounded by the discrep-
onstrate the superiority of xenon in terms of reducing intraop- ancy of MAC between groups. We attempted to explore the
erative and postoperative opioid consumption or short-term effect of such between-studies variables by subgroup analyses
postoperative pain. Many of the included studies used con- or to reduce the effect of heterogeneity by sensitivity analyses.
tinuous remifentanil infusion; thus, intraoperative opioid There was also a potential risk of publication bias, because
consumption might not reflect the analgesic effect of xenon. we only included articles published in English and some
Furthermore, xenon wears off quickly. Unless xenon is admin- comparisons in the meta-analysis had 4 or fewer studies.
istered intranasally after surgery,79 reduction of postoperative Egger intercept regression showed that all but one of our
opioid consumption or short-term pain is not expected. results has a low risk of publication bias. It should be noted
that, while analyses of some of the end points were based
Postoperative Cognitive Dysfunction on a great number of studies, for example, hemodynamics,
Although xenon is thought to be neuroprotective via various conclusions for some end points were drawn from only a few
mechanisms,8084 our systematic review found 2 studies4,66 trials. We tried to discern this by specifying the numbers of
that did not support such a notion. With <40 patients in both trials and participants included for each analysis. The final
studies, the insignificant finding may reflect a lack of statis- conclusion was also made taking into account the quality of
tical power (type II error) rather than a true negative out- analysis for each end point.
come. We were unable to conduct a meta-analysis because The results of Aldrete scores should be interpreted with
the studies used different parameters for neurocognitive caution. Despite being an ordinal parameter, most studies
assessment. The mechanism of postoperative cognitive dys- reported the mean and SD rather than the median and quar-
function remains unclear and seems to be independent of tile interquartile range. Thus, we analyzed this end point
the type of anesthesia, general versus regional.85,86 This is an parametrically, although the current statistical approach
important topic for future research. was less than ideal. In addition, the ideal end point should
be the time to meet the criteria for PACU discharge (i.e., time
Other Clinical Issues to Consider to Aldrete score 8), but such data were not available for
None of the included RCTs suggested an association of analysis. Most of the samples were relatively small (approx-
xenon anesthesia with malignant hyperthermia and diffu- imately 1030 subjects per group). The CIs of some analyses
sion hypoxemia. One RCT55 reported no significant differ- were wide. Studies with larger sample size are needed.
ence in creatinine clearance or blood nitrogen level between
xenon and sevoflurane anesthesia. There is no RCT study- CONCLUSIONS
ing xenon in patients with impaired renal function, coagu- Xenon anesthesia provides more stable intraoperative blood
lopathy, or preexisting pulmonary diseases. We were thus pressure, lower heart rate, and faster emergence from anes-
unable to assess the use of xenon among these patients. thesia than volatile and propofol anesthesia, but xenon is
associated with a higher risk of PONV.
Cost of Xenon Anesthesia Our results may help anesthesiologists who use xenon
The major obstacle of using xenon for general anesthesia is cost. to anticipate the hemodynamic changes and manage the
A study69 in 1999 revealed that the cost of using xenon is about changes proactively. Xenon may be a choice of anesthesia if
4.2 to 9.7 times higher than N2O-isoflurane for a 60- to 420-min- faster emergence from anesthesia is required. The increased
ute closed-circuit anesthesia. In 2009, the cost of xenon for a risk of PONV may preclude the routine use of xenon.
2-hour anesthesia is about 30 times more than volatile anesthesia Furthermore, xenon may increase the readiness for PACU
or 15 times more than propofol anesthesia.87 More than half of discharge but does not seem to be associated with shorter
the cost is for priming and flushing. Methods for saving xenon PACU, ICU, or hospital stays. Xenon seems to have no effect
include using closed-circuit low-flow anesthesia, setting up sep- on opioid consumption and postoperative cognitive dysfunc-
arate circuits for induction and maintenance (and only prime tion, yet more data are required to draw robust conclusions. E

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Meta-Analysis on Xenon Anesthesia

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