Network Met Analysis

BJA Advance Access published February 4, 2015
British Journal of Anaesthesia Page 1 of 11

doi:10.1093/bja/aeu446
A Bayesian network meta-analysis on the effect of inodilatory

agents on mortality
T. Greco 1, M. G. Calabro` 1, R. D. Covello 1, M. Greco 1, L. Pasin1, A. Morelli 2, G. Landoni 1* and A. Zangrillo1
1
2
Department of Anaesthesiology and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy
Department of Anaesthesiology and Intensive Care, La Sapienza University, Rome, Italy
* Corresponding author. E-mail: landoni.giovanni@hsr.it
Editors key points
They used a network

meta-analytical method
to allow comparison of
drugs that had not
previously been directly
compared.
Of the drugs examined,
only levosimendan
appeared to reduce
mortality (compared with
placebo).
Methods. Relevant studies were independently searched in BioMedCentral, MEDLINE/PubMed,

Embase, and the Cochrane Central Register of clinical trials (updated on May 1, 2014). The
criteria for inclusion were: random allocation to treatment with at least one group receiving
dobutamine, enoximone, levosimendan, or milrinone and at least another group receiving
the above inodilators or placebo, performed in cardiac surgical patients. The endpoint was
to identify differences in mortality at longest follow-up available.
Results. The 46 included trials were published between 1995 and 2014 and randomised 2647
patients. The Bayesian network meta-analysis found that only the use of levosimendan was
associated with a decrease in mortality when compared with placebo (posterior mean of
OR0.48, 95% CrI 0.28 to 0.80). The posterior distribution of the probability for each
inodilator to be the best and the worst drug showed that levosimendan is the best agent to
improve survival after cardiac surgery. The sensitivity analyses performed did not produce
different interpretative result.
Conclusion. Levosimendan seems to be the most efficacious inodilator to improve survival
in cardiac surgery.
Keywords: anaesthesia - meta-analysis; anaesthetics i.v.; cardiovascular anaesthesia; surgery
cardiovascular
Accepted for publication: 10 September 2014
Cardiac surgery is frequently complicated by low cardiac

output syndrome (LCOS); cardiogenic shock is associated
with significant morbidity and mortality.
The combination of cardiac inotropy, peripheral vasodilation and decreased after load, gained inodilators the role of
first line drugs in cardiogenic shock.1 This family encompasses
older drugs like dobutamine, the phosphodiesterase 3 (PDE-3)
inhibitors (enoximone and milrinone) and the new calcium
sensitizer levosimendan. There is no doubt that inodilators
can effectively improve haemodynamic parameters1 but
they are associated with side effects2 and some observational
trials found a significant association between inotropes
administration and increased mortality in cardiac surgery.3 5
Even if inodilators are often used in cardiac surgery and
more than 1 million cardiac surgery procedures are performed
worldwide every year, no large multicentre randomised trial
exists to document differences in mortality when using different inodilators in cardiac surgery. Most randomised controlled
trials performed on inodilators in cardiac surgery are small

and, even if mortality data is often reported, it is difficult to determine which is the best agent in terms of survival. Furthermore, most published trials compare levosimendan vs
placebo and milrinone vs placebo while it would be desirable
to have direct comparison between inodilators. Preliminary
evidence derived from meta-analyses of randomised trials,
suggests that levosimendan reduces mortality in cardiac
surgery but data are not updated, are not focused on inodilators and no attempt to grade the different inodilators was performed so far. The inclusion of indirect comparisons might in
fact add pieces of information in a setting with scarce direct
comparisons.
Our research question was to investigate which inodilator is
associated with the lowest mortality after cardiac surgery. To
achieve this aim we first identified and merged all randomised
trials ever published on any inodilator drug (levosimendan,
enoximone, milrinone and dobutamine) in adult cardiac
& The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
Downloaded from http://bja.oxfordjournals.org/ at Main Library of Gazi University on February 4, 2015
The authors examined the

effect of inodilator drugs
on survival of adults
following cardiac surgery.
Background. Inodilators are commonly used in critically ill patients, but their effect on survival
has not been properly studied to date. The objective of this work was to conduct a network
meta-analysis on the effects of inodilators on survival in adult cardiac surgery patients, and
to compare and rank drugs that have not been adequately compared in head-to-head trials.
BJA
surgery that reported mortality data. We therefore performed
a Bayesian network meta-analysis of randomised trials
to grade all the inodilators in order to allow physicians to optimize cost-effectiveness analyses in their centres. A network
meta-analysis is a statistical technique for comparison of different treatments that were never properly studied through
adequately powered randomised controlled trials, but that
can be compared through a third common comparator.6 7 On
the basis of statistical inference, it is possible to identify the
superior treatment, reaching, through indirect comparison, reliable conclusions otherwise hard or impossible to achieve.
Methods
Search strategy and study selection

Relevant studies were independently searched in BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Central
Register of clinical trials by two expert investigators.
Literature search, developed according to Biondi-Zoccai and
colleagues,8 were last updated in May 1, 2014 and included
the following PubMed research string: ((heart OR cardiac OR
myocard* OR coronary) AND (operatin* OR operation OR
surger*) AND (levosimendan OR simdax OR ((phosphodiesterase OR pde) AND inhibitor*) OR amrinone OR milrinone OR
enoximone OR toborinone OR dobutamine OR dobutrex))
AND (randomized controlled trial[pt] OR controlled clinical
trial[pt] OR randomized controlled trials[mh] OR random allocation[mh] OR double-blind method[mh] OR single-blind
method[mh] OR clinical trial[pt] OR clinical trials[mh] OR (clinical trial[tw] OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR
tripl*[tw]) AND (mask*[tw] OR blind[tw])) OR (latin square[tw])
OR placebos[mh] OR placebo*[tw] OR random*[tw] OR research
design[mh:noexp] OR comparative study[tw] OR follow-up
studies[mh] OR prospective studies[mh] OR cross-over studies[mh] OR control[tw] OR controls[tw] OR controlled[tw]
OR prospectiv*[tw] OR volunteer*[tw]) NOT (animal[mh]
NOT human[mh]) NOT (comment[pt] OR editorial[pt] OR
meta-analysis[pt] OR practice-guideline[pt] OR review[pt])).
Further hand or computerised searches involved recent
(2010 2014) international conference proceedings (Supplementary Appendix S1).
inclusion criteria were used for potentially relevant studies:

random allocation to treatment with at least one group receiving dobutamine, enoximone, levosimendan, or milrinone and
at least another group receiving dobutamine, enoximone,
levosimendan, milrinone or placebo (since patients undergoing cardiac surgery often require inotropic agents to survive,
it is often impossible to compare a drug to a placebo in this
context; most authors of the included trials treated their
patients with the best available standard treatment and then
added or not the study drug; as a consequence, placebo in
this meta-analysis was considered as placebo on top of standard treatment or as standard treatment alone). Studies had
to be performed in an adult cardiac surgery setting with no
restriction in dose and time of administration. The exclusion
criteria were duplicate publications (in this case the article
reporting the longest follow-up was abstracted), nonhuman
experimental studies, and lack of outcome (survival) data.
Two investigators independently assessed articles for inclusion
criteria and selected studies for the final analysis, with divergences finally resolved by consensus.
Data abstraction and study characteristics

