PERIOPERATIVE MEDICINE

Effects of Volatile Anesthetics on Mortality and

Postoperative Pulmonary and Other Complications in
Patients Undergoing Surgery
A Systematic Review and Meta-analysis
Christopher Uhlig, M.D., Thomas Bluth, M.D., Kristin Schwarz, M.Sc., Stefanie Deckert, M.Sc.,
Luise Heinrich, M.Sc., Stefan De Hert, M.D., Ph.D., Giovanni Landoni, M.D.,
Ary Serpa Neto, M.D., Ph.D., Marcus J. Schultz, M.D., Ph.D., Paolo Pelosi, M.D., F.E.R.S.,
Jochen Schmitt, M.D., Ph.D., Marcelo Gama de Abreu, M.D., M.Sc., Ph.D., D.E.S.A.
This article has been selected for the Anesthesiology CME Program. Learning objectives
and disclosure and ordering information can be found in the CME section at the front
of this issue.
ABSTRACT

Background: It is not known whether modern volatile anesthetics are associated with less mortality and postoperative pulmo-
nary or other complications in patients undergoing general anesthesia for surgery.
Methods: A systematic literature review was conducted for randomized controlled trials fulfilling following criteria: (1) popu-
lation: adult patients undergoing general anesthesia for surgery; (2) intervention: patients receiving sevoflurane, desflurane, or
isoflurane; (3) comparison: volatile anesthetics versus total IV anesthesia or volatile anesthetics; (4) reporting on: (a) mortality
(primary outcome) and (b) postoperative pulmonary or other complications; (5) study design: randomized controlled trials.
The authors pooled treatment effects following Peto odds ratio (OR) meta-analysis and network meta-analysis methods.
Results: Sixty-eight randomized controlled trials with 7,104 patients were retained for analysis. In cardiac surgery, volatile anesthet-
ics were associated with reduced mortality (OR = 0.55; 95% CI, 0.35 to 0.85; P = 0.007), less pulmonary (OR = 0.71; 95% CI,
0.52 to 0.98; P = 0.038), and other complications (OR = 0.74; 95% CI, 0.58 to 0.95; P = 0.020). In noncardiac surgery, volatile
anesthetics were not associated with reduced mortality (OR = 1.31; 95% CI, 0.83 to 2.05, P = 0.242) or lower incidences of pul-
monary (OR = 0.67; 95% CI, 0.42 to 1.05; P = 0.081) and other complications (OR = 0.70; 95% CI, 0.46 to 1.05; P = 0.092).
Conclusions: In cardiac, but not in noncardiac, surgery, when compared to total IV anesthesia, general anesthesia with
volatile anesthetics was associated with major benefits in outcome, including reduced mortality, as well as lower incidence of
pulmonary and other complications. Further studies are warranted to address the impact of volatile anesthetics on outcome in
noncardiac surgery. (Anesthesiology 2016; 124:1230-45)

A PPROXIMATELY 234 million major surgical pro-

cedures are undertaken worldwide every year,1 and
about 7 million patients develop major complications that
result in 1 million deaths during surgery or hospital stay.1
Even if solely anesthesia-related mortality with 34 per mil-
lion is extremely low, in-hospital postsurgical mortality lies
between 0.5 and 4%.2,3 Both pulmonary and other (nonpul-
monary) complications contribute importantly to increase
morbidity and mortality in surgery patients in the postop-
erative period.3–5
The type of anesthesia has the potential to affect pulmonary
and other complications, since several anesthetic agents may
confer organ protection. In experimental studies, the modern
volatile anesthetics sevoflurane,6 desflurane,7 and isoflurane8
What We Already Know about This Topic
• The type of anesthesia has the potential to affect pulmonary
and other complications, since several anesthetic agents may
confer organ protection. Whether modern volatile anesthetics
are associated with less mortality and postoperative pulmo-
nary or other complications in patients undergoing general
anesthesia for surgery remains unknown.
What This Article Tells Us That Is New
• In this systematic literature review and meta-analysis con-
ducted for 68 randomized controlled trials including 7,104
patients, it was found that in cardiac, but not in noncardiac,
surgery, when compared to total intravenous anesthesia, gen-
eral anesthesia with volatile anesthetics was associated with
major benefits in outcome, including reduced mortality, as well
as lower incidence of pulmonary and other complications.

This article is featured in “This Month in Anesthesiology,” page 1A. Corresponding article on page 1213. Supplemental Digital Content is
available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article.
Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). Drs. Uhlig and
Bluth contributed equally to this article.
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2016; 124:1230-45

