The Effect of Inotropes and Vasopressors On Mortality

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The Effect of Inotropes and Vasopressors on

Mortality
A Meta-analysis of Randomized Clinical Trials
A. Belletti; M. L. Castro; S. Silvetti1, T. Greco; G. Biondi-Zoccai; L. Pasin; A. Zangrillo; G. Landoni1
Br J Anaesth. 2015;115(5):656-675.
Abstract and Introduction

Abstract
Background: Inotropes and vasopressors are frequently administered to critically ill patients in
order to improve haemodynamic function and restore adequate organ perfusion. However,
some studies have suggested a possible association between inotrope administration and
increased mortality. We therefore performed a meta-analysis of randomized trials published in
the last 20 yr to investigate the effect of these drugs on mortality.
Methods: BioMedCentral, PubMed, Embase and the Cochrane Central Register were searched
(all updated April 8th, 2015). Inclusion criteria were: random allocation to treatment, at least one
group receiving an inotropic or vasopressor drug compared with at least one group receiving a
non-inotropic/vasopressor treatment, study published after 1st January 1994, and systemic drug
administration. Exclusion criteria were overlapping populations, studies published as abstract
only, crossover studies, paediatric studies and lack of data on mortality.
Results: A total of 28 280 patients from 177 trials were included. Overall, pooled estimates
showed no difference in mortality between the group receiving inotropes/vasopressors and the
control group [4255/14 036 (31.7%) vs 4277/14 244 (31.8%), risk ratio=0.98 (0.961.01), P for
effect=0.23, P for heterogeneity=0.30, I 2=6%]. A reduction in mortality was associated with
inotrope/vasopressor therapy use in settings of vasoplegic syndromes, sepsis and cardiac
surgery. Levosimendan was the only drug associated with improvement in survival. Subgroup
analysis did not identify any groups with increased mortality associated with
inotrope/vasopressor therapy.
Conclusions: Our systematic review found that inotrope/vasopressor therapy is not associated
with differences in mortality in the overall population and in the majority of subsettings.
Introduction
Inotropes and vasopressors are frequently used in critically ill patients to correct haemodynamic
derangements and provide adequate organ perfusion.[1,2] Although these medications effectively
improve cardiac performance and haemodynamic parameters, they could also have important
side-effects such as arrhythmias, increased myocardial oxygen consumption, myocardial
ischaemia, and metabolic alterations.[3] Most of the routinely used inotropic and vasopressor
agents exert their haemodynamic effect through enhancement of the adrenergic pathway.
[2,3]
Unfortunately, there is growing evidence that excessive adrenergic stimulation is detrimental
during critical illness.[4,5]
In fact, there is evidence from both randomized[68] and observational trials,[9,10] and also meta-
analyses,[11] done in the heart failure setting, that despite improvements in haemodynamic
function, inotropic agents might reduce survival. Moreover, some recent observational trials also
suggest a possible harmful effect in cardiac surgery.[12,13]
However, given the fact that treatment with inotropes/vasopressors is generally reserved in
extremis for the most severely ill patients, association with increased mortality could be
coincidental, particularly in non-randomized trials.[14] Several clinical trials in a wide range of
clinical settings have been performed with controversial results; nevertheless, few large
randomized studies exist. We therefore performed a meta-analysis of randomized clinical trials
(RCT) evaluating inotrope/vasopressor therapy in adults to elucidate the effect of these drugs
on survival.
