Safety and Efficacy of Volatile Anesthetic

Agents Compared With Standard Intravenous

Midazolam/Propofol Sedation in Ventilated Critical
Care Patients: A Meta-analysis and Systematic
Review of Prospective Trials
Angela Jerath, FRCPC, FANZCA, MBBS, BSc,* Jonathan Panckhurst, MBChB,† Matteo Parotto, PhD, MD,*
Nicholas Lightfoot, FANZCA, MBChB,† Marcin Wasowicz, PhD, MD,* Niall D. Ferguson, FRCPC, MSc,‡
Andrew Steel, FRCPC, FFICM, FRCA, MBBS, BSc,* and W. Scott Beattie, PhD, FRCPC*

BACKGROUND: Inhalation agents are being used in place of intravenous agents to provide
sedation in some intensive care units. We performed a systematic review and meta-analysis
of prospective randomized controlled trials, which compared the use of volatile agents versus
intravenous midazolam or propofol in critical care units.
METHODS: A search was conducted using MEDLINE (1946–2015), EMBASE (1947–2015), Web
of Science index (1900–2015), and Cochrane Central Register of Controlled Trials. Eligible stud-
ies included randomized controlled trials comparing inhaled volatile (desflurane, sevoflurane,
and isoflurane) sedation to intravenous midazolam or propofol. Primary outcome assessed the
effect of volatile-based sedation on extubation times (time between discontinuing sedation and
tracheal extubation). Secondary outcomes included time to obey verbal commands, proportion
of time spent in target sedation, nausea and vomiting, mortality, length of intensive care unit,
and length of hospital stay. Heterogeneity was assessed using the I2 statistic. Outcomes were
assessed using a random or fixed-effects model depending on heterogeneity.
RESULTS: Eight trials with 523 patients comparing all volatile agents with intravenous mid-
azolam or propofol showed a reduction in extubation times using volatile agents (difference in
means, −52.7 minutes; 95% confidence interval [CI], −75.1 to −30.3; P < .00001). Reductions
in extubation time were greater when comparing volatiles with midazolam (difference in means,
−292.2 minutes; 95% CI, −384.4 to −200.1; P < .00001) than propofol (difference in means,
−29.1 minutes; 95% CI, −46.7 to −11.4; P = .001). There was no significant difference in time
to obey verbal commands, proportion of time spent in target sedation, adverse events, death,
or length of hospital stay.
CONCLUSIONS: Volatile-based sedation demonstrates a reduction in time to extubation, with
no increase in short-term adverse outcomes. Marked study heterogeneity was present, and
the results show marked positive publication bias. However, a reduction in extubation time was
still evident after statistical correction of publication bias. Larger clinical trials are needed to
further evaluate the role of these agents as sedatives for critically ill patients.  (Anesth Analg
2016;XXX:00–00)

S
edation is a cornerstone of intensive care unit (ICU)
therapy and is required by >85% of patients.1 Sedative
medications are used to assist tolerance of endo-
tracheal intubation, mechanical ventilation, invasive
From the *Department of Anesthesia and Pain Medicine, Toronto General
Hospital, Toronto, Ontario, Canada; †Department of Anesthesia and
Pain Medicine, Middlemore Hospital, Auckland, New Zealand; and
‡Interdepartmental Division of Critical Care, University of Toronto, Ontario,
Canada.
Accepted for publication August 24, 2016.
Funding: Alternative Funding Plan (AFP), Mount Sinai Hospital-University
Health Network Academic Medical Organization.
Conflict of Interest: See Disclosures at the end of the article.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.anesthesia-analgesia.org).
Address correspondence to Angela Jerath, FRCPC, FANZCA, MBBS, BSc,
Department of Anesthesia and Pain Medicine, Toronto General Hospital,
3-EN 200 Elizabeth St, Toronto, ON, M5G 2C4 Canada. Address e-mail to
Angela.Jerath@uhn.ca.
Copyright © 2016 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000001634
procedures, and to manage agitation.2 Midazolam and pro-
pofol are 2 of the most commonly used intravenous seda-
tive agents.3,4 Metabolism and clearance of these agents rely
on adequate function of renal and hepatic systems, with
many agents also producing active metabolites.2 Critically
ill patients commonly demonstrate hepatic and renal dys-
function, delaying systemic clearance of these drugs. This
is often compounded by oversedation associated with
high doses of these agents, which occurs in up to 60% of
ICU patients.5 Slow clearance of these agents leads to drug
hangover, which slows down patient awakening, return of
airway reflexes, and extubation times.2 Furthermore, these
intravenous sedatives are associated with delirium.5,6
Volatile-based ICU sedation entails the delivery of
inhaled isoflurane, sevoflurane, or desflurane anesthetic
agents. These volatile agents have a long tradition of use
within the operating room to provide general anesthe-
sia. Their use within the ICU has largely been confined
to the management of status asthmaticus and epilepti-
cus.7,8 However, there is increased interest in their use as