Anesthesiology, V 124 • No 6 1230 June 2016

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 PERIOPERATIVE MEDICINE
have been shown to reduce the size of myocardial infarction.
Such effect has been ascribed to different mechanisms, includ-
ing inhibition of mitochondrial permeability transition pores
as well as activation of complex signaling pathways in the
myocardial cells.9,10 Also in the lungs, volatile anesthetics may
protect against lung injury11 and attenuate inflammation.12
However, in contrast to experimental studies, clinical trials
have shown inconsistent results regarding organ protection by
volatile anesthetics,13–15 which seems to be restricted to patients
undergoing cardiac surgery.16–18 To our knowledge, the protec-
tive effects of volatile anesthetics against postoperative compli-
cations in a mixed surgical patient population, consisting of
cardiac and noncardiac surgery, have not been addressed so far.
We conducted a systematic review and meta-analysis
of randomized controlled trials (RCTs) comparing volatile
anesthetics with total IV anesthesia (TIVA) regarding patient
outcome. We hypothesized that, compared to TIVA, the use
of volatile anesthetics during general anesthesia is associated
with reduced mortality and incidence of postoperative pul-
monary and other complications in noncardiac and cardiac
surgery patient populations.
Materials and Methods
Study Type and Registration
We conducted a systematic review of RCTs in accordance
with a previously registered protocol (International Pro-
spective Register of Systematic Reviews registration no.
CRD42014008699). The presented review was performed
according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines.19 A com-
plete PRISMA checklist is presented in table 1 of Supple-
mental Digital Content 1, http://links.lww.com/ALN/B270.
Identification of Relevant Studies
Three databases (EMBASE, MEDLINE, The Cochrane
Central Register of Controlled Trials [CENTRAL]) were sys-
tematically searched for relevant trials published as journal
article from inception until August 23, 2014 without language
Submitted for publication March 21, 2015. Accepted for publica-
tion January 18, 2016. From the Department of Anesthesiology and
Intensive Care Medicine, Pulmonary Engineering Group, Univer-
sity Hospital Dresden, Technische Universität Dresden, Dresden,
Germany (C.U., T.B., M.G.d.A.); Division of Health Care Sciences,
Center for Clinical Research and Management Education, Dresden
International University, Dresden, Germany (C.U.); Center for Evi-
dence-Based Healthcare, University Hospital Dresden, Technische
Universität Dresden, Dresden, Germany (K.S., S.D., L.H., J.S.);
Department of Anesthesiology, Ghent University Hospital, Faculty
of Medicine and Health Sciences, Ghent University, Ghent, Belgium
(S.D.H.); Department of Anesthesia and Intensive Care, IRCCS San
Raffaele Scientific Institute, and Vita-Salute San Raffaele University,
Milan, Italy (G.L.); Department of Critical Care Medicine, Hospital
Israelita Albert Einstein, and Program of Post-Graduation, Research
and Innovation, Faculdade de Medicina do ABC, São Paulo, Brazil
(A.S.N.); Department of Intensive Care, Academic Medical Center,
Amsterdam, The Netherlands (M.J.S.); and Department of Surgical
Sciences and Integrated Diagnostics, IRCCS San Martino IST, Uni-
versity of Genoa, Genoa, Italy (P.P.).
Anesthesiology 2016; 124:1230-45 1231 Uhlig et al.
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restriction. Personal files and reference lists of relevant review
articles for additional trials were also reviewed. Detailed search
strings and reference lists are listed in table 2 of Supplemental
Digital Content 1, http://links.lww.com/ALN/B270.
Eligibility Criteria
We included only RCTs with patients undergoing cardiac
or noncardiac surgical interventions. Studies investigating
modern volatile anesthetics (sevoflurane, desflurane, isoflu-
rane) versus TIVA, with respect to mortality or postoperative
pulmonary or other complications were considered.
Inclusion criteria with respect to “patients, intervention,
comparator, outcomes, study design” (PICOS) criteria20 were
as follows: (1) population: adult patients (age more than 18 yr)
undergoing general anesthesia for elective or also emergency
surgery; (2) intervention: patients receiving anesthesia with vola-
tile anesthetics; (3) comparator: volatile anesthetics versus TIVA,
or single volatile anesthetics versus each other; (4) outcomes:
mortality (primary endpoint), as the longest reported mortality,
or in-hospital mortality, or 30-day mortality. Secondary end-
points were 90-day, 180-day, or 1-yr mortality (according to the
definition by the authors of the original article), or postopera-
tive pulmonary complications21 (hypoxemia, acute respiratory
distress syndrome [ARDS], pulmonary infiltrates, pneumonia,
pleural effusions, atelectasis, pneumothorax, bronchospasm,
cardiopulmonary edema, aspiration pneumonitis; for detailed
description, see table 3 of Supplemental Digital Content 1,
http://links.lww.com/ALN/B270), or other postoperative com-
plications (including overall cardiac events, myocardial infarc-
tion, acute renal failure, hepatic failure, disseminated intravasal
coagulation, extrapulmonary infection, gastrointestinal failure,
coma; for detailed description, see table 4 of Supplemental
Digital Content 1, http://links.lww.com/ALN/B270), or inten-
sive care unit (ICU) length of stay (LOS, days) or ICU-free
days, LOS hospital (days); (5) study design: RCT. Postopera-
tive pulmonary and other complications represented collapsed
composites of the respective single complications. A trial was
included if the predefined PICOS criteria with respect to popu-
lation, intervention, comparison study, and at least one primary
outcome were reported. RCTs published as abstract or letter
only or addressing nitrous oxide were excluded.
Trial Selection and Data Abstraction
The articles for this review were selected by examining titles,
abstracts, and the full text if a potentially relevant trial was
identified. We translated non-English reports into English,
as necessary. Two reviewers (C.U. and T.B.), independently
and in duplicate, abstracted data on the a priori defined
inclusion PICOS criteria. An attempt was made twice to
contact authors in order to request any necessary informa-
tion not contained in articles.
Risk of Bias Assessment and Strength of Evidence
Risk of bias was assessed as previously described in
detail by our group elsewhere.22 Briefly, in duplicate and