Baseline, procedural and outcome data were independently
abstracted by two trained investigators, with divergences
resolved by consensus (Table 1). The following data were
extracted and collected in a spreadsheet file: author identification, year and journal of publication, study comparators, treatment sample sizes, type of surgery, longest follow-up and
mortality.
The endpoints of the present review was to identify differences in mortality at the longest follow-up available between each inodilator agent and to identify if one or more
were superior or inferior in terms of survival, using standard
meta-analyses and Bayesian network meta-analyses. When
a study had missing or incomplete data on survival we contacted all authors by e-mail, letter or both.
Internal validity and risk of bias assessment

The internal validity of each trial included in this review was
critically evaluated for bias according to The Cochrane Collaboration methods, i.e. judging the risk for selection, performance, attrition, detection and reporting biases. We evaluated
the potential source of bias by applying a rating of Yes, No
or Unclear to denote whether adequate measures were
taken to protect against each potential source of bias in each
study. The overall risk of bias was expressed as low, moderate
or high. Publication bias was assessed by visually inspecting
funnel plots.
Study selection
Statistical analysis
References obtained from database, literature searches with

cross-check of references and experts were first independently
examined on a title/abstract level by two investigators and
then, if potentially relevant, retrieved as complete articles.
No language restriction was enforced and non-English articles
were translated and included in the analyses. The following
For each trial, the proportion of deaths were analysed and

expressed as the logarithm of odds ratio (OR) and of its standard error (SE). Whenever possible we used results from
intention-to-treat population.
Each arm of the trials was classified according to its primary
treatment strategy. The primary treatment strategies of interest in
Page 2 of 11
To understand whether inodilators might influence patients

survival after adult cardiac surgery we carried out a Bayesian
network meta-analysis to compare the effect on mortality
of levosimendan, enoximone, milrinone and dobutamine.
A Bayesian network meta-analysis is a valid method of indirectly comparing drugs that did not undergo sufficient
head-to-head comparison in the original clinical trials.6 7
Greco et al.
BJA
Effect of inodilatory agents on mortality
Table 1 Description of the 46 studies included in the meta-analysis. CPB, cardiopulmonary bypass; OP, off-pump; CABG, coronary artery bypass
graft; ICU, intensive care unit; NA, not available. *Study published as abstract only
Year
Surgery
Contrast
Number of
patients
Longest follow-up
Abacilar AF9
2013
CABG
Levosimendan vs placebo on top of

standard treatment
100 vs 100
5 days
Al-Shawaf E10
2006
CABG
Levosimendan vs milrinone
14 vs 16
48 h
Alvarez J11
2005
CPB
Levosimendan vs dobutamine
15 vs 15
Hospital stay
Alvarez J12
2006
CABG, valve
25 vs 25
15 days
Arbeus M13
2009
CABG
Milrinone vs placebo on top of standard

treatment
22 vs 22
Hospital stay
Barisin S14
2004
OPCABG

standard treatment
21 vs 10
Hospital stay
Bautin A*15
2011
NA
Levosimendan vs standard treatment
33 vs 31
Hospital stay
Baysal A16
2014
Mitral valve surgery
67 vs 66
30 days
Carmona MJ17
2010
NA
Milrinone vs dobutamine
10 vs 10
2 years
Couture P18
2007
CABG

treatment
25 vs 25
Hospital stay
De Hert SG19
2007
CPB
Levosimendan vs milrinone
15 vs 15
38 days
Doolan LA20
1997
CPB

treatment
15 vs 15
30 days
Ensinger H21
1999
NA
Dobutamine vs placebo on top of

standard treatment
8 vs 8
3 days
Erb J22
2014
CABG, valve surgery

standard treatment
19 vs 18
6 months
Eriksson HI23
2009
CABG

standard treatment
30 vs 30
33 days
Ersoy O24
2013
Valve surgery
10 vs 10
24 h
Feneck RO25
2001
NA
Milrinone vs dobutamine
60 vs 60
3 days
Gandham R26
2013
Mitral valve repair or

replacement
30 vs 30
36 h
Hachenberg T27
1997
Mitral valve repair
Enoximone vs dobutamine
10 vs 10
72 h
Hadadzadeh M28
2013
OPCABG

treatment
40 vs 40
ICU stay
Hayashida N29
1999
CABG
Milrinone vs standard treatment
12 vs 12
72 h
Husedzinovic I30
2005
OPCABG

standard treatment
12 vs 13
60 min
Jarvela K31
2008
Aortic valve surgery and/or

CABG

standard treatment
12 vs 12
1 year
Jebeli M32
2010
CABG

treatment
35 vs 35
Hospital stay
Jo HR33
2010
OPCABG

treatment
20 vs 20
Hospital stay
Kodali RK34
2013
OPCABG

standard treatment
15 vs 15
24 h
Kwak YL35
2004
OPCABG

treatment
29 vs 33
Hospital stay
Lahtinen P36
2009
Valve or valve and CABG

standard treatment
103 vs 104
Hospital stay
Lee JH37
2006
OPCABG

treatment
24 vs 26
Hospital stay
Leppikangas H38
2011
Valve and CABG

standard treatment
12 vs 12
4 days
Levin R39
2008
NA
69 vs 68
Hospital stay
Levin R40
2012
CABG

standard treatment
127 vs 125
48 h
Continued
Page 3 of 11
First author
BJA
Greco et al.
Table 1 Continued
Year
Surgery
Contrast
Number of
patients
Longest follow-up
Lilleberg J41
1998
CABG

standard treatment
15 vs 8
1h
Modine T42
2005
OPCABG
Dobutamine vs standard treatment
16 vs 16
30 days
Mollhoff T43
1999
CABG

treatment
11 vs 11
Hospital stay
Nijhawan N44
1999
CPB

standard treatment
12 vs 6
8h
Parviainen I45
1995
CABG
Dobutamine vs standard treatment
11 vs 11
90 min
Ristikankare A46
2012
CABG