Methods
Search Strategy
We developed a search strategy aimed to include any RCT performed in adults with at least one
group treated with an inotropic or vasopressor drug in any clinical setting (Search strategy for
PubMed provided as Supplementary data
Appendix http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1). Pertinent studies were
independently searched (all searches updated January 31st, 2014) in PubMed, BioMedCentral,
Embase, and the Cochrane Central Register of clinical trials, by two trained investigators. In
addition, references of retrieved articles and pertinent reviews were scanned to identify further
studies
Study Selection
References were first independently examined at a title/abstract level by two investigators, with
divergences resolved by consensus, and then, if potentially pertinent, retrieved as complete
articles. Inclusion criteria were: random allocation to treatment, at least one group receiving an
inotropic or vasopressor drug compared with at least one group receiving a non-
inotropic/vasopressor treatment (including placebo or best available treatment), study published
after 1st January 1994, and systemic drug administration. We decided to include in our study
only drugs that are routinely administered and are available in USA or in Europe (). Definition of
a drug as an inotrope or a vasopressor is described in Supplementary data Table
S1 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1. The exclusion criteria were:
overlapping populations (in this case we referred to the first article published while retrieved
data from the article with the longest follow-up available), studies published as abstract only,
crossover studies, paediatric populations, and lack of data on mortality. No language restriction
was applied. Two investigators independently assessed compliance to selection criteria and
selected studies for the final analysis, with divergences resolved by consensus.
Table 1. List of studied drugs together with the number of comparisons performed using
each drug (total number of papers=175; total number of trials=177; total number of
comparisons=189)
Drug Number of studies

Catecholamines 58
Dobutamine 15
Dopamine 23
Dopexamine 16
Ephedrine 2
Epinephrine 6
Isoproterenol 1
Norepinephrine 0
Phenylephrine 2
Phosphodiesterase-3 inhibitors 32
Amrinone 5
Enoximone 10
Milrinone 18
Vasopressin and analogues 25
Terlipressin 13
Vasopressin 12
Others 64
Digoxin 10
Levosimendan 48
Methylene blue 6
Data Abstraction and Analysis
Data regarding number of patients, treatment type, clinical setting, follow-up and mortality were
independently abstracted by four trained investigators. Corresponding authors of retrieved
articles reporting no data on mortality were contacted by email to obtain missing data. The
primary endpoint of the present study was mortality at the longest follow-up available.
Computations were performed with RevMan (Review Manager version 5.2, The Nordic
Cochrane Center, The Cochrane Collaboration, Copenaghen, 2012) and Stata (Stata Statistical
Software: release 13, StataCorp LP, College Station, Texas). Hypothesis of statistical
heterogeneity was tested by means of Cochran Q test, with statistical significance set at the
two-tailed 0.10 level, whereas extent of statistical consistency was measured with I 2, defined as
100% X (Q-df)/Q, where Q is Cochran's heterogeneity statistic and df the degrees of freedom.
As the test has low power in a meta-analysis in which studies have small sample size or are few
in number, we set statistical significance for hypothesis of heterogeneity at a P value of 0.10.
Data on mortality were extrapolated to compute the individual and pooled risk ratio (RR) with
pertinent 95% confidence interval (CI), by means of Mantel-Haenszel method and with a fixed-
effect model in case of low statistical inconsistency (I 225%), or with random-effect model
(which better accommodates clinical and statistical variations) in case of moderate or high
statistical inconsistency (I 2>25%). Egger's linear regression test and Begg's adjusted-rank
correlation test were performed to assess the presence of publication bias. Quality of included
trials was assessed according to the Cochrane Handbook for Systematic Reviews of
Interventions.
In addition to the principal analysis considering all the studies that fulfilled inclusion criteria, we
also performed secondary analyses to investigate specific clinical settings and the effect of the
different drugs (definitions of medical conditions used for subgroup analysis are presented in
Supplementary data Table S2 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1).
Moreover, we investigated the effect of the study drugs at different follow-up. For studies
investigating more than two comparators (e.g. dobutamine vs levosimendan vs placebo), the
different groups were either aggregated as a single group or analysed separately, depending on
the specific analysis performed.
Additional sensitivity analyses performed included studies randomizing more than 100 patients,
studies judged to carry a low risk of bias, studies with prophylactic vs therapeutic drug
administration, and studies with placebo as comparator. We sequentially removed each study
and re-analysed the remaining dataset (producing a new analysis for each study removed). We
also sequentially removed simultaneously all the studies performed in a specific setting, and
repeated the analysis simultaneously removing all the studies performed with a specific agent.