independently, two reviewers (C.U. and T.B.) assessed
trial methodological quality using the risk of bias tool
recommended by the Cochrane Collaboration.23 For each
trial, the risk of bias was reported as “low,” “unclear,” or
“high” in the following domains: random sequence gen-
eration, allocation concealment, blinding of participants
and personnel, blinding of outcome assessment, incom-
plete outcome data, selective reporting, and other bias.23
We assessed the item “selective outcome reporting” as
“unclear” risk if the study protocol was not published or
registered previously. For each outcome, we independently
and in duplicate rated the overall quality of evidence (con-
fidence in effect estimates) using the Grading of Recom-
mendations, Assessment, Development and Evaluations
approach in which trials begin as high-quality evidence,
but may be rated down by one or more of five catego-
ries of limitations: risk of bias, inconsistency, indirectness,
imprecision, and reporting bias.24 Finally, the overall risk
of bias for an individual trial was categorized as “low” (if
the risk of bias was low in all domains), “unclear” (if the
risk of bias was unclear in at least one domain, with no
high risk of bias domains), or “high” (if the risk of bias was
high in one or more domains). Disagreement was resolved
by discussion and consensus.
Data Synthesis
For direct comparison of volatile anesthetics and TIVA, the
pooled odds ratio (OR) and 95% CIs of binary outcomes
were calculated using the OR method as described else-
where.25 For direct and indirect comparison of the specific
anesthetic agent (sevoflurane vs. desflurane vs. isoflurane vs.
TIVA), a multivariate random effects network meta-analysis
was performed.26,27 These data are presented as network plot,
plots of cumulative ranking probability, and forest plot.28–30
For ICU and hospital LOS, the mean difference (MD) and
95% CI were calculated. Detailed description of statistical
methods regarding Peto OR meta-analysis and the multivari-
ate random effects network meta-analysis is given in Supple-
mental Digital Content 2, http://links.lww.com/ALN/B271.
Statistical heterogeneity was assessed by the I2 statistic.
Substantial heterogeneity was predefined as I2 greater than
50%, which differed from the protocol previously pub-
lished (International Prospective Register of Systematic
Reviews registration no. CRD42014008699) in order to
be even more conservative. Publication bias was addressed
visually using a funnel plot. The Egger31 regression models
for publication bias were also used. An a priori defined sub-
group analysis of outcomes in cardiac and noncardiac sur-
gical procedures was performed. Heart surgery, regardless
of the use of cardiopulmonary bypass, was included in the
cardiac surgery group. A posteriori the originally intended
analysis of a mixed surgical population combining cardiac
and noncardiac surgery patients was discarded because of
the artificiality of such a population. Therefore, only the
results of the subgroup analysis are reported.
Anesthesiology 2016; 124:1230-45 1232 Uhlig et al.
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Volatile Anesthetics and Outcome
All analyses were performed using STATA (­Version MP 11;
Stata Corp LP, USA).
Results
Trial Identification
The search yielded 5,073 publications, from which the flow-
chart is depicted in figure 1. Twenty-one articles published
in languages other than English and German were translated
into English to assess their eligibility. Of 1,076 potentially
eligible studies, 46 were not an RCT, 13 studies did not
match the population criteria, 80 had a nonselected compar-
ator anesthetic agent (nitrous oxide), 24 compared general
anesthesia to regional anesthesia, and 845 studies did not
report on the primary outcome investigated herein (mortal-
ity); all were excluded. The remaining 68 publications were
retained and their data meta-analyzed. Complete references
of the included articles are shown in table 5 of Supplemental
Digital Content 1, http://links.lww.com/ALN/B270.
Trial Characteristics
The main characteristics of the trials retained for meta-analy-
sis are shown in figure 2 and table 1. Table 6 of Supplemental
Digital Content 1, http://links.lww.com/ALN/B270, depicts
detailed information of the trials. The 68 meta-analyzed
RCTs included data from 7,104 patients published from
1989 to 2014. Sixty-five RCTs (6,716 patients) compared
volatile anesthetics (n = 3,506 total, sevoflurane n = 1,895,
desflurane n = 708, isoflurane n = 903) to TIVA (n = 3,210).
Forty-five RCTs enrolled a total of 4,890 cardiac surgery
patients of whom 2,587 received volatile anesthetics (sevo-
flurane n = 1,077, desflurane n = 673, isoflurane n = 837)
and 2,303 received TIVA. Patients from surgical fields other
than cardiac surgery were investigated in 20 RCTs including
a total of 1,826 subjects allocated to volatile anesthetics in
919 cases (sevoflurane n  =  818, desflurane n  =  35, isoflu-
rane n  =  66) and to TIVA in 907 cases. Three trials (388
patients; two cardiac surgery) compared volatile anesthetics
(sevoflurane n = 177, desflurane n = 58, isoflurane n = 153)
among each other without a TIVA control group32–34 and
were included in the network meta-analysis only. Detailed
information regarding the number of patients enrolled in
the articles reporting pulmonary and other complications is
given in Supplemental Digital Content 1, http://links.lww.
com/ALN/B270.
Risk of Bias
The risk of bias assessment using the Cochrane tool is sum-
marized in figure  3. Most RCTs had unclear risk of bias.
Detailed information regarding risk of bias assessment is
provided in table 7 of Supplemental Digital Content 1,
http://links.lww.com/ALN/B270. The funnel plot for main
outcomes (fig. 1 of Supplemental Digital Content 2, http://
links.lww.com/ALN/B271) suggests no statistically signifi-
cant publication bias.
 PERIOPERATIVE MEDICINE

Fig. 1. Flowchart. Three databases (Excerpta Medica Database [EMBASE], Medical Literature Analysis and Retrieval System
Online [MEDLINE], and the Cochrane Central Register for Controlled Trials [CENTRAL]) were searched in addition to a manual
search for eligible articles. Titles and abstracts of 5,073 articles were screened and 1,076 full texts assessed for eligibility. Finally,
the data of 68 articles were included in qualitative and quantitative data synthesis.