XXX 2016 • Volume XXX • Number XXX www.anesthesia-analgesia.org

1
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 Volatile-Based Sedation: Meta-analysis and Systematic Review
general ICU sedatives because the early trial performed
by Kong et al9 demonstrated faster patient awakening and
extubation times. The associated adverse effects of these
agents include nausea and vomiting and possible fluoride-
induced nephrotoxicity.10 Volatile agents are a novel seda-
tion modality that has the potential to expand our current
sedation treatment options. The primary objective of this
analysis is to systematically review and meta-analyze the
efficacy and safety of volatile agents for sedation among
adult patients admitted to critical care units compared with
standard intravenous midazolam or propofol sedation.
METHODS
This review adhered to the methodology as described in the
Cochrane Handbook for Systematic Reviews of Interventions.11
Inclusion and Exclusion Criteria
Eligible studies included were published single or multi-
center randomized controlled trials (RCTs) in which adult
(>18 years of age) ICU patients received either inhaled
volatile anesthetic agent or intravenous benzodiazepines
or propofol-based sedation. Patients within medical, sur-
gical, and specialized cardiac ICUs were included. There
was no restriction to sample size. Quasirandomized trials,
crossover, case-control, or case series studies were excluded.
Inhaled volatile anesthetic agents include the use of isoflu-
rane, sevoflurane, or desflurane anesthetic agents.
Electronic Search Strategy
Eligible trials were identified using MEDLINE (1946–2015),
EMBASE (1947–2015), Web of Science index (1900–2015),
and Cochrane Central Register of Controlled Trials. Search
terms included volatile anesthetics, intensive care units,
randomized controlled trial limited to human, adults, and
English language. In addition, we reviewed trial registries
to discern both unreported and/or ongoing trials (clinical-
trials.gov). Abstracts required the full article for consider-
ation. We also perused the reference list of identified studies
and review articles to identify any other studies.
Methods of Review
The literature search was performed by 2 teams of 2 inde-
pendent reviewers with the aid of a librarian. Reasons for
exclusion were noted. Data were extracted by both teams
using a data abstraction form and disagreements resolved
by consensus. Trial bias was assessed using the Cochrane
Risk of Bias tool.11 The primary outcome for this review was
time to extubation (time between discontinuing sedation
and tracheal extubation). Secondary outcomes included
other clinical sedation and safety outcomes. Additional
sedation outcomes were time to obey verbal commands
(time between discontinuing sedation to squeezing hand
and moving toes on command), proportion of time spent in
target sedation, duration of mechanical ventilation, length
of stay in the ICU, and length of hospital stay. Patient safety
was assessed by nausea and vomiting requiring pharma-
cological treatment, creatinine levels (12- to 24-hour post-
sedation or postoperatively), and death. In addition to
these outcomes, reviewers extracted the number of patients
and type of ICU within each study, age, sex, duration of
2   
www.anesthesia-analgesia.org
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
sedation, sedative agents used, and dose (when available).
Primary authors were contacted for missing information.
Statistical Analysis
The primary outcome of time to extubation and other con-
tinuous outcomes were assessed using the difference in
means (95% confidence interval [CI]). Dichotomous data
were assessed using the risk ratio or difference (95% CI). If
the full text article had data presented as median, interquar-
tile range, and range, the mean and standard deviation were
calculated using the methods outlined by Wan et al12 (unless
available from the author). Heterogeneity was assessed via
calculation of the I2 statistic, where values >50% indicated
moderate heterogeneity. A random-effects model was used
when combined studies demonstrated at least moderate
heterogeneity; otherwise, a fixed-effects model was used.
Publication bias was assessed using a funnel plot, as well as
an Egger regression test for funnel plot asymmetry. A sensi-
tivity analysis was performed using the trim and fill method
(with a random-effects model) to impute potentially miss-
ing studies generating a symmetric plot.13,14 Data synthesis
was completed using Review Manager 5.3 provided by the
Cochrane Collaboration (Oxford, United Kingdom) and
metafor package in R software v 3.02.11,15 To control for mul-
tiple testing, Bonferroni method was used to adjust P values
by dividing the conventional P value of .05 by the number
of main hypotheses (n = 9). Therefore, P values <.006 were
considered statistically significant.
Subgroup Analyses
The initial analysis compared the entire class of volatile
agents with all intravenous agents (midazolam or propo-
fol). A priori subgroup analyses were performed comparing
volatile agents with midazolam and propofol separately.
Sufficient studies were also available to compare sevo-
flurane with propofol and isoflurane with midazolam
separately.
Sensitivity Analysis
An additional analysis was performed comparing time
with extubation outcomes in trials that were sponsored by a
pharmaceutical company versus trials that were sponsored
by a grant or institution.
We calculated the power and sample size required for the
primary outcome, time to extubation, and clinically impor-
tant outcomes such as ICU length of stay. Using a 2-tailed
2-sample t test with type I error probability of 5%, power of
80%, and standard deviation of 848, a sample of 252 patients
(126 per group) would be required to detect a 300-minute
difference in extubation time between volatile-based seda-
tion and intravenous midazolam.9,16–18 To detect a reduction
in ICU length of stay by 12 hours with a standard deviation
of 74, a sample size of 1194 patients (597 per group) would
be required.16,18–24
RESULTS
Study Identification and Selection
The initial search identified 2173 records. We removed 506
duplicate records plus an additional 1623 records that failed
to meet inclusion criteria (1534 non-ICU or non-volatile
anesthesia & analgesia
 trials, 39 reviews/meta-analyses, 27 animal, 13 pediatric, 3
scavenging, and 1 trial update). Forty-four full-text articles
were assessed for eligibility, which were reduced to 15 trials
with a total of 989 patients for this meta-analysis (Figure 1;
Supplemental Digital Content, Supplemental Appendix 1,
http://links.lww.com/AA/B532).9,16–29 A full list of search
articles that were reviewed and excluded is available from
the authors.
Study Characteristics
Main characteristics of the 15 RCTs are summarized in
Table 1. Fourteen trials were parallel RCTs, and 1 trial had
3 arms. Three authors published 2 articles with different
reported outcomes that appear to have been conducted
within the same clinical trial population.16,17,21,26,28,29
The majority of patients within these trials were male
(45%–95%), with the mean age ranging from 52 to 69
years (Table 1). Out of 15 trials, 6 were set within cardiac
ICUs, and the remainder were set in surgical and mixed
medical-surgical ICUs. Short-term sedation (duration of
sedation of <24 hours) is likely to involve 10 trials pre-
dominantly set within cardiac ICUs.9,19–25,27,29 Seven trials
used sevoflurane, 6 used isoflurane, 1 used desflurane,
and 1 trial randomized patients to either sevoflurane or
isoflurane sedation.
Quality Assessment
Selection, performance, detection, attrition, and reporting
bias were assessed as high, low, or unclear. The trial dates
ranged from 1989 to 2015 (Figure  2). Study quality was
highly variable, with many poorly documented trial char-
acteristics within the early studies.
XXX 2016 • Volume XXX • Number XXX www.anesthesia-analgesia.org
3
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Time to Extubation. Eight studies totaling 523 patients
reported this outcome.9,16–18,20,21,24,27 All 3 volatile agents
were represented and compared with either midazolam or
propofol. Volatile agents showed faster extubation times in
comparison with intravenous sedatives (difference in means,
−52.7 minutes; 95% CI, −75.1 to −30.3; P < .00001) but with
an I2 of 92%, indicating high statistical heterogeneity (Figure
3A). Subgroup analyses based on the type of medication
were performed. Four studies compared all volatile agents
with midazolam in 143 patients and demonstrated that
volatile agents reduced extubation time (difference in means,
−292.2 minutes; 95% CI, −384.4 to −200.1; P < .00001) with
moderate statistical heterogeneity (Figure 3B).9,16–18 Three of
these trials with 110 patients allowed direct comparison of
isoflurane with midazolam and showed a similar reduction in
extubation time (difference in means, −265.2 minutes; 95% CI,
−361.8 to −168.7; P < .00001; I2 0%).9,16,17 Five studies compared
all volatile agents (sevoflurane used in 3 trials, desflurane
in 1 trial, and sevoflurane or isoflurane used in 1 trial) with
intravenous propofol in 399 patients and showed a difference
in means of −29.1 minutes (95% CI, −46.7 to −11.4; P = .001) with
a high degree of statistical heterogeneity (Figure 3C).18,20,21,24,27
Review of these studies showed that extubation times within
both the control and the volatile arms were significantly faster
in the trials performed by Meiser et al27 and Hellström et al.21
Removal of these 2 trials showed a reduction in extubation
time (difference in means, −146.0; 95% CI, −207.3 to −84.8;
P < .00001) with lower heterogeneity (I2 38%). Four trials
with 310 patients compared sevoflurane with propofol and
showed a statistically nonsignificant reduction in extubation
time (difference in means, −114.3; 95% CI, −215.3 to −13.3;
P = .03; I2 90%).18,20,21,24
Figure 1. PRISMA study flow chart. ICU indicates
intensive care unit.
 Volatile-Based Sedation: Meta-analysis and Systematic Review