In addition, we computed both the pooled odds ratio (OR) and risk difference (RD) to assess the
effect of the analysis method on our result. Finally we carried out a metaregression model to
assess the effect of duration of treatment, mortality in the control group and age on the global
estimate.
Statistical significance was set at the two-tailed 0.05 level for hypothesis testing of effect, and
0.10 for hypothesis testing of heterogeneity. P values unadjusted for multiplicity are reported
throughout.
The present systematic review was conducted in keeping with Preferred Reporting Items for
Systematic Reviews and Meta-analysis.[15,16]
Results
Database searches and snowballing yielded a total of 16 237 titles. Excluding 15 530
nonpertinent titles or abstracts, 707 papers were retrieved in complete form and assessed
according to selection criteria (Fig. 1).
Figure 1.
Flow diagram for the selection of studies.
Excluded papers are available in the Supplementary data

Appendix http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1, together with the reason for
exclusion (Supplementary data Table
S3 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1). The most common reasons for
exclusion were: no outcome data even after contacting the corresponding authors (260 studies),
inotropic/vasopressors comparator (103 studies), studies published before 1st January 1994 (31
studies), overlapping populations (30 studies), and paediatric population (20 studies); additional
reasons for exclusion are presented in Fig. 1. A total of 532 articles were excluded; therefore,
175 papers, describing 177 trials, were included in the final analyses (, Supplementary data
Table S4 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1).
Table 2. Details of the 177 included trials, listed in alphabetic order of first author. ICU,
Intensive Care Unit *data provided by the corresponding author
Pati
Co Con
First ents Longes Inotropes/ Inotropes/
ntr trols
author ' t Study Control vasopress vasopress
Setting ols mor
(Study mea follow- drugs treatment ors ors
pati talit
acronim) n up patients mortality
ents y
age
Cardia
Levosi
Abacillar c 60. Hospit
mend Placebo 100 100 0 0
17
surger 6 al stay
an
y
Liver
cirrhosi
50. Hospit Terlipr
Abid18 s Octreotide 163 161 9 7
3 al stay essin
compli
cations
Cardiol Dobut
ogy 4 amine,
Adamop
Acute 70 month levosi Placebo 46 23 7 4
oulos *19
heart s mend
failure an
Cardia
c 64. Hospit Dopex Placebo,
Adluri20 14 28 0 0
surger 5 al stay amine fenoldopam
y
Cardiol
Altenber
ogy Levosi
ger 69. 24
Chroni mend Placebo 63 57 1 4
(LevoRe 5 weeks
c heart an
p)21
failure
Amar22 Major 57. 30 Digoxi Diltiazem 35 35 5 1
non- 5 days n
cardiac
surger
y
Cardia
c 62. Hospit Milrino
Arbeus23 Placebo 22 22 1 0
surger 5 al stay ne
y
Dat
Cardia a
Levosi
c not Hospit
Asaad24 mend Placebo 10 10 0 0
surger rep al stay
an
y orte
d
Cardia
Bach, c ICU Dopex
65 Placebo 17 16 0 1
199925 surger stay amine
y
Cardia
Placebo,
Bach, c Dopex
63 18 h epidural 13 27 0 1
200226 surger amine
anesthesia
y
Cardiol
Dobut
ogy
61. amine,
Bader27 Chroni 5 days Placebo 89 47 2 0
5 enoxi
c heart
mone
failure
Cardia
c 63. ICU Amrin
Badner28 Placebo 16 14 0 0
surger 9 stay one
y
Major
non-
cardiac
surger
Baldwin2 y 66. Dopa
5 days Placebo 18 19 2 0
9
9 mine
Vascul
ar
surger
y
Barisin30 Cardia 60. Hospit Levosi Placebo 21 10 0 0
c 9 al stay mend
surger an
y
Cardia
Levosi
c 57. 30 Standard
Baysal 31
mend 64 64 4 10
surger 5 days treatment
an
y
Intensi
Bellomo ve 3
62. Hospit Dopa
Placebo 163 165 71 68
2
Care 0 al stay mine
Unit
Cardia
Berende c 61. Hospit Dopex
Placebo 30 14 0 0
s33
surger 5 al stay amine
y
Cardiol
ogy Levosi
Berger 55. Prostaglan
Chroni 1 yr mend 39 36 6 7
*34 6 din E1
c heart an
failure
Major
non-
cardiac
surger
Biancofi 48. Hospit Dopa Placebo,
y 48 92 1 2
ore35
7 al stay mine fenoldopam
Liver
transpl
antatio
n
1238
Cardiol
month
ogy Levosi
26. s
Biteker36 Acute mend Placebo 12 12 3 3
6 (mean
heart an
=20.9
failure
(9)
Cardia
c 68. Hospit Dopa Fenoldopa
Bove37 40 40 3 4
surger 5 al stay mine m
y
Brackbill Cardia 63. 30 Milrino Nesiritide 20 20 0 0
38
c 9 days ne
surger
y
Cardia
Levosi
Bragado c 67. ICU
ttir39 surger 4 stay
an
y
Intensi
Brienza ve 4
68.