Fig. 2. Trial characteristics. (A) Network plot of all included trials. Circle size represents the number of patients, and bar size rep-
resents the number of trials. The total number of comparisons exceeds 68 since some trials investigated more than two groups.
(B) Surgical field of included trials. TIVA = total IV anesthesia.

Evidence Synthesis
Mortality. All included trials reported either in-hospital,
30-day, 180-day, or 1-yr mortality (fig. 2). Based on our
evidence synthesis of outcome data from 4,840 patients
in 45 trials, we estimate that compared to TIVA, volatile
anesthetics reduced the overall mortality in the subgroup
of cardiac surgery (OR  =  0.55; 95% CI, 0.35 to 0.85;
z = 2.71; P = 0.007; I2 = 8.5%; fig. 4). Meta-analysis of out-
come data of 1,876 patients in 20 trials enrolling patients
undergoing noncardiac surgery did not show a statistically
significant effect of volatile anesthetics compared to TIVA
on either overall mortality (OR  =  1.31; 95% CI, 0.83 to
2.05; z = 1.17; P = 0.242; I2 = 0.0%) or in-hospital mortal-
ity (OR = 1.16; 95% CI, 0.53 to 2.51; z = 0.37; P = 0.711;
I2 = 0.0%) (fig. 5). Network meta-analysis among the dif-
ferent volatile agents showed no reduction of overall and
in-hospital mortality, irrespective of the surgical procedure
(figs. 6 and 7). Plots of cumulative ranking probability are
depicted in figure 2 of Supplemental Digital Content 2,
http://links.lww.com/ALN/B271.
Postoperative Pulmonary Complications. As depicted
in figure  8, volatile anesthetics were associated with less

Anesthesiology 2016; 124:1230-45 1233 Uhlig et al.

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 Volatile Anesthetics and Outcome

Table 1.  Trial Characteristics

Volatiles TIVA
Type of (No. of (No. of Type of Type of Type of PPC OC
Author Surgery Patients) Patients) Volatile TIVA Mortality Recorded Recorded

Alvarez 1990 Cardiac 13 17 Iso Fenta In-hospital,

180 d
Amr 2010 Cardiac 15 15 Iso Benzo 360 d Yes
Baki 2013 Cardiac 20 20 Des Prop 90 d
Ballester 2011 Cardiac 18 20 Sevo Prop In-hospital Yes
Beck-S 2008 Abdominal 30 34 Sevo Prop In-hospital
Beck-S 2012 Abdominal 48 17 Sevo Prop In-hospital Yes Yes
Bein 2005 Cardiac 24 26 Sevo Prop In-hospital Yes Yes
Bharti 2008 Cardiac 15 15 Sevo Prop In-hospital Yes Yes
Biboulet 2012 Orthopedic 14 14 Sevo Prop 30 d Yes
Bignami 2012 Cardiac 50 50 Sevo Prop In-hospital, Yes Yes
30 d, 360 d
Braz 2013 ENT 15 15 Iso Prop In-hospital Yes Yes
Cavalca 2008 Cardiac 21 22 Sevo Prop In-hospital Yes Yes
Conno 2009 Thoracic 27 27 Sevo Prop In-hospital Yes Yes
Conzen 2003 Cardiac 10 10 Sevo Prop In-hospital Yes
Cromheecke 2006 Cardiac 15 15 Sevo Prop In-hospital Yes
De Hert 2002 Cardiac 10 10 Sevo Prop In-hospital Yes
De Hert 2003 Cardiac 15/15 15 Sevo, Des Prop In-hospital Yes
De Hert 2004 Cardiac 150 50 Sevo Prop In-hospital Yes
De Hert II 2004 Cardiac 80/80 160 Sevo, Des Prop, Benzo In-hospital Yes Yes
De Hert 2009 Cardiac 132/137 145 Sevo, Des n.a. 30 d, 90 d, Yes
360 d
Deegan 2010 Breast 17 15 Sevo Prop In-hospital Yes
Eremeev 2011 Cardiac 12 12 Sevo Prop In-hospital
Flier 2010 Cardiac 41 43 Iso Prop 30 d, 360 d Yes Yes
Frassdorf 2009 Cardiac 20 10 Sevo Prop In-hospital
Fudickar 2014 Vascular 20 20 Sevo Prop In-hospital Yes
Garcia 2005 Cardiac 37 35 Sevo Prop In-hospital,
180 d, 360 d
Gaszynski 2011 Abdominal 41 40 Sevo Prop In-hospital
Godet 1990 Vascular 10 10 Iso Fenta In-hospital Yes Yes
Gravel 1999 Cardiac 15 15 Sevo Prop In-hospital Yes Yes
Guarracino 2006 Cardiac 57 55 Des Prop 30 d Yes Yes
Helman 1992 Cardiac 100 100 Des Benzo In-hospital Yes
Howie 1996 Cardiac 23 21 Iso Fenta In-hospital
Huang 2011 Cardiac 30 59 Iso Prop, Benzo In-hospital
Jovic 2012 Cardiac 11 11 Sevo Prop In-hospital Yes Yes
Kendall 2004 Cardiac 10 10 Iso Prop In-hospital Yes
Kirov 2007 Cardiac 12 24 Iso Prop, Benzo In-hospital, 30 d
Ko 2008 Abdominal 35 35 Des Prop In-hospital Yes Yes
Ko 2010 Abdominal 37/37 0 Sevo, Des n.a. In-hospital Yes Yes
Kortekaas 2014 Cardiac 11 10 Sevo Prop In-hospital, 30 d
Kottenberg 2012 Cardiac 39 33 Iso Prop In-hospital
Landoni 2007 Cardiac 59 61 Des Prop 30 d Yes Yes
Lee 2006 Cardiac 20 20 Iso Prop, Benzo In-hospital Yes
Lee 2012 Thoracic 24 24 Sevo Prop In-hospital Yes Yes
Leung 1991 Cardiac 62 124 Iso Benzo In-hospital Yes
Lindholm 2013 Vascular 97 96 Sevo Prop 30 d Yes Yes
Lorsomradee 2006 Cardiac 160 160 Sevo Prop In-hospital Yes Yes
Lurati Buse 2012 General, 184 201 Sevo Prop 360 d Yes
­Orthopedic,
Vascular
Mahmoud 2011 Thoracic 25 25 Iso Prop 30 d Yes
Mazoti 2013 ENT 16 18 Iso Prop In-hospital
Meco 2007 Cardiac 14 14 Des Prop, Benzo In-hospital Yes
(Continued)