Table 1.  Characteristics of Included Studies

Volatile end-
tidal %, mean
(SD)
Infusion
Admission Exposure Age (y) Male Duration dose, mean
Study n ICU Diagnosis Control Mean (SD) n (%) Sedation (h) (SD) Funding
Kong et al (1989)9 60 MSICU Not specified Isoflurane 67.5 (15.3) 20 (66.6) 18.5 (4.3) .2% (.08) Unknown
Midazolam 67.5 (13) 25 (83.3) 18 (3.0) 3.1 (2.2)
mg/h
Kong et al (1990)25 60 MSICU Postsurgery, other Isoflurane 66.2 (10.7) 17 (65) 18.2 (5.1) … Unknown
Midazolam 65.5 (11.2 18 (90) 18.3 (4.5) …
Spencer et al 60 MSICU Not specified Isoflurane 62 (15.6) 19 (63.3) 36 (29.3) … Pharma
(1991)26 Midazolam 68 (11.3) 21 (70) 36 (25) …
Spencer and Willatts
(1992)16
Meiser et al (2003)27 60 SICU Postsurgery Desflurane 65 (23) 19 (68) 11.5 (5.7) 3.5% (.5) Pharma
(esophagectomy, Propofol 59.9 (22) 17 (61) 9.7 (5.3) 4.4 (1.1)
gastrointestinal mg/k/h
malignancy,
abdominal aortic
aneurysm,
orthopedics)
Sackey et al (2004)17 40 MSICU Trauma, Isoflurane 60 (10.3) 9 (45) 52 (21) .3% (.18) Pharma
Sackey et al (2008)28 postsurgery, Midazolam 60 (15.3) 12 (60) 32 (23.3) …
respiratory
failure, airway
obstruction,
peritonitis,
sepsis
Röhm et al (2008)20 70 CVICU CABG Sevoflurane 64.6 (8.6) 28 (80) 8.1 (3.1) .7% (.5)a Institution
Propofol 66.4 (8) 25 (71.4) 8.4 (4.2) 2.4 (1.1)
mg/k/h
Röhm et al (2009)19 130 SICU Postsurgery (major Sevoflurane 67 (10) 46 (72) 9.2 (4.3) … Institution
abdominal,
Propofol 67 (8) 44 (72) 9.3 (4.7) 2.1 (.6)
vascular,
mg/k/h
thoracic, CABG,
aortic valve
replacement)
Mesnil et al (2011)18 60 MSICU Trauma, Sevoflurane 52 (23) 10 (53) 50 (23.7) … Institution
postsurgery, Propofol 54 (13.3) 9 (64) 57 (40) …
pneumonia,
respiratory Midazolam 55 (22.2) 10 (71) 50 (24.4) …
failure, sepsis