4 days
Dopa Fenoldopa
50 50 1 0
0
Care 8 mine m
Unit
Cardiol
Nesiritide
Burger ogy
14 Dobut (two
(PRECE Acute 61 86 169 2 4
days amine different
DENT)41 heart
doses)
failure
Cardia
Callawa 65. Hospit Vasop
c Placebo 167 158 162 154
y42
5 al stay ressin
arrest
Cardia
Carcoan c 63. Hospit Dopa Placebo,
25 50 0 0
a43 surger 8 al stay mine mannitol
y
Cardiol
Chen ogy
4 Acute
180 Dopa Placebo,
(ROSE) 70 122 238 16 34
days mine nesiritide
4
heart
failure
Shock
47. 30 Vasop Standard
Cohn45 38 40 13 11
Traum 2 days ressin treatment
a
Cardiol
ogy
71. Dopa Furosemid
Cotter46 Chroni 72 h 14 6 1 0
5 mine e
c heart
failure
Cardia
Couture c 4
68. Hospit Milrino
Placebo 25 25 2 0
7
surger 5 al stay ne
y
Cardiol
ogy
66. Enoxi
Cowley48 Chroni 1 yr Placebo 75 76 27 18
6 mone
c heart
failure
Cardiol
Cuffe
ogy
(OPTIM 60 Milrino
Acute 66 Placebo 479 472 49 41
E- days ne
heart
CHF)49
failure
Major
non-
cardiac
surger
y Hospit Dopex
Davies50 73 Placebo 60 64 3 3
Haemo al stay amine
dynami
c
optimiz
ation
Major
non-
cardiac
surger
de 60. Hospit Dopa
y Placebo 13 17 0 1
Lasson51 1 al stay mine
Vascul
ar
surger
y
Placebo,
combinatio
Anaph
ns of
de ylaxis 36. Epine
96 h promethazi 123 505 0 7
Silva52 preven 5 phrine
ne and
tion
hydrocortis
one
Cardia
c 63. Hospit Dopex
Dehne53 Placebo 24 24 0 0
y
Della Major 50. Hospit Dopa Fenoldopa 21 22 3 2
non-
cardiac
surger
y
Rocca54 5 al stay mine m
Liver
transpl
antatio
n
Major
non-
cardiac
surger Sodium
66. Hospit Amrin
Dentz55 y Nitroprussi 10 10 1 0
6 al stay one
Vascul de
ar
surger
y
Major
non-
86. Hospit Ephed
Di Roio56 cardiac Placebo 10 10 0 0
5 al stay rine
surger
y
Digitalis
Cardiol 2858
Investig
ogy month
ation 63. Digoxi 340 119
Chroni s Placebo 3397 1181
Group 4 n 3 4
c heart (mean
(DIG
failure =37)
Trial)57
Cardia
c 30 Milrino
Doolan58 66 Placebo 15 15 0 0
surger days ne
y
Standard
Cardia treatment,
Hospit Vasop
Ducros59 c 56 nitroglyceri 14 30 14 28
al stay ressin
arrest n+vasopres
sin
Shock
ICU Vasop Standard
Dnser60 68 24 24 17 17
Vasodil stay ressin treatment
atory
Ephed
Cardia
rine,
El- c 37. 30
phenyl Placebo 120 30 2 1
Tahan61 surger 2 days
ephrin
y
e
Cardia
Ensinge c ICU Dobut
59 Placebo 8 8 0 0
r62 surger stay amine
y
Cardia
6 Levosi
c 66.