Anesthesiology 2016; 124:1230-45 1234 Uhlig et al.

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 PERIOPERATIVE MEDICINE

Table 1.  (Continued)

Volatiles TIVA
Type of (No. of (No. of Type of Type of Type of PPC OC
Author Surgery Patients) Patients) Volatile TIVA Mortality Recorded Recorded
Ndoko 2007 Cardiac 128 124 Iso Prop 180 d
Parsons 1994 Cardiac 25 25 Des Benzo In-hospital Yes
Piriou 2007 Cardiac 36 36 Sevo Prop In-hospital
Rex 2009 n.d. 26 25 Sevo Prop In-hospital
Royse 2011 Cardiac 91 89 Des Prop In-hospital Yes Yes
Schoen 2011 Cardiac 59 60 Sevo Prop In-hospital Yes Yes
Searle 1996 Cardiac 133/140 0 Iso, Sevo n.a. In-hospital
Slogoff 1989 Cardiac 248 254 Iso Sufenta In-hospital
Song 2010 Abdominal 50 50 Sevo Prop In-hospital Yes
Song 2012 Thoracic 176 177 Sevo Prop 180 d
Soro 2012 Cardiac 36 37 Sevo Prop, Benzo In-hospital
Story 2001 Cardiac 120/120 120 Iso, Sevo Prop In-hospital Yes
Thomson 1991 Cardiac 20/21 0 Iso, Des n.a. In-hospital
Tritapepe 2007 Cardiac 75 75 Des Prop 30 d Yes
Xu 2014 Thoracic 20 20 Sevo Prop In-hospital Yes Yes
Yildirim 2009 Cardiac 20/20 20 Iso, Sevo Prop 30 d Yes Yes
Yoo 2014 Cardiac 56 56 Sevo Prop In-hospital
Zangrillo 2011 Thoracic, 44 44 Sevo Prop In-hospital, Yes
Vascular 30 d, 360 d

References refer to table 5 of the Supplemental Digital Content 1, http://links.lww.com/ALN/B270.

Benzo = benzodiazepines; Des = desflurane; ENT = ear–nose–throat surgery; Fenta = fentanyl; Iso = isoflurane; n.a. = not applicable; n.d. = not defined; OC = other
postoperative complications; PPC = postoperative pulmonary complications; Prop = propofol; Sevo = sevoflurane; Sufenta = sufentanyl; TIVA = total IV anesthesia.