Hellström et al 100 CVICU CABG Sevoflurane 65 (8) 37 (76) 2.8 (.9) 0.8% (.2) Pharma/
(2011)29 Propofol 66 (11) 42 (84) 3.1 (1.4) 2 (.7) industry
Hellström et al mg/k/h
(2012)21
Soro et al (2012)23 75 CVICU CABG Sevoflurane 68.3 (10.7) 27 (75) Not Not specified Nil
specifieda
Propofol 69.4 (9.3) 30 (81.1)
Steurer et al (2012)22 117 CVICU Aortic valve, Sevoflurane 63 (12.4) 32 (69) Not Not specified Pharma
mitral valve, specifiedb
combined cardiac Propofol 64 (14.7)
procedures
Jerath et al (2015)24 157 CVICU CABG Sevo/Iso 65 (9) 61 (91) Not Not specified Grant
specifiedb
Propofol 63 (10) 70 (95)
Abbreviations: CABG, coronary artery bypass grafts; CVICU, cardiovascular intensive care unit; Iso, isoflurane; MSICU, medical surgical intensive care unit; Sevo,
sevoflurane; SICU, surgical intensive care unit.
a
Extrapolated from figure.
b
Cardiac surgical population and thus duration of sedation likely <24 h.

4   
www.anesthesia-analgesia.org anesthesia & analgesia
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 Figure 2. Risk of bias assessment.
Subgroup analyses were also performed based on the
duration of sedation. Three longer-term sedation trials
(duration of sedation >24 hours), with 130 patients predom-
inantly performed in mixed medical-surgical ICUs showed
a large reduction in time to extubation (difference in means,
−314.5 minutes; 95% CI, −452.2 to −176.7; P < .00001; I2
30%).16–18 Five short-term sedation trials (duration of seda-
tion <24 hours) with 393 patients were largely performed
for postoperative sedation and showed a smaller reduction
in time to extubation (difference in means, −30.9 minutes;
95% CI, −49.2 to −12.7; P = .0009; I2 92%).9,20,21,24,27 As men-
tioned previously, removal of trials performed by Meiser et
al27 and Hellström et al21 maintained faster extubation times
XXX 2016 • Volume XXX • Number XXX www.anesthesia-analgesia.org
5
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
within the volatile groups (difference in means, −156.6;
95% CI, −230.0 to −83.1; P < .0001) with lower statistical
heterogeneity (I2 56%). The influence of pharmaceutical or
industry sponsorship was reviewed, with 4 trials receiving
commercial sponsorship, 3 trials were grant or internally
funded, and funding for 1 older trial was unknown (Table
1). The type of funding did not negatively impact the above
findings, with reductions in time to extubation remaining
larger within the nonindustry funded trials (difference in
means, −195.8; 95% CI, −311.6 to −79.9).
Other Sedation Outcomes. Four studies assessed the time to
obey verbal commands upon discontinuing sedation (Table 2).
 Volatile-Based Sedation: Meta-analysis and Systematic Review

Figure 3. Time to extubation (min). CI indicates confidence interval.

Table 2.  Summary of Secondary Outcomes

Mean Difference or
a
Risk Ratio
No. No. b
Risk Difference P
Outcome Studies Participants (95% CI) Heterogeneity (I2) Value
Time to obey verbal commands (min)9,16,17, 27 4 198 −26.1 (−59.4 to 7.2) 71% .12
% Time spent in target sedation17,18 2 73 −1.1 (−13.8 to 11.5) 0% .86
Duration of mechanical ventilation (h)18–21 4 341 −2.0 (−3.9 to −.2) 66% .03
Nausea and vomiting20,21,24,27 4 363 1.2 (.7 to 2.2)a 13% .47
Serum creatinine19,24–26,29 5 446 .7 (−5.4 to 6.8) 0% .83
Intensive care unit length of stay (h)16,18–24 8 700 −.05 (−1.1 to 1.0) 0% .92
Hospital length of stay (d)19–24 6 610 −.03 (−.2 to .1) 56% .74
Hospital mortality9,17,24 3 241 0 (−.02 to .03)b 0% .95
Abbreviation: CI, confidence interval.

There was no significant difference in this outcome
(difference in means, −26.2; 95% CI, −59.4 to 7.2; P = .12;
I2 71%).9,16,17,27 Only 2 studies with 73 patients assessed the
proportion of time patients spent within a target sedation
range.17,18 There was no significant difference between
inhaled volatile and intravenous agents (difference in
means, −1.1; 95% CI, −13.8 to 11.5; P = .86; I2 0%). Duration
of mechanical ventilation was available in 4 trials (3 short-
term and 1 longer-term sedation trial) using sevoflurane.18–21
With 341 patients, duration of mechanical ventilation was
not different between volatile and intravenous sedation
groups (difference in means, −2.0 hours; 95% CI, −3.9 to
−.2; P = .03) and showed high heterogeneity (I2 66%). As
mentioned previously, removal of the trial by Hellström
et al21 reduced the duration of mechanical ventilation using
sevoflurane sedation (difference in means, −3.1 hours;