standard treatment
30 vs 30
Hospital stay
Shah B47
2014
OPCABG

standard treatment
25 vs 25
30 days
Sharma P48
2013
CABG, mitral valve surgery

standard treatment
20 vs 20
Hospital stay
Song JW49
2011
OPCABG

treatment
31 vs 31
Until the end of distal

anastomosis
Tritapepe L50
2006
CABG

standard treatment
12 vs 12
Hospital stay
Tritapepe L51
2009
CABG

standard treatment
53 vs 53
30 days
van der Maaten JM52
2007
Aortic valve replacement
Enoximone vs standard treatment
17 vs 17
18 h
this Bayesian network meta-analysis were 1) placebo, 2) levosimendan, 3) enoximone, 4) milrinone, 5) dobutamine. The pairwise
association between each treatment (also called direct estimate)
was delineated by a graphical representation of the network. In
the diagram each node represents a single anaesthetic agent
and each edge connects treatments that have been directly compared in one or more RCTs.
We performed pairwise meta-analyses to look at the direct
comparisons. In the standard meta-analyses, a magnitude
of heterogeneity between-studies was represented by the
degree of inconsistency (I 2), while uncertainty over whether
apparent heterogeneity due to the effects of chance (random
error) was expressed using p-value from Cochrane Q statistic.
The presence of effect-modifiers due heterogeneity was considered acceptable with one chi-square P-value .0.10. Mortality data from individual studies were analysed to compute
pooled OR with pertinent 95% confidence intervals (CI) by
means of the inverse of variance method with fixed effect
model in case of low statistical inconsistency (I 2 25%) or by
means of DerSimonian-Laird method with random effect
model (which better accommodates clinical and statistical variations) in case of moderate or high statistical inconsistency
(I 2 .25%). The number need to treat (NNT) was computed
for the significant associations. The robustness of the standard
meta-analysis was assessed by sequentially removing each
study from the overall dataset and reanalysing the remaining
datasets.
The Bayesian network analysis was carried out modeling the
outcome mortality with the Bayesian hierarchical model (binomial model with logit link function) using Markov chain Monte
Page 4 of 11
Carlo (MCMC) approach. Pooled ORs comparing different

inodilators were estimated from the mean of the posterior
distribution obtained with Bayesian analysis. The indirect
estimate was calculated by means of consistency equation
Log(OR)23 Log(OR)13-Log(OR)12, namely as difference from
the direct estimates having a common arm. The corresponding
95% credibility intervals (CrI) were obtained by the normal
approximation.
A credible interval is a probability interval or rather a probabilistic region around a posterior moment, and its use is
similar to a frequentist confidence interval. We carried out
the Bayesian networkmeta-analyses with both the fixed or
random effect model and we selected the better model in
terms of fit and parsimony, calculating the posterior mean of
residual deviance (Dres) and the Deviance Information Criterion
(DIC) statistics.
The consistency assumption, that means no discrepancy
between direct and indirect comparisons, was verified in the
Bayesian network analysis, by evaluating a probability .0.5 of
the difference of both the consistency and inconsistency residual
deviance. Furthermore, we compared the results obtained fitting
the consistency model, estimating only the effects between
each study treatment (levosimendan, enoximone, milrinone,
dobutamine) and the reference one (placebo) and deriving the
indirect treatment effects by consistency equation, and the inconsistency model, which provides the prior distribution for all
possible combinations of treatments.54 55
To explore the relation between log-risk of mortality and the
length of study follow-up (in days), we performed Bayesian
meta-regression analyses. Sensitivity Bayesian analysis was
First author
BJA
Results
Description of included trials
Figure 1 shows the flowchart for the selection of randomised
trials. The references of major exclusions are available after contacting the authors. Forty-six randomised clinical trials9 53 were
included in the final analysis (Table 1). The study characteristics
of included trials are detailed in Supplementary Appendix S3.
Briefly, the 46 trials randomised 2647 patients, including 1044

(39%) patients receiving placebo, 893 (34%) receiving levosimendan, 390 (15%) receiving milrinone, 273 (10%) receiving
dobutamine, and 47 (1.8%) receiving enoximone.
Nineteen (41%) of the randomised controlled trials were at
low risk of bias while 52 and 7% were at moderate and high risk
of bias respectively, lacking important details on the method
used to generate random sequence, on allocation or on the intention to treat analyses (Supplementary Table S1).The lack of
blinding was the main bias and the main reason of low quality
for the included trials.
Quantitative data synthesis

The network configuration in Figure 2 connects treatments
that have been directly compared in one or more RCTs and
shows that almost half of the studies compared levosimendan
vs placebo.
We also performed eight simple pairwise meta-analyses
comparing each agent against each other agent (Supplementary Figures S1 and S2). Only the use of levosimendan was associated with a reduction in mortality. The reduction in mortality
was present when levosimendan was compared with placebo
(35/725 [4.8%] in the levosimendan group vs 64/698 [9.2%]
in the placebo group, OR0.54, 95% CI 0.35 to 0.83, P for
effect0.005, P for heterogeneity0.9, I 2 0%, NNT23, with
20 studies included) and when compared with dobutamine
(8/139 [5.8%] in the levosimendan group vs 18/138 [13%]
in the dobutamine group, OR0.39, 95% CI 0.16 to 0.95, P for
1512 new abstracts retrieved
1389 titles/articles not eligible for inclusion

(not relevant to the study question)
123 abstracts eligible for inclusion and

detailed assessment
77 articles excluded because of prespecified criteria:

36 studies with no outcome data
12 studies with overlapping populations
8 observational studies
6 studies with not pharmacological comparator
6 studies with pediatric patients
5 retracted papers
4 abstract published before 2010
46 articles finally included in the

network meta-analysis
Fig 1 Flow diagram - description of selection process of included studies.
Page 5 of 11
carried out with a different vague prior distribution for the

between-trials variance (Univariate distribution replaced the
Inverse-Gamma distribution), with low risk of bias trials, with
studies not supported by a drug company and removing the
largest trial.
Due to zero-cell events in each comparisons that included
enoximone treatment (mortality data were reported but no
patient died in the studies including enoximone), we carried
out a sub Bayesian network meta-analysis combining enoximone and milrinone groups. Other methodological details for
the Statistical analyses and for the conduction of the Bayesian
network meta-analyses are reported in the Supplementary
Appendix S2.
Finally, we calculated the posterior distribution of the probability to be the first, the second, the third and the worst treatment and we show the correspondent cumulative rank curves.
The statistical analysis was performed by STATA (release 11,
College Station, TX) and winBUGS (release 1.4, freeware available by BUGS project).
BJA
Greco et al.
Placebo
OR
)
83
0.
5
.3 s
(0 die
4
5 tu
0. 0 s
R= 2
.0
udy
1 st
OR
=0.
Dobutamine
OR=0.39 (0.160.95)
4 studies
y
tud
1s
Enoximone
Milrinone
Fig 2 Network configuration - for each comparison is displayed the estimate effect and number of studies analysed.
effect0.039, P for heterogeneity0.6, I 2 0% NNT14, with