postoperative pulmonary complications compared to
TIVA in patients who underwent cardiac surgical pro-
cedures (OR  =  0.71; 95% CI, 0.52 to 0.98; z  =  2.07;
P = 0.038; I2 = 6.0%; fig. 8). In noncardiac surgery, com-
pared to TIVA, volatile anesthetics were not associated
with lower incidence of postoperative pulmonary compli-
cations (OR  =  0.67; 95% CI, 0.42 to 1.05; P  =  0.081;
I2 = 53.5%; fig. 8). Compared to TIVA, none of the single
volatile anesthetics reduced pulmonary complications
(figs. 6 and 7).
Other Complications. In cardiac surgery patients, com-
pared to TIVA, volatile anesthetics were associated with
lower incidence of other postoperative complications
(OR = 0.75; 95% CI, 0.58 to 0.96; z = 2.26; P = 0.024;
I2 = 38.6%; fig. 8), but such association was not observed
in noncardiac surgical procedures (OR  =  0.70; 95% CI,
0.46 to 1.05; z = 1.78; P = 0.075; I2 = 0.0%; fig. 9). Such
differences were more pronounced with desflurane and
sevoflurane (fig. 6). In noncardiac surgical procedures,
compared to TIVA, none of the single volatile anesthetics
reduced other complications (fig. 7).
Length of ICU and Hospital Stay. The meta-analysis of ICU
and hospital LOS are depicted in figures 4 to 7 of Supple-
mental Digital Content 2, http://links.lww.com/ALN/
B271. In cardiac surgery patients, volatile anesthetics were
associated with no statistical significant reduction of ICU
and hospital LOS compared to TIVA (MD = −0.09; 95%
CI, −0.40 to 0.22; z  =  0.57; P  =  0.57; I2  =  89%; fig. 4
of Supplemental Digital Content 2, http://links.lww.com/
ALN/B271; MD = 0.86; 95% CI, −0.84 to 2.55; z = 0.99;
P = 0.32; I2 = 34%, fig. 6 of Supplemental Digital Con-
tent 2, http://links.lww.com/ALN/B271; respectively). In
noncardiac surgery patients, volatile anesthetics were asso-
ciated with no statistical significant reduction of ICU LOS
(MD = −0.68; 95% CI, −1.80 to 0.45; z = 1.18; P = 0.24;
I2 = 72%, fig. 5 of Supplemental Digital Content 2, http://
links.lww.com/ALN/B271), but with reduced hospital
LOS (MD  =  −0.80; 95% CI, −1.57 to −0.02; z  =  2.02;
P = 0.04; I2 = 0%; fig. 7 of Supplemental Digital Content
2, http://links.lww.com/ALN/B271) compared to TIVA.
Discussion
The main results of this systematic review and meta-analy-
sis were that general anesthesia with volatile anesthetics, as
compared to TIVA, was associated with reduced mortality
and lower risk of pulmonary and other complications in car-
diac, but not in noncardiac, surgery.
To our knowledge, this is the first systematic review and
meta-analysis addressing the effects of volatile anesthetics
on outcome in different surgical patient groups, including
68 trials that investigated 7,104 patients in total. Other
strengths of our analysis are the use of PRISMA guidelines19
and a literature search in three databases without language or
time restrictions. Furthermore, we incorporated a network
meta-analysis with indirect and direct comparisons to evalu-
ate the contribution of individual volatile anesthetics.
Cardiac Surgery
In patients undergoing general anesthesia for cardiac surgery,
volatile anesthetics are associated with lower mortality. These

Anesthesiology 2016; 124:1230-45 1235 Uhlig et al.

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 Volatile Anesthetics and Outcome

Fig. 3. Risk of bias assessment. Risk of bias was assessed using the Cochrane risk of bias tool.23 P = primary outcome;
S = secondary outcome; SP = study personnel. References refer to table 5 of the Supplemental Digital Content 1, http://links.
lww.com/ALN/B270.

findings are in agreement with a previous meta-analysis in compared to TIVA, which are likely related to cardioprotec-
the field.18 This may result from the observation of reduced tive properties of those agents. In the heart, volatile anesthet-
postoperative complications with volatile anesthetics ics induce coronary vasodilation,35 promote early activation

Anesthesiology 2016; 124:1230-45 1236 Uhlig et al.

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 PERIOPERATIVE MEDICINE

Fig. 4. Mortality in cardiac surgery. Values are presented as odds ratio (OR) and 95% CI. Statistical analyses were performed
using the Peto OR method. Statistical significance was accepted α less than 0.05. (A) Forest plot of overall mortality for
cardiac surgery patients, which represents the mortality of the longest available follow-up. Twenty-four trials were excluded
due to no events. (B) Forest plot of in-hospital mortality for cardiac surgery patients. Twenty-three trials were excluded due
to no events. TIVA = total IV anesthesia; VOL = volatile anesthetics; volatiles = volatile anesthetics. *Events were given as
event per patient and overall number of events per patient. References refer to table 5 of the Supplemental Digital Content 1,
http://links.lww.com/ALN/B270.

of protective enzymes by phosphorylation and translocation
of cellular key proteins (early phase of preconditioning),6
and result in delayed transcriptional changes of protective
and antiprotective proteins (late phase of precondition-
ing).36 In addition, volatile anesthetics may have decreased
inflammation in the lungs, attenuating ventilator-induced
lung injury. We did not find any RCTs that have addressed
the role of volatile anesthetics in reducing lung inflamma-
tion in nonthoracic surgery. In a study in patients undergo-
ing thoracic anesthesia, compared to TIVA, sevoflurane and
desflurane reduced the release of proinflammatory cytokines
in the ventilated lung.37 Accordingly, other investigators
were able to show a reduced inflammatory response of the
nonventilated lung during general anesthesia with sevoflu-
rane compared to propofol.38 Those findings are in line with
experimental data from lung injury models, where the use of
volatile anesthetics reduced lung inflammation.11,12 Besides
the modulation of the inflammatory response, volatile anes-
thetics also induce bronchodilation, possibly decreasing the
mechanical stress on lung units. Volatile anesthetics were

Anesthesiology 2016; 124:1230-45 1237 Uhlig et al.