6   
www.anesthesia-analgesia.org anesthesia & analgesia
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 95% CI, −4.5 to −1.6; P < .0001) with improved statistical
heterogeneity (I2 0%).
Adverse Effects. Nausea and vomiting were reported in 4
trials totaling 363 patients (Table 2).20,21,24,27 There was no
significant difference in nausea and vomiting between the 2
sedation modalities (risk ratio, 1.2; 95% CI, .7 to 2.2; I2 13%).
Serum fluoride levels were measured during and after
sedation within 3 trials.19,25,26 All trials showed that fluoride
levels were significantly elevated within the volatile group
in comparison with standard intravenous sedatives, with
levels often peaking 12 to 16 hours after discontinuation of
sedation.25,26 Serum fluoride levels were not combined for
additional analysis, given marked differences in timing of
measurement and how the results were reported. However,
5 trials with 446 patients have reported serum creatinine
levels during and after sedation periods. Serum creatinine
levels were combined at 12 to 24 hours after sedation (or
after surgery in 1 short-term sedation trial), given that it
was a consistent time point, and fluoride levels remain high
within the postsedation period.19,24–26,29 The studies included
4 short-term and 1 longer-term sedation trial. No difference
in serum creatinine was seen (difference in means, .7;
95% CI, −5.4 to 6.8; P = .83; I2 0%; Table 2). Assessment of
cardiovascular stability has been performed by measuring
various hemodynamic indices (heart rate, blood pressure,
cardiac index, systemic vascular resistance index, stroke
volume variation, and central venous pressure) and the use
of vasoactive drugs.9,18,23,27,29 A single long-term sedation trial
performed by Mesnil et al18 demonstrated that significantly
fewer patients receiving sevoflurane sedation required
vasoactive drug support in comparison with midazolam
and propofol sedation. However, the majority of trials have
shown no difference in patient hemodynamics between
inhalational and intravenous sedation techniques.
Death and Length of Stay. In-hospital mortality was assessed
in 3 trials with 241 patients. There was no significant
difference between types of sedation (risk difference,
0; 95% CI, −.02 to .03; P = .95; I2 0%).9,17,24 Length of ICU
stay and length of hospital stay were assessed in 8 and 6
trials, respectively. Both outcomes showed no significant
difference between the 2 sedation modalities (Table 2).
Publication Bias. A funnel plot on the meta-analysis
looking at time to extubation using 8 trials shows a lack of
negative trials and a positive publication bias (Figure 4A).
Egger regression test for funnel plot asymmetry was also
significant (P < .0001). The trim and fill method imputed 4
studies to improve symmetry of the funnel plot, with the
adjusted mean difference of extubation times estimated at
−37.9 minutes (95% CI, −62.7 to −13.1; P = .003).
DISCUSSION
Our results show that the use of inhaled volatile agents
reduces time to tracheal extubation in comparison with stan-
dard intravenous sedatives by about 53 minutes. This is most
striking in the comparison of all volatile agents, including
isoflurane specifically, with midazolam (265–292 minutes).
Similar findings were noted in comparisons with propofol,
although the clinical difference was smaller (29 minutes).
XXX 2016 • Volume XXX • Number XXX www.anesthesia-analgesia.org
7
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Clearance of volatile agents through simple pulmonary
exhalation with minimal systemic metabolism is likely to
account for the faster extubation times. Benzodiazepines
demonstrated a larger difference in extubation times than
propofol. This is likely attributable to different pharmaco-
kinetic properties of these intravenous agents, with propo-
fol possessing faster systemic clearance with no significant
metabolites in comparison with midazolam.2,30
Despite volatile agents demonstrating faster extubation
times, this failed to translate into shorter lengths of stay.
However, this analysis identified no difference in nausea
and vomiting or in-hospital mortality in patients sedated
using volatile agents. These mortality findings have been
further supported by a recent retrospective study of 200
surgical ICU patients sedated with either isoflurane or mid-
azolam/propofol for >96 hours.31 Risk-adjusted analysis
demonstrated that volatile-based sedation was associated
with lower in-hospital death (adjusted odds ratio .35; 95%
CI, .18 to .68; P = .002) and 1-year mortality (adjusted odds
ratio .41; 95% CI, .21 to .81; P = .01). The low incidence of
nausea and vomiting among patients receiving volatile
agents is likely secondary to the low doses required for
ICU sedation, which are approximately one third (.3 mini-
mum alveolar concentration) the dose required for general
anesthesia. With several studies showing elevated serum
fluoride levels with the use of volatile agents, we failed to
demonstrate any nephrotoxic effects up to 24 hours after
sedation.17,19,26 These findings are in keeping with case series
demonstrating similar findings.32,33
This study has several limitations. This analysis included
many older trials in which current standards of randomiza-
tion, allocation concealment, and selective reporting crite-
ria were not formally documented within the article. The
current trials are small, with variation in study quality,
analgesic regimens, use of daily sedation breaks, report-
ing depth of sedation, type of sedative drug, and duration
of use, which may have added to the clinical heterogene-
ity and affected treatment outcomes. Comparison of all
volatile agents with intravenous sedatives was initially per-
formed, given that pulmonary clearance of volatile agents
is a unique class effect that avoids systemic metabolism
required by our traditional intravenous agents. However,
additional subanalyses were performed given that the dif-
ferent pharmacokinetic properties of midazolam, propofol,
and between the volatile agents with desflurane showing
the fastest clearance, followed by sevoflurane and isoflu-
rane. These subanalyses confirmed faster extubation times
using volatile-based sedation with reduced statistical het-
erogeneity. Furthermore, heterogeneity was improved
after removal of the trials performed by Meiser et al27 and
Hellström et al,21 which showed faster extubation times in
both control and volatile arms. These may have been influ-
enced by institutional weaning protocols, dose of opioids,
and use of regional analgesia techniques. Faster emergence
within the trial performed by Meiser et al27 may be influ-
enced by the use of desflurane and the common use of
epidural analgesia within this surgical population. Lower
doses of intraoperative opioid and midazolam were noted
within the cardiac surgical population of the trial performed
by Hellström et al21 in comparison with other similar
 Volatile-Based Sedation: Meta-analysis and Systematic Review