four studies included). For each pairwise comparison, the
overall funnel plot did not show an important asymmetrical
shape of estimate distribution (Supplementary Figure S3).The
superiority of levosimendan vs placebo was confirmed when
sequentially removing each study while the superiority of
levosimendan vs dobutamine was lost when removing one
large trial.39
The Bayesian network meta-analysis (Table 2) found that
only the use of levosimendan was associated with a decrease
in mortality. The survival benefit was limited to the comparison
with placebo (posterior mean of OR0.48, 95% CrI 0.28 to
0.80) with the model having a good fit (Dres 155.8 and
DIC183.7). The validity of consistency analysis were confirmed by a low probability in favour of inconsistency model
(probability0.01). The similarity between the effect estimated by both consistency and inconsistency model, was
shown in the Supplementary Figure S4.
Furthermore, the Bayesian meta-regressions of average
follow-up against log-risk of mortality showed no significant
time-related effects on mortality (regression coefficient0.005
CrI 20.001 to 0.011, days).
Table 3 show the results of sensitivity analyses: the beneficial effect of levosimendan vs placebo was confirmed changing
the prior distribution, with studies not supported by a drug
company and removing the largest study,40 however, analysing the 19 low risk of bias trials, this superiority was lost.
We also performed a second analysis combining the enoximone and milrinone groups (Dres 155.9 and DIC183.7) to
overcome the zero-cell count problem (Table 2) and confirmed
that levosimendan was better than placebo.
Table 4 reports the posterior distribution of the probability for
each inodilator to be the best and the worst drug, showing that
Page 6 of 11
levosimendan is the best agent to improve survival after cardiac

surgery. Figure 3 shows the cumulative rank curves of the probability to be the first, the second, the third and the worst treatment, confirming that levosimendan is the best treatment.
Discussion
The main finding of this study is that only treatment with levosimendan is associated with mortality reduction in cardiac
surgery. This Bayesian network meta-analysis suggested that
levosimendan is associated with the lowest risk of mortality
among the comparators included in the study: the inodilators
PDE-3 inhibitors enoximone and milrinone, the classic dobutamine and placebo. The superiority of levosimendan vs placebo
was confirmed both in the simple pairwise and in Bayesian
network meta-analysis while the superiority of levosimendan
vs dobutamine was present in the pairwise but not confirmed
in the network meta-analysis. These findings should be treated with caution because the statistical significance was lost
when sensitivity analyses including only low risk of bias study
were performed and because no multicentre randomised trial
to confirm these findings exists. Notably, the Bayesian metaanalysis failed to rank inodilators: with the notable exception
of levosimendan, the other studied drugs are either similar
one each other or not properly studied so far not allowing to
reach a statistically significant difference among them in mortality, even using indirect comparisons.
The real effects of inodilators on mortality in cardiac surgery
have been the white whale for many years. Our study summarises the data on mortality from all randomised trials on
inodilators in a single picture, including direct and indirect
comparisons. Levosimendan was superior to placebo and,
overall, it was the best agent to reduce perioperative mortality.
1 stu
dy
43
2 s (0.05
tud
ies 3.53)
15
)
.85
02
(0.4 es
i
07
=1. 2 stud
1
Levosimendan
0
(
stu 0.10
die 1
s 0.
OR
=1
BJA
Table 2 Posterior distribution of mean and 95% credible interval, for the inodilator difference effects, derived by Bayesian hierarchical model with
Markov Chain Monte Carlo algorithm. * Indirect treatment difference effect calculated from consistency equation. Significant treatment difference
effect
Contrast
Overall Bayesian network meta-analysis
Combining enoximone and milrinone

groups
OR
OR
Levosimendan vs placebo
0.48
Enoximone vs placebo
1.53
95% credible interval
95% credible interval
0.28 to 0.80
0.48
,0.01 to .100
1.12
0.39 to 3.25
0.28 to 0.80
Milrinone vs placebo
1.12
0.40 to 3.25
Dobutamine vs placebo
1.45
0.44 to 4.68
1.47
0.44 to 4.66
Enoximone vs levosimendan*
3.20
,0.01 to .100
2.32
0.71 to 7.62
Milrinone vs levosimendan*
2.35
0.73 to 7.59
3.06
0.85 to 10.98
3.03
0.83 to 11.04
0.73
,0.01 to .100
Dobutamine vs enoximone*
0.95
,0.01 to .100
1.32
0.27 to 6.41
Dobutamine vs milrinone*
1.29
0.27 to 6.25
Table 3 Sensitivity analyses. Posterior distribution of mean and 95% credible interval, for the inodilator difference effects, derived by Bayesian
hierarchical model with Markov Chain Monte Carlo algorithm. * Indirect treatment difference effect calculated from consistency equation.
Significant treatment difference effect

Contrast
Levosimendan vs placebo
Enoximone vs placebo
Inverse-Gamma as prior
distribution (46 trials)
Low risk of bias trials

(19 trials)
Studies not supported by a

drug company
(40 studies)
Removing the largest trial

(45 trials)
OR
95% credible
interval
OR
OR
OR
0.48
0.28 to 0.81
.100 ,0.01 to .100
95% credible
interval
95% credible
interval
0.32
0.01 to 4.49
0.36
0.18 to 0.71
1.06
,0.01 to .100
1.60
,0.001 to .100
0.54
,0.01
95% credible
interval
0.29 to 0.95
,0.01 to .100
Milrinone vs placebo
1.14
0.40 to 3.24
3.33
0.16 to .100
1.02
0.33 to 3.26
1.19
0.41 to 3.55
Dobutamine vs placebo
1.46
0.45 to 4.83
0.03
,0.01 to .100
1.12
0.27 to 4.22
1.65
0.46 to 5.47
3.34
,0.01 to .100
4.39
,0.001 to .100
Enoximone vs
levosimendan*
.100 ,0.01 to .100
,0.01
,0.01 to .100
Milrinone vs
levosimendan*
2.36
0.74 to 7.54
10.44
0.11 to .100
2.79
0.75 to 10.45
2.20
0.64 to 7.54
Dobutamine vs
levosimendan*
3.03
0.83 to 11.05
0.08
,0.01 to .100
3.06
0.67 to 13.96
3.04
0.79 to 11.74
Milrinone vs enoximone*
0.01 ,0.01 to .100
3.13
,0.01 to .100
0.64
,0.001 to .100
,0.01
,0.01 to .100
Dobutamine vs
enoximone*
0.01 ,0.01 to .100
0.03
,0.01 to .100
0.70
,0.001 to .100
,0.01
,0.01 to .100
Dobutamine vs milrinone*
1.29
0.01
,0.01 to .100
1.10
0.19 to 6.41
0.27 to 6.18
A meta-regression, performed to detect if differences in the