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 Volatile Anesthetics and Outcome

Fig. 5. Mortality in noncardiac surgery. Values are presented as odds ratio (OR) and 95% CI. Statistical analyses were performed
using the Peto OR method. Statistical significance was accepted α less than 0.05. (A) Forest plot of overall mortality for noncardiac
surgery patients, which represents the mortality of the longest available follow-up. Thirteen were trials excluded due to no events.
(B) Forest plot of in-hospital mortality for noncardiac surgery patients. Twelve trials were excluded due to no events. TIVA = total IV
anesthesia; VOL = volatile anesthetics; volatiles = volatile anesthetics. *Events were given as event per patient and overall number
of events per patient. References refer to table 5 of the Supplemental Digital Content 1, http://links.lww.com/ALN/B270.

found to alleviate bronchoconstriction in patients with
chronic obstructive lung disease,39 suggesting a possible role
for this mechanism. Furthermore, the antiinflammatory
effects of volatile anesthetics40,41 are not limited to the lungs
or heart, but affect also other organs, including brain,42,43
kidneys,44,45 and liver.46–49 In addition, a more recent meta-
analysis demonstrated a reduction of acute kidney injury
and renal failure after cardiac surgery under general anes-
thesia with volatile anesthetics compared to TIVA.50 Such
effects might be related to favorable transcriptional changes
in pro- and antiprotective mechanisms, as demonstrated for
sevoflurane.51
The fact that, in cardiac surgery patients, lower incidences
of pulmonary and other complications were not associated
with reduced LOS in ICU or hospital might be due to stan-
dard operating procedures determining a minimal period of
stay for this type of surgery.
Noncardiac Surgery
In noncardiac surgery procedures, compared to TIVA, volatile
anesthetics were not associated with reduced mortality. There
are different possible explanations for this observation. First,
since most of the protective effects of volatile anesthetics seem
to be related to cardiac preconditioning9,52 and the surgical
population in the analysis also included patients less prone
to cardiac complications, beneficial effects may have been
diluted in the analysis of this surgical population. Second,
the presence of comorbidities that influence the risk of death,

Anesthesiology 2016; 124:1230-45 1238 Uhlig et al.

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 PERIOPERATIVE MEDICINE

Fig. 6. Indirect comparisons among volatile anesthetics during cardiac surgery. Values are presented as summary odds ratio (mean)
and as 95% CI. Statistical analyses were performed using network meta-analysis method. (A) Forest plot per treatment of overall
mortality, which represents the mortality of the longest available follow-up. (B) Forest plot per treatment of in-hospital mortality.
(C) Forest plot per treatment of postoperative pulmonary complications. (D) Forest plot per treatment of other (nonpulmonary)
complications. DES = desflurane; ISO = isoflurane; SEV = sevoflurane; TIVA = total IV anesthesia.

for example, cancer, may have acted as confounders. Third,
the population investigated may have been more heteroge-
neous than the cardiac surgery population. In fact, studies
retained for analysis included thoracic, vascular, and abdomi-
nal surgery, likely reducing the power of the meta-analysis to
identify an effect on mortality. The lack of potential benefit
of volatile anesthetics in reducing pulmonary and other com-
plications in the noncardiac surgery is possibly due to a high
heterogeneity among trials. It is worth noting that studies of
noncardiac surgical patients that were retained for analysis
showed an association between the use of volatile anesthet-
ics and reduced hospital LOS, compared to TIVA. However,
since only a few trials reported hospital LOS, the noncardiac
surgery population might have not been adequately repre-
sented, and this finding should be interpreted with caution.
Possible Implications of the Findings
The results of this systematic review and meta-analysis sug-
gest that, in patients undergoing cardiac surgery, and pro-
vided no contraindication is present, volatile anesthetics
should be preferred over TIVA as a strategy to improve post-
operative outcome. Nevertheless, it must be kept in mind
that coronary artery bypass graft, off-pump or on-pump
with cardiopulmonary bypass, and noncoronary artery
bypass graft surgery (e.g., valve surgery) have been evaluated
together, whereas most patients underwent coronary artery
bypass graft surgery.
In noncardiac surgery patients, volatile anesthetics seem
not to be associated with a relevant outcome benefit com-
pared to TIVA. However, mortality after noncardiac surgery
was relatively high (≈7.2%), suggesting that high-risk pro-
cedures may have been selected, precluding extrapolation of
the results to low- and mid-risk surgery.
Given the importance of organ protection during surgery,
large RCTs investigating the potential of volatile anesthet-
ics to reduce pulmonary and other complications also in
noncardiac surgery patients are highly needed. The current
results might be valuable for estimation of effect sizes and
sample size calculations when designing such studies. Such a
trial should be powered for mortality and assess pulmonary

Anesthesiology 2016; 124:1230-45 1239 Uhlig et al.

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 Volatile Anesthetics and Outcome

Fig. 7. Indirect comparisons among volatile anesthetics during noncardiac surgery. Values are presented as summary odds ratio
(mean) and as 95% CI. Statistical analyses were performed using network meta-analysis method. (A) Forest plot per treatment
of overall mortality, which represents the mortality of the longest available follow up. (B) Forest plot per treatment of in-hospital
mortality. (C) Forest plot per treatment of postoperative pulmonary complications. (D) Forest plot per treatment of other (nonpul-
monary) complications. DES = desflurane; ISO = isoflurane; SEV = sevoflurane; TIVA = total IV anesthesia.