Figure 4. A, Funnel plot assessing time to tra-

cheal extubation without trim and fill adjust-
ments in 8 trials (mean difference, −52.7 min;
95% confidence interval [CI], −75.1 to −30.3;
B P < .00001); B, Trim and fill funnel plot. Closed
circles refer to original studies, and open circles
are imputed studies (mean difference, −37.9 min;
95% CI, −62.7 to −13.1; P = .003).9,16–18,20,21,24,27

studies.20,21,24 We also note that faster extubation times with-
out a positive translation on other important ICU outcomes,
such as length of stay or mortality, may not be clinically
meaningful. This meta-analysis is underpowered, at 58.5%,
to detect a clinically meaningful reduction in the ICU length
of stay of 12 hours. Currently, we lack a large, well-pow-
ered clinical trial to assess these clinically important ICU
end points, and additional research is required to evalu-
ate whether volatile-based sedation truly impacts patient
care beyond extubation times. The funnel plot reveals that
there is a large publication bias with current trials reporting
predominantly positive results. We used a nonparametric
method called trim and fill that imputed the studies missing
from the meta-analysis to improve symmetry of the funnel

8   
www.anesthesia-analgesia.org anesthesia & analgesia
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 plot and demonstrated that faster extubation times were
still evident using volatile agents. This technique assumes
that data should be symmetrical and may be affected by
study heterogeneity. Despite statistical correction of these
results, negative trials are lacking in the literature and
data from ongoing active trials, and undertaking a larger
clinical study would be valuable to assess these agents.34,35
Although meta-analyses combine similar studies, they may
still be underpowered to assess certain clinical outcomes
and increase the chance of type II error.36 Given our find-
ings and the potential benefit of volatile agents to improve
outcomes for critical care patients, a large well-conducted
clinical trial is now required.
An important outcome that we were unable to address is the
impact upon ICU-related delirium. Several studies did mea-
sure and demonstrate no significant difference in the incidence
of postextubation agitation, hallucinations, and delusional
memories, but combining these data was not performed given
varied definitions and measurement tools.20,21,27,28 Sedation,
particularly with benzodiazepine agents, is a recognized risk
factor for developing delirium, which affects 30% to 80% of
ICU patients.6,37 Unfortunately, the current trials provide lim-
ited information on this outcome, and the effect of either short-
term or longer-term use of volatile agents remains unknown.
Furthermore, dexmedetomidine has recently become avail-
able, and its use in the ICU has gained considerable attention.
At present, there are no trials comparing volatiles with dex-
medetomidine and whether the above advantages of volatiles
would remain requires additional investigation.
In 2013, the Society of Critical Care Medicine updated
guidelines and combined the overlapping management of
sedation, pain, and delirium for ICU patients.2 Given the
association of benzodiazepines with drug-induced delir-
ium, tolerance, withdrawal, and slow systemic clearance in
ICU patients with drug hangover, there is rising interest in
identifying alternative sedation modalities. Prolonged use
of propofol is often prohibitive given its higher cost, risk of
hemodynamic instability, and hypertriglyceridemia.2 The use
of volatile agents within the ICU poses a novel and attractive
sedative option. This class of drug confers several advan-
tages over standard intravenous medications, including rapid
onset, bronchodilation, hemodynamic stability at low seda-
tion doses, and breath-by-breath end-tidal gas monitoring
that correlates with cerebral concentration that aids drug titra-
tion to minimize oversedation.7,30 However, the use of volatile
agents in critical care environments requires specialized drug
delivery systems, gas scavenging, and education of critical
care nurses and intensivists with no anesthesia background
regarding this technique. There has also been concern sur-
rounding the potential of neurotoxicity of volatile and intra-
venous agents (ketamine, benzodiazepines, and propofol) in
vulnerable, developing pediatric brains and cognitive dys-
function in elderly patients.38–41 This area of research has pro-
duced conflicting results, with evidence that volatile agents
may also provide neuroprotection.42,43 Clinical studies have
been limited by the inability to separate the effects of volatile
agents from the surgical stress response, comorbidities, and
the underlying clinical disease process.44,45 Recent results from
the multicenter General Anesthesia Spinal trial demonstrated
no difference in cognitive outcomes in infants undergoing
XXX 2016 • Volume XXX • Number XXX www.anesthesia-analgesia.org
9
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
inguinal herniorrhaphy surgery who received either sevoflu-
rane-based general or awake regional anesthesia.46
Our results indicate that volatile agents promote rapid
extubation and may be the ultimate fast-track agent for