length of follow up weighted on results, showed no significant
effect of time on mortality. These findings confirm previous evidence from meta-analyses of randomised controlled studies
that showed a beneficial effect of levosimendan on survival
in the populations of cardiac surgery56 and critically ill patients.57
However, previous analyses lacked the indirect comparisons and
the ranking among different comparators and did not focus on
inodilators, therefore their results were less robust and useful
than the present results. Furthermore, they either included any
settings of critically ill patients57 or, when focusing on cardiac
surgery, were not as updated as the present analysis.56
1.39
0.27 to 7.08
We performed a Bayesian network meta-analysis to answer

an important clinical question: what is the effect of levosimendan, enoximone, milrinone and dobutamine on survival in
adult patients undergoing cardiac surgery? The Bayesian
network meta-analysis approach was deemed to be the most
appropriate because it can integrate direct and indirect effect
estimates and can compare drugs that did not undergo sufficient head-to-head comparison in the original clinical trials.
In this way, it was possible to identify levosimendan as the
best treatment according to published randomised evidence.
We focused on adult patients undergoing cardiac surgery
and receiving inodilator because this is a widespread and
Page 7 of 11
Dobutamine vs levosimendan*
Milrinone vs enoximone*
BJA
Greco et al.
Table 4 Posterior distribution of the probability to be the best and the worst for each inodilators drug, derived by Bayesian hierarchical model with
Markov Chain Monte Carlo algorithm
Drugs
Overall Bayesian network meta-analysis
Combining enoximone and milrinone groups
Probability to be the best
Probability to be the worst
Probability to be the best
Probability to be the worst
Levosimendan
0.5146
0.0001
0.9088
0.0002
Enoximone
0.4424
0.5421
0.0674
0.2874
Milrinone
0.0302
0.1370
Dobutamine
0.0114
0.2605
0.0028
0.1274
Placebo
0.0014
0.0603
0.0028
0.1274
Cumulative prob to be
the best
the second
Levosimendan
the third
Enoximone
Placebo
the fourth
Milrinone
the worst
Dobutamine
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
the best
Levosimendan
the second
Placebo
the third
the worst
Enoximone-Milrinone
Dobutamine
Fig 3 Cumulative rank curves - probability to be the first, the second, the third and the worst for each treatment.
relatively standardised setting and because inodilators are

the most frequently used and studied agents worldwide in
this setting.
While levosimendan has been demonstrated to be the safest
among inodilators, its main drawback resides in its high costs.
Treatment with levosimendan might increase patient cost per
recovery.58 However, higher drug expenses are balanced by its
beneficial effect on the length of hospital stay and on complications.59 While this is true for developed countries, treatment
Page 8 of 11
with levosimendan seems to be nonetheless expensive and

thus not always available in every country for economic reasons.
The probability to be the best or the worse inodilator, reported in Table 4, should not be underestimated, as it enables physicians worldwide to choose the best drug for their
patient, basing their decision on their local resources. Nonetheless, it should be remembered that our findings should be taken
cautiously because the statistical significance was lost when
sensitivity analyses including only low risk of bias study were
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BJA
performed. To confirm the findings of this study, a large multicentre factorial randomised controlled trial comparing levosimendan vs PDE-3 inhibitors, dobutamine and placebo should
be conducted. Alternatively, we should wait for the results of
the two large multicentre randomised trials should comparing
levosimendan vs placebo on top of the best available treatment that are running so far in Europe (NCT00994825) and in
the United States (NCT02025621).
Limitations
Conclusions
This manuscript is the most updated and methodologically
strongest meta-analysis on the effect of inodilators on mortality in cardiac surgery. Using Bayesian network meta-analyses
techniques, we attempted ranking among different inodilators
that have never properly been compared one each other, and
identified levosimendan to be the best inodilator to improve
survival in adult cardiac surgery. Since meta-analyses are hypothesis generating and our findings were not confirmed
when limiting the analysis to low risk of bias studies, these
results should be confirmed by large multicentre RCTs.
Supplementary material
Supplementary material is available at British Journal of
Anaesthesia online.
Authors contributions
T.G.: definition of intellectual content, Literature search, Data
acquisition, Data analysis, Statistical analysis, Manuscript
preparation, Manuscript editing. M.G.C.: literature search,
Data acquisition, Manuscript review. R.D.C.: literature search,
Data acquisition, Manuscript editing. M.G.: design, Literature
Page 9 of 11
The major weakness of indirect meta-analysis is that confounding can be a major bias. That is, the risk status of one
study cohort may be markedly different of another. Furthermore, several RCTs included in our meta-analysis were of suboptimal quality. Nonetheless, our conclusions are based on
41% of studies of high quality and all the sub-analyses performed confirmed that levosimendan treatment improves
survival when compared with placebo. Notably, thirty-six
further studies were excluded because they lacked data on
mortality outcome and authors did not answer to our request
to provide these data. This limited the power of the analysis
and the precision of results. At the same time, we focused on
mortality, the most clinically relevant outcome and the one
less subject to interpretation, we used several databases to
identify the pertinent studies and we focused on randomised
trials only. The comparisons included different numbers of
trials depending on study drugs, while trials differed by
number of included patients, surgical settings and mortality
risk of their populations. Some studies only included patients
with low cardiac output syndrome after cardiac surgery,
without other specifications. A large part of included studies
did not report on funding, thus making more difficult to draw
conclusion on the possible influence of drug companies on
the results of the original papers. Data from trials on enoximone had zero-cell counts and we had to repeat a second analysis combining PDE-3 inhibitors. Dose and length of drugs
administration were heterogeneous and not reported in our
tables, nonetheless they corresponded to local routine practice. At the same time, since inotropic drugs are often considered to be lifesaving in cardiac surgery most trials had
placebo on top of standard treatment as comparator and not
placebo only. Bayesian network meta-analysis incorporates
both direct and indirect comparisons between treatments.
However indirect evidence is susceptible to confounding,6
and thus should be interpreted with caution since it does not
always agree with the corresponding direct estimates.7 Since
the indirect estimate derives results from the direct effects
of two treatments vs a third common comparator, it can confound the overall results because it not always agrees with
the corresponding direct estimates. This bias results in a
greater pooled estimate variability.7 Like heterogeneity in traditional random-effects models of meta-analysis, the comparison between the consistency and the inconsistency model is
used to quantify variation among estimates and is incorporated into the estimate of the confidence interval.60 The discrepancy between consistency and inconsistency estimates
could be used to evaluate the convergence between direct