and other complications systematically. Currently, a large
trial comparing the effects of sevoflurane, desflurane, and
isoflurane with TIVA in cardiac surgery is being performed
(clinicaltrials.gov identifier NCT02105610).
Limitations
The present systematic review and meta-analysis has several
limitations. First, the quality of the trials is heterogeneous,
with relatively large overall risk of bias. Second, most tri-
als were relatively small and either did not report any, or
reported only a few events, which jeopardizes the generaliz-
ability of the findings, especially with regard to mortality.
The internal validity of those trials could be compromised
by underreporting, and the external validity may be affected
if the study population has different properties compared
to the general population. However, we made adjustments
for the effect size with respect to trials with small sample
size and used the Peto OR method,25,53 which offers a more
precise statistical analysis for rare events than a fixed or ran-
dom effects model as proposed by Mantel and Haenszel54
or DerSimonian and Liard.55 Furthermore, a network meta-
analysis was performed, which included all trials regard-
less of the number of events. Third, publications within a
time period of three decades were included, and we cannot
exclude the possibility that other time-dependent factors,
for example, advances in postoperative care, influenced the
results. Fourth, we cannot rule out that publication bias did
impair our analysis, since negative results are more likely
not to be published. Fifth, pulmonary and other complica-
tions were analyzed as collapsed composite outcomes from
events with different degrees of severity. For example, ARDS
and atelectasis were counted in the same way. In addition,
the assessment and definition of those complications dif-
fered across the trials retained in the analysis, increasing the
risk of bias. Sixth, postoperative complications are impor-
tantly influenced by the type of surgery,3,56,57 which may
overwhelm the role of anesthetic agents. Nevertheless, we
conducted a separate analysis of cardiac and noncardiac
surgery. Furthermore, in cardiac surgery, coronary artery
bypass graft, off-pump or on-pump with cardiopulmonary

Anesthesiology 2016; 124:1230-45 1240 Uhlig et al.

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 PERIOPERATIVE MEDICINE

Fig. 8. Postoperative complications in cardiac surgery. Values are presented as odds ratio (OR) and 95% CI. Statistical analyses
were performed using the Peto OR method. Statistical significance was accepted α less than 0.05. (A) Forest plot of postopera-
tive pulmonary complications of cardiac surgery patients. Three trials excluded due to no events. (B) Forest plot of other (non-
pulmonary) complications in cardiac surgery patients. Eight trials were excluded due to no events. TIVA = total IV anesthesia;
VOL = volatile anesthetics; volatiles = volatile anesthetics. *Events are given as event per patient and overall number of events
per patient. References refer to table 5 of the Supplemental Digital Content 1, http://links.lww.com/ALN/B270.

bypass, and noncoronary artery bypass graft surgery (e.g.,
valve surgery) have been evaluated together, whereas most
patients underwent coronary artery bypass graft surgery.
Thus, generalization of the findings for all types of cardiac
surgery may be inappropriate. Seventh, mortality rates were
relatively low in cardiac surgery, likely due to sampling bias
of small trials and use of narrow inclusion criteria that might
have resulted in inclusion of mainly low- and medium-risk
procedures. Eighth, we did not address the use of opioids,
which might have potential cardiac protective effects.58,59
Conclusions
In cardiac, but not in noncardiac, surgery, compared to TIVA,
general anesthesia with volatile anesthetics was associated
with major benefits in outcome, including reduced mortality,

Anesthesiology 2016; 124:1230-45 1241 Uhlig et al.

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 Volatile Anesthetics and Outcome

Fig. 9. Postoperative complications in noncardiac surgery. Values are presented as odds ratio (OR) and 95% CI. Statistical
analyses were performed using the Peto OR method. Statistical significance was accepted α less than 0.05. (A) Forest plot of
postoperative pulmonary complications of noncardiac surgery patients. One trial was excluded due to no events. (B) Forest plot
of other (nonpulmonary) complications of noncardiac surgery patients. Two trials were excluded due to no events. TIVA = total IV
anesthesia; VOL = volatile anesthetics; volatiles = volatile anesthetics. *Events are given as event per patient and overall number
of events per patient. References refer to table 5 of the Supplemental Digital Content 1, http://links.lww.com/ALN/B270.

as well as lower incidence of pulmonary and other complica-
tions. Further studies are warranted to address the impact of
volatile anesthetics on outcome in noncardiac surgery.
Acknowledgments
The authors express their gratitude to Silke Thrun, LIB, Li-
brary of the Departments of Surgery and Anesthesiology and
Intensive Care Medicine, University Hospital Dresden, Dres-
den, Germany, and Susanne Henninger Abreu, B.Pd., R.N.,
Department of Anesthesiology and Intensive Care Medicine,
University Hospital Dresden, Technische Universität Dres-
den, Dresden, Germany, for providing articles; Roman Rodi-
onov, M.D., Ph.D., University Center for Vascular Medicine
and Department of Medicine III, Section Angiology, Uni-
versity Hospital Dresden, Technische Universität Dresden;

Anesthesiology 2016; 124:1230-45 1242 Uhlig et al.

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 PERIOPERATIVE MEDICINE
Martin Böke, Ph.D., Institute of Ethnology, University of Co-
logne, Cologne, Germany; Anja Eckardt, M.D., Department
of Gynecology and Obstetrics, Oberlausitz-Kliniken Baut-
zen, Bautzen, Germany; and Lorenzo Ball, M.D., Depart-
ment of Surgical Sciences and Integrated Diagnostics, IRCCS
San Martino IST, University of Genoa, Genoa, Italy, for their
assistance with article translation. The authors are indebted
to Michael Andreae, M.D., Department of Anesthesiology,
Montefiore Medical Center, Albert Einstein College of Medi-
cine, Bronx, New York, for revising the article.
Competing Interests
The authors declare no competing interests.
Correspondence
Address correspondence to Dr. Gama de Abreu: Depart-
ment of Anesthesiology and Intensive Care Medicine,
Pulmonary Engineering Group, University Hospital
Dresden, Technische Universität Dresden, Fetscherstr. 74,
01307 Dresden, Germany. mgabreu@uniklinikum-dresden.
de. This article may be accessed for personal use at no charge
through the Journal Web site, www.anesthesiology.org.
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