postoperative patients and promote faster weaning in com-
plex ICU patients requiring longer-term sedation. These
findings were greater in comparison with the use of intra-
venous midazolam than propofol. However, there is limited
literature assessing the safety and efficacy of these agents
in the short term and the longer term, and the current trials
demonstrate marked heterogeneity and high probability of
publication bias. Currently, these data do not support the
regular use of this technique, but given the current data and
potential of these agents to improve patient outcomes, a
well-designed, adequately powered RCT within a homoge-
neous population to truly understand the potential clinical
effects of this sedation modality is required.
ACKNOWLEDGMENTS
The authors thank Drs M. Steurer and P. Sackey for provid-
ing information for this analysis.
DISCLOSURES
Conflicts of Interest: This analysis includes a trial conducted by the
author group.24,35 The authors have no financial conflicts of interest.
Name: Angela Jerath, FRCPC, FANZCA, MBBS, BSc.
Contribution: This author helped to study the concept, collect and
analyze the data, and develop the manuscript.
Name: Jonathan Panckhurst, MBChB.
Contribution: This author helped collect the data.
Name: Matteo Parotto, PhD, MD.
Contribution: This author helped collect and analyze the data and
prepare the manuscript.
Name: Nicholas Lightfoot, FANZCA, MBChB.
Contribution: This author helped collect and analyze the data and
prepare the manuscript.
Name: Marcin Wasowicz, PhD, MD.
Contribution: This author helped prepare and review the
manuscript.
Name: Niall D. Ferguson, FRCPC, MSc.
Contribution: This author helped to review the manuscript.
Name: Andrew Steel, FRCPC, FFICM, FRCA, MBBS, BSc.
Contribution: This author helped to review the manuscript.
Name: W. Scott Beattie, PhD, FRCPC.
Contribution: This author helped study the concept and review the
manuscript.
This manuscript was handled by: Avery Tung, MD, FCCM.
REFERENCES
1. Weinert CR, Calvin AD. Epidemiology of sedation and
sedation adequacy for mechanically ventilated patients in
a medical and surgical intensive care unit. Crit Care Med.
2007;35:393–401.
2. Barr J, Fraser GL, Puntillo K, et al; American College of Critical
Care Medicine. Clinical practice guidelines for the manage-
ment of pain, agitation, and delirium in adult patients in the
intensive care unit. Crit Care Med. 2013;41:263–306.
3. Mehta S, Burry L, Fischer S, et al; Canadian Critical Care Trials
Group. Canadian survey of the use of sedatives, analgesics, and
neuromuscular blocking agents in critically ill patients. Crit
Care Med. 2006;34:374–380.
4. Payen JF, Chanques G, Mantz J, et al. Current practices in
sedation and analgesia for mechanically ventilated critically
ill patients: a prospective multicenter patient-based study.
Anesthesiology. 2007;106:687–695.
5. Jackson DL, Proudfoot CW, Cann KF, Walsh TS. The incidence
of sub-optimal sedation in the ICU: a systematic review. Crit
Care. 2009;13:R204.
 Volatile-Based Sedation: Meta-analysis and Systematic Review
6. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk
factors and consequences of ICU delirium. Intensive Care Med.
2007;33:66–73.
7. Bierman MI, Brown M, Muren O, Keenan RL, Glauser FL.
Prolonged isoflurane anesthesia in status asthmaticus. Crit Care
Med. 1986;14:832–833.
8. Kofke WA, Young RS, Davis P, et al. Isoflurane for refractory sta-
tus epilepticus: a clinical series. Anesthesiology. 1989;71:653–659.
9. Kong KL, Willatts SM, Prys-Roberts C. Isoflurane compared
with midazolam for sedation in the intensive care unit. BMJ.
1989;298:1277–1280.
10. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study
of dose response in man. JAMA. 1973;225:1611–1616.
11. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews
of Interventions, version 5.1.0 [updated March 2011]. The Cochrane
Collaboration. 2011.
12. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and
standard deviation from the sample size, median, range and/
or interquartile range. BMC Med Res Methodol. 2014;14:135.
13. Talebi M. Study of publication bias in meta-analysis using trim
and fill method. Int Res J Appl Basic Sci. 2013;4:31–36.
14. Viechtbauer W. Conducting meta-analyses in R with the meta-
for package. J Stat Software. 2010;36:1–48.
15. R Core Team. R: A Language and Environement for Statistical
Computing. Vienna, Austria: R Foundation for Statistical
Computing; 2013.
16. Spencer EM, Willatts SM. Isoflurane for prolonged sedation in
the intensive care unit; efficacy and safety. Intensive Care Med.
1992;18:415–421.
17. Sackey PV, Martling CR, Granath F, Radell PJ. Prolonged isoflu-
rane sedation of intensive care unit patients with the anesthetic
conserving device. Crit Care Med. 2004;32:2241–2246.
18. Mesnil M, Capdevila X, Bringuier S, et al. Long-term seda-
tion in intensive care unit: a randomized comparison between
inhaled sevoflurane and intravenous propofol or midazolam.
Intensive Care Med. 2011;37:933–941.
19. Röhm KD, Mengistu A, Boldt J, Mayer J, Beck G, Piper SN.
Renal integrity in sevoflurane sedation in the intensive
care unit with the anesthetic-conserving device: a com-
parison with intravenous propofol sedation. Anesth Analg.