and indirect comparisons.61 Although the consistency hypothesis was not rejected in this Bayesian network meta-analyses,
additional methodological and empirical work needs to be
done to evaluate the direct and indirect comparisons across
a number of types of interventions. Bayesian network metaanalyses assume that patients enrolled in the individual
studies could have been sampled from the same theoretical
population, and that similar comparators between different
trials have a consistent risk-benefit ratio. Furthermore, traditional limitations of meta-analyses62 due to variations in
the treatment regimens, in populations or major subgroups
within trials, and in the conduction of the trials also apply to
this Bayesian network meta-analysis.
After reading our study, physicians might consider choosing
levosimendan when needing to use an inodilator in cardiac
surgery. This drug is the most frequently studied and the only
one with a documented effect on mortality reduction in this
setting when compared with placebo. At the same time, the
other inodilators have never been properly compared with
placebo or in head to head comparisons to other inodilators.
In particular, enoximone was compared only once against
placebo and once against dobutamine in spite of being extensively used in several countries. Moreover, even using Bayesian
network techniques it is not possible to reach definite conclusions on their effects on mortality and on their ranking when
compared with other inodilators. Since most evidence comes
from small single centre studies and levosimendan is still an expensive drug, there is still need to wait for the results of large
multicentre RCTs that will have to confirm the benefit of levosimendan on survival and on clinically relevant outcomes in
cardiac surgery.
BJA
search, Data analysis, Statistical analysis, Manuscript review.
L.P.: definition of intellectual content, Data acquisition, Manuscript preparation. A.D.: concepts, Design, Definition of intellectual content, Manuscript preparation, Manuscript review. G.L.:
concepts, Design, Definition of intellectual content, Data
analysis, Manuscript preparation, Manuscript review, Guarantor. A.Z.: concepts, Design, Definition of intellectual content,
Manuscript editing, Manuscript review.
Acknowledgements
Greco et al.
14
15
16
We thank P. Zuppelli for the data entry and A. Carpanese and

D. Winterton for the careful revision of the manuscript.
17
Declaration of interest
References
1 Gillies M, Bellomo R, Doolan L, Buxton B. Bench-to-bedside review:
Inotropic drug therapy after adult cardiac surgery -- a systematic
literature review. Crit Care 2005; 9: 266 79
2 Fellahi JL, Fischer MO, Daccache G, Gerard JL, Hanouz JL. Positive
inotropic agents in myocardial ischemia-reperfusion injury: a
benefit/risk analysis. Anesthesiology 2013; 118: 14605
3 Fellahi JL, Parienti JJ, Hanouz JL, Plaud B, Riou B, Ouattara A. Perioperative use of dobutamine in cardiac surgery and adverse
cardiac outcome: propensity-adjusted analyses. Anesthesiology
2008; 108: 979 87
4 Shahin J, DeVarennes B, Tse CW, Amarica DA, Dial S. The relationship
between inotrope exposure, six-hour postoperative physiological
variables, hospital mortality and renal dysfunction in patients
undergoing cardiac surgery. Crit Care 2011; 15: R162
5 Nielsen DV, Hansen MK, Johnsen SP, Hansen M, Hindsholm K,
Jakobsen CJ. Health Outcomes with and without Use of Inotropic
Therapy in Cardiac Surgery: Results of a Propensity Score-matched
Analysis. Anesthesiology 2014; 120: 1098108
6 Baker SG, Kramer BS. The transitive fallacy for randomized trials: if A
bests B and B bests C in separate trials, is A better than C? BMC Med
Res Methodol 2002; 2: 13
7 Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003; 326: 472
8 Biondi-Zoccai GG, Agostoni P, Abbate A, Testa L, Burzotta F. A simple
hint to improve Robinson and Dickersins highly sensitive PubMed
search strategy for controlled clinical trials. Int J Epidemiol 2005;
34: 2245
9 Abacilar AF, Dogan OF. Levosimendan use decreases atrial fibrillation in patients after coronary artery bypass grafting: a pilot
study. Heart Surg Forum 2013; 16: E287 94
10 Al-Shawaf E, Ayed A, Vislocky I, Radomir B, Dehrab N, Tarazi R. Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery.
J Cardiothorac Vasc Anesth 2006; 20: 353 7
11 Alvarez J, Taboada M, Rodrguez J, et al. Hemodynamic effects
of levosimendan following cardiac surgery. Rev Esp Anestesiol
Reanim 2005; 52: 389 94
12 Alvarez J, Bouzada M, Fernandez AL, et al. Hemodynamic effects of
levosimendan compared with dobutamine in patients with low
cardiac output after cardiac surgery. Rev Esp Cardiol 2006; 59: 33845
13 Arbeus M, Axelsson B, Friberg O, Magnuson A, Bodin L, Hultman J.
Milrinone increases flow in coronary artery bypass grafts after
Page 10 of 11
18
19
20
21
22
23
24
25
26
27
28
29
30
Landoni G received modest speaker fees from Orion.
cardiopulmonary bypass: a prospective, randomized, double-blind,