2009;108:1848–1854.
20. Röhm KD, Wolf MW, Schöllhorn T, Schellhaass A, Boldt J, Piper
SN. Short-term sevoflurane sedation using the anaesthetic con-
serving device after cardiothoracic surgery. Intensive Care Med.
2008;34:1683–1689.
21. Hellström J, Öwall A, Sackey PV. Wake-up times following
sedation with sevoflurane versus propofol after cardiac sur-
gery. Scand Cardiovasc J. 2012;46:262–268.
22. Steurer MP, Steurer MA, Baulig W, et al. Late pharmacologic
conditioning with volatile anesthetics after cardiac surgery. Crit
Care. 2012;16:R191.
23. Soro M, Gallego L, Silva V, et al. Cardioprotective effect of sevo-
flurane and propofol during anaesthesia and the postoperative
period in coronary bypass graft surgery: a double-blind ran-
domised study. Eur J Anaesthesiol. 2012;29:561–569.
24. Jerath A, Beattie SW, Chandy T, et al; Perioperative Anesthesia
Clinical Trials Group. Volatile-based short-term sedation in
cardiac surgical patients: a prospective randomized controlled
trial. Crit Care Med. 2015;43:1062–1069.
25. Kong KL, Tyler JE, Willatts SM, Prys-Roberts C. Isoflurane
sedation for patients undergoing mechanical ventilation:
metabolism to inorganic fluoride and renal effects. Br J Anaesth.
1990;64:159–162.
26. Spencer EM, Willatts SM, Prys-Roberts C. Plasma inorganic flu-
oride concentrations during and after prolonged (greater than
24 h) isoflurane sedation: effect on renal function. Anesth Analg.
1991;73:731–737.
10   
www.anesthesia-analgesia.org
Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
27. Meiser A, Sirtl C, Bellgardt M, et al. Desflurane compared with
propofol for postoperative sedation in the intensive care unit.
Br J Anaesth. 2003;90:273–280.
28. Sackey PV, Martling CR, Carlswärd C, Sundin O, Radell PJ.
Short- and long-term follow-up of intensive care unit patients
after sedation with isoflurane and midazolam–a pilot study.
Crit Care Med. 2008;36:801–806.
29. Hellström J, Öwall A, Bergström J, Sackey PV. Cardiac out-
come after sevoflurane versus propofol sedation following
coronary bypass surgery: a pilot study. Acta Anaesthesiol Scand.
2011;55:460–467.
30. Preckel B, Bolten J. Pharmacology of modern volatile anaesthet-
ics. Best Pract Res Clin Anaesthesiol. 2005;19:331–348.
31. Bellgardt M, Bomberg H, Herzog-Niescery J, et al. Survival after
long-term isoflurane sedation as opposed to intravenous sedation
in critically ill surgical patients. Eur J Anaesthesiol. 2015;32:1–8.
32. Osborne MA, Eddleston JM, McNicoll W. Inorganic fluo-
ride concentration after long-term sedation with isoflurane.
Intensive Care Med. 1996;22:677–682.
33. Goldberg ME, Cantillo J, Larijani GE, Torjman M, Vekeman D,
Schieren H. Sevoflurane versus isoflurane for maintenance of
anesthesia: are serum inorganic fluoride ion concentrations of
concern? Anesth Analg. 1996;82:1268–1272.
34. Soukup J, Selle A, Wienke A, Steighardt J, Wagner NM, Kellner
P. Efficiency and safety of inhalative sedation with sevoflurane
in comparison to an intravenous sedation concept with propo-
fol in intensive care patients: study protocol for a randomized
controlled trial. Trials. 2012;13:135.
35. Jerath A, Ferguson ND, Steel A, Wijeysundera D, Macdonald
J, Wasowicz M. The use of volatile anesthetic agents for long-
term critical care sedation (VALTS): study protocol for a pilot
randomized controlled trial. Trials. 2015;16:560.
36. Mascha EJ. Alpha, beta, meta: guidelines for assessing
power and type I error in meta-analyses. Anesth Analg.
2015;121:1430–1433.
37. Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an over-
view. Ann Intensive Care. 2012;2:49.
38. Chiao S, Zuo Z. A double-edged sword: volatile anesthetic
effects on the neonatal brain. Brain Sci. 2014;4:273–294.
39. Mandal PK, Ritchie K, Fodale V. Anesthetics and its impact on the
brain and Alzheimer’s disease. J Alzheimers Dis. 2014;39:223–225.
40. Stevens MF, Werdehausen R, Gaza N, et al. Midazolam acti-
vates the intrinsic pathway of apoptosis independent of ben-
zodiazepine and death receptor signaling. Reg Anesth Pain Med.
2011;36:343–349.
41. Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink
A. Propofol-induced apoptosis of neurones and oligodendro-
cytes in fetal and neonatal rhesus macaque brain. Br J Anaesth.
2013;110(suppl 1):i29–i38.
42. Kitano H, Kirsch JR, Hurn PD, Murphy SJ. Inhalational
anesthetics as neuroprotectants or chemical precondition-
ing agents in ischemic brain. J Cereb Blood Flow Metab.
2007;27:1108–1128.
43. Payne RS, Akca O, Roewer N, Schurr A, Kehl F. Sevoflurane-
induced preconditioning protects against cerebral ischemic
neuronal damage in rats. Brain Res. 2005;1034:147–152.
44. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthe-
sia and learning disabilities in a population-based birth cohort.
Anesthesiology. 2009;110:796–804.
45. Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive
performance in children: no evidence for a causal relationship.
Twin Res Hum Genet. 2009;12:246–253.
46. Davidson AJ, Disma N, de Graaff JC, et al; GAS Consortium.
Neurodevelopmental outcome at 2 years of age after general
anaesthesia and awake-regional anaesthesia in infancy (GAS):
an international multicentre, randomised controlled trial.
Lancet. 2016;387:239–250.
anesthesia & analgesia