placebo-controlled study. J Cardiothorac Vasc Anesth 2009; 23: 4853
Barisin S, Husedzinovic I, Sonicki Z, Bradic N, Barisin A, Tonkovic D.
Levosimendan in off-pump coronary artery bypass: a four-times
masked controlled study. J Cardiovasc Pharmacol 2004; 44: 703 8
Bautin A. Efficacy of levosimendan pretreatment in high risk
cardiac surgery patients. Interact Cardiovasc Thorac Surg 2011
Abstract C4-2 available at http://icvts.oxfordjournals.org/content/
12/Supplement_1/iv.full (accessed 17 December 2014)
Baysal A, Yanartas M, Dogukan M, Gundogus N, Kocak T, Koksal C.
Levosimendan Improves Renal Outcome in Cardiac Surgery: A
Randomized Trial. J Cardiothorac Vasc Anesth 2014; 28:
586 94
Carmona MJ, Martins LM, Vane MF, Longo BA, Paredes LS,
Malbouisson LM. Comparison of the effects of dobutamine and milrinone on hemodynamic parameters and oxygen supply in patients
undergoing cardiac surgery with low cardiac output after anesthetic induction. Rev Bras Anestesiol 2010; 60: 23746
Couture P, Denault AY, Pellerin M, Tardif JC. Milrinone enhances systolic, but not diastolic function during coronary artery bypass grafting surgery. Can J Anaesth 2007; 54: 50922
De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ. The
effects of levosimendan in cardiac surgery patients with poor left
ventricular function. Anesth Analg 2007; 104: 766 73
Doolan LA, Jones EF, Kalman J, Buxton BF, Tonkin AM. A placebocontrolled trial verifying the efficacy of milrinone in weaning highrisk patients from cardiopulmonary bypass. J Cardiothorac Vasc
Anesth 1997; 11: 3741
Ensinger H, Rantala A, Vogt J, Georgieff M, Takala J. Effect of
dobutamine on splanchnic carbohydrate metabolism and amino
acid balance after cardiac surgery. Anesthesiology 1999; 91: 158795
Erb J, Beutlhauser T, Feldheiser A, et al. Influence of levosimendan
on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery. J Int Med Res 2014;
42: 750 64
Eriksson HI, Jalonen JR, Heikkinen LO, et al. Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular
function. Ann Thorac Surg 2009; 87: 44854
Ersoy O, Boysan E, Unal EU, et al. Effectiveness of prophylactic levosimendan in high-risk valve surgery patients. Cardiovasc J Afr 2013;
24: 260 4
Feneck RO, Sherry KM, Withington PS, Oduro-Dominah A. European
Milrinone Multicentre Trial Group. Comparison of the hemodynamic
effects of milrinone with dobutamine in patients after cardiac
surgery. J Cardiothorac Vasc Anesth 2001; 15: 306 15
Gandham R, Syamasundar A, Ravulapalli H, et al. A comparison of
hemodynamic effects of levosimendan and dobutamine in
patients undergoing mitral valve repair/replacement for severe
mitral stenosis. Ann Card Anaesth 2013; 16: 11 5
Hachenberg T, Mollhoff T, Holst D, Hammel D, Brussel T. Cardiopulmonary effects of enoximone or dobutamine and nitroglycerin on
mitral valve regurgitation and pulmonary venous hypertension.
Hadadzadeh M, Hosseini SH, Mostafavi Pour Manshadi SM, et al.
Effect of milrinone on short term outcome of patients with myocardial dysfunction undergoing off-pump coronary artery bypass graft:
a randomized clinical trial. Acta Med Iran 2013; 51: 6816
Hayashida N, Kawara T, Tomoeda H, et al. Influence of milrinone on
internal mammary artery grafts. Kyobu Geka 1999; 52: 9937
Husedzinovic I, Barisin S, Bradic N, Barisin A, Sonicki Z, Milanovic R.
Levosimendan as a new strategy during off-pump coronary artery
BJA
31
32
33
34
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
intramucosal pH after cardiac surgery. Br J Anaesth 1995; 74:

277 82
Ristikankare A, Poyhia R, Eriksson H, Valtonen M, Leino K, Salmenpera M.
Effects of levosimendan on renal function in patients undergoing coronary artery surgery. J Cardiothorac Vasc Anesth 2012; 26: 5915
Shah B, Sharma P, Brahmbhatt A, et al. Studyof levosimendanduring offpumpcoronaryartery bypass grafting in patients with LV dysfunction: a
double-blind randomized study. Indian J Pharmacol 2014; 46: 2934
Sharma P, Malhotra A, Gandhi S, Garg P, Bishnoi A, Gandhi H. Preoperative levosimendan in ischemic mitral valve repair. Asian Cardiovasc Thorac Ann 2013; 0: 17
Shi Y, Denault AY, Couture P, Butnaru A, Carrier M, Tardif JC. Biventricular diastolic filling patterns after coronary artery bypass graft
surgery. J Thorac Cardiovasc Surg 2006; 131: 1080 6
Song JW, Jo YY, Jun NH, Kim HK, Kwak YL. The effect of milrinone on the
intraoperative hemodynamics during off-pump coronary bypass
surgery in patients with an elevated echocardiographic index of the
ventricular filling pressure. Korean J Anesthesiol 2011; 60: 18591
Tritapepe L, De Santis V, Vitale D, et al. Preconditioning effects of
levosimendan in coronary artery bypass grafting--a pilot study. Br
J Anaesth 2006; 96: 694 700
Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pretreatment improves outcomes in patients undergoing coronary
artery bypass graft surgery. Br J Anaesth 2009; 102: 198204
van der Maaten JM, de Vries AJ, Rietman GW, Gallandat Huet RC,
De Hert SG. Effects of preemptive enoximone on left ventricular
diastolic function after valve replacement for aortic stenosis.
Greco T, Landoni G, Biondi-Zoccai G, DAscenzo F, Zangrillo A. A
Bayesian network meta-analysis for binary outcome: how to do it.
Stat Methods Med Res Advance Access published on 28 October,
2013
Greco T, Landoni G, Saleh O, Zangrillo A. Case study in anesthesia
and intensive care. In: Biondi-Zoccai G, ed. Network Meta-Analysis:
Evidence Synthesis with Mixed Treatment Comparison. Hauppauge,
NY: Nova Science Publishers, 2014; 26381
Landoni G, Mizzi A, Biondi-Zoccai G, et al. Reducing mortality in
cardiac surgery with levosimendan: a meta-analysis of randomized
controlled trials. J Cardiothorac Vasc Anesth 2010; 24: 517
Landoni G, Biondi-Zoccai G, Greco M, et al. Effects of levosimendan
on mortality and hospitalization. A meta-analysis of randomized
controlled studies. Crit Care Med 2012; 40: 634 46
Cleland JGF, Takala A, Apajasalo M, Zethraeus N, Kobelt G. Intravenous levosimendan treatment is cost-effective compared with
dobutamine in severe low-output heart failure: an analysis based
on the international LIDO trial. Eur J Heart Fail 2003; 5: 101 8
De Lissovoy G, Fraeman K, Teerlink JR, et al. Hospital costs for treatment of acute heart failure: economic analysis of the REVIVE II
study. Eur J Health Econ 2010; 11: 18593
Biondi-Zoccai G, Lotrionte M, Landoni G, Modena MG. The rough
guide to systematic reviews and meta-analyses. HSR Proc Intensive
Care Cardiovasc Anesth 2011; 3: 16173
Biondi-Zoccai G, Landoni G, Modena MG. A journey into clinical evidence: from case reports to mixed treatment comparisons. HSR
Proc Intensive Care Cardiovasc Anesth 2011; 3: 936
Greco T, Zangrillo A, Biondi-ZoccaI G, Landoni G. Meta-analysis: pitfalls and hints. Heart, Lung and Vessels 2013; 5: 219 22
Handling editor: J. G. Hardman
Page 11 of 11
35
bypass grafting: double-blind randomized placebo-controlled trial.

Croat Med J 2005; 46: 950 6
Jarvela K, Maaranen P, Sisto T, Ruokonen E. Levosimendan in aortic
valve surgery: cardiac performance and recovery. J Cardiothorac
Vasc Anesth 2008; 22: 693 8
Jebeli M, Ghazinoor M, Mandegar MH, et al. Effect of milrinone on
short-term outcome of patients with myocardial dysfunction
undergoing coronary artery bypass graft: A randomized controlled
trial. Cardiol J 2010; 17: 73 8
Jo HR, Lee WK, Kim YH, et al. The effect of milrinone infusion on right
ventricular function during coronary anastomosis and early outcomes in patients undergoing off-pump coronary artery bypass
surgery. Korean J Anesthesiol 2010; 59: 92 8
Kodalli RK, Sundar AS, Vakamudi M, et al. Effect of levosimendan on
hemodynamic changes in patients undergoing off-pump coronary
artery bypass grafting: a randomized controlled study. Ann Card
Anaesth 2013; 16: 94 9
Kwak YL, Oh YJ, Shinn HK, Yoo KJ, Kim SH, Hong YW. Haemodynamic
effects of a milrinone infusion without a bolus in patients undergoing off-pump coronary artery bypass graft surgery. Anaesthesia
2004; 59: 32431
Lahtinen P, Pitkanen O, Polonen P, Turpeinen A, Kiviniemi V,
Uusaro A. Levosimendan reduces heart failure after cardiac
surgery: a prospective, randomized, placebo-controlled trial. Crit
Care Med 2011; 39: 2263 70
Lee JH, Oh YJ, Shim YH, Hong YW, Yi G, Kwak YL. The effect of milrinone on the right ventricular function in patients with reduced right
ventricular function undergoing off-pump coronary artery bypass
graft surgery. J Korean Med Sci 2006; 21: 854 8
Leppikangas H, Jarvela K, Sisto T, et al. Preoperative levosimendan
infusion in combined aortic valve and coronary bypass surgery. Br
J Anaesth 2011; 106: 298 304
Levin RL, Degrange MA, Porcile R, et al. The calcium sensitiser
levosimendan gives superior results to dobutamine in postoperative
low cardiac output syndrome. Rev Esp Cardiol 2008; 61: 4719
Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative
levosimendan decreases mortality and the development of low
cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol 2012; 17: 125 30
Lilleberg J, Nieminen MS, Akkila J, et al. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow
and myocardial substrate utilization early after coronary artery
bypass grafting. Eur Heart J 1998; 19: 6608
Modine T, Decoene C, Al-Ruzzeh S, et al. Dobutamine improves thoracic aortic blood flow during off-pump coronary artery bypass
surgery: results of a prospective randomised controlled trial. Eur J
Cardiothorac Surg 2005; 27: 289 95
Mollhoff T, Loick HM, Van Aken H, et al. Milrinone modulates endotoxemia, systemic inflammation, and subsequent acute phase response
after cardiopulmonary bypass (CPB). Anesthesiology 1999; 90: 7280
Nijhawan N, Nicolosi AC, Montgomery MW, Aggarwal A, Pagel PS,
Warltier DC. Levosimendan enhances cardiac performance after
cardiopulmonary bypass: a prospective, randomized placebocontrolled trial. J Cardiovasc Pharmacol 1999; 34: 219 28
Parviainen I, Ruokonen E, Takala J. Dobutamine-induced dissociation between changes in splanchnic blood flow and gastric

Network Met Analysis

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Network Met Analysis

Загружено:

Авторское право:

Доступные форматы

BJA Advance Access published February 4, 2015

British Journal of Anaesthesia Page 1 of 11

A Bayesian network meta-analysis on the effect of inodilatory

* Corresponding author. E-mail: landoni.giovanni@hsr.it

Editors key points

They used a network

Methods. Relevant studies were independently searched in BioMedCentral, MEDLINE/PubMed,

Cardiac surgery is frequently complicated by low cardiac

trials performed on inodilators in cardiac surgery are small

Downloaded from http://bja.oxfordjournals.org/ at Main Library of Gazi University on February 4, 2015

The authors examined the

Search strategy and study selection

inclusion criteria were used for potentially relevant studies:

Data abstraction and study characteristics

Internal validity and risk of bias assessment

References obtained from database, literature searches with

For each trial, the proportion of deaths were analysed and

Downloaded from http://bja.oxfordjournals.org/ at Main Library of Gazi University on February 4, 2015

To understand whether inodilators might influence patients

Effect of inodilatory agents on mortality

Levosimendan vs placebo on top of

Milrinone vs placebo on top of standard

Levosimendan vs placebo on top of

Levosimendan vs standard treatment

Mitral valve surgery

Levosimendan vs standard treatment

Milrinone vs placebo on top of standard

Milrinone vs placebo on top of standard

Dobutamine vs placebo on top of

CABG, valve surgery

Levosimendan vs placebo on top of

Levosimendan vs placebo on top of

Levosimendan vs standard treatment

Mitral valve repair or

Mitral valve repair

Milrinone vs placebo on top of standard

Milrinone vs standard treatment

Levosimendan vs placebo on top of

Aortic valve surgery and/or

Levosimendan vs placebo on top of

Milrinone vs placebo on top of standard

Milrinone vs placebo on top of standard

Levosimendan vs placebo on top of

Milrinone vs placebo on top of standard

Valve or valve and CABG

Levosimendan vs placebo on top of

Milrinone vs placebo on top of standard

Valve and CABG

Levosimendan vs placebo on top of

Levosimendan vs placebo on top of

Downloaded from http://bja.oxfordjournals.org/ at Main Library of Gazi University on February 4, 2015

Levosimendan vs placebo on top of

Dobutamine vs standard treatment

Milrinone vs placebo on top of standard

Levosimendan vs placebo on top of

Dobutamine vs standard treatment

Levosimendan vs placebo on top of

Levosimendan vs placebo on top of

CABG, mitral valve surgery

Levosimendan vs placebo on top of

Milrinone vs placebo on top of standard

Until the end of distal

Levosimendan vs placebo on top of

Levosimendan vs placebo on top of