Erb J63 month mend Placebo 19 18 4 5
surger 5
s an
y
Cardia
Levosi
Eriksson c 31
64 mend Placebo 30 30 0 2
I64 surger days
an
y
Cardia
Levosi
c 47. Hospit
Ersoy65 mend Placebo 10 10 0 0
surger 6 al stay
an
y
Liver
Escorsel cirrhosi
55. 6 Terlipr Sclerothera
l s 105 114 26 19
5 weeks essin py
(TEST)66 compli
cations
Cardiol
Feldma
ogy
n 26 Enoxi
Chroni 63 Placebo 101 100 38 31
(EMOTE weeks mone
c heart
)67
failure
Liver
cirrhosi
6 Terlipr Somatostat
Feu68 s 57 80 81 13 13
weeks essin in
compli
cations
Flevari69 Cardiol 66. 3 Levosi Placebo 30 15 3 1
ogy 7 month mend
Acute s an
heart
failure
Cardia Dopa
Grdeb
c 62. Hospit mine, Standard
ck, 23 12 0 0
surger 3 al stay dopex treatment
199570
y amine
Cardia
Grdeb
c 64. 30 Dopex
ck, Placebo 10 8 1 0
surger 7 days amine
1995b71
y
Cardiol
ogy
Coron 61. Hospit Dopa
Gare M72 Placebo 34 34 0 1
ary 4 al stay mine
angiog
raphy
Cardiol
Giamou
ogy
zis 75. 60 Dopa Furosemid
Acute 30 30 3 3
(DAD- 7 days mine e
heart
HF) 73
failure
Cardia
Gueugni 61. Vasop Standard 145 142
c 1 yr 1442 1424
aud74 5 ressin treatment 2 2
arrest
Cardia
Hadadz c 62. ICU Milrino
Placebo 40 40 1 1
adeh 75
surger 4 stay ne
y
Cardia Amrin
Operat
Hamada c 64.
ing
one, Standard
20 10 0 0
76
surger 9 milrino treatment
room
y ne
Cardia
c
surger
y 55. Hospit Vasop
Hasija77 Placebo 15 32 0 0
Vasopl 3 al stay ressin
egic
syndro
me
Cardia
Hayashi c Milrino
63 72 h Placebo 12 12 0 0
da78 surger ne
y
Major
non-
cardiac
surger
53. 10 Terlipr Standard
Hong79 y 21 20 0 0
1 days essin treatment
Liver
transpl
antatio
n
Cardiol
ogy
Digoxi Amiodaron
Hou80 Atrial 70 24 h 24 26 0 1
n e
fibrillati
on
Cardiol
Huseby ogy 6 Levosi
e Acute 64 month mend Placebo 30 31 1 4
(LEAF) heart
81
s an
failure
Cardia
Levosi
Husedzi c 60. Hospit
novi*82 surger 9 al stay
an
y
Cardiol
ogy 18 Levosi
Ikonomi
Acute 63 month mend Placebo 21 21 0 0
dis*83
heart s an
failure
Cardiol
ogy
59. Digoxi Verapamil
Innes84 Atrial 24 h 22 19 0 0
8 n + quinidine
fibrillati
on
Cardia
64. Hospit Epine
Jacobs85 c Placebo 272 262 261 257
6 al stay phrine
arrest
Cardia 6 Isopro
Standard
Jaffe86 c 67 month tereno 37 42 36 40
treatment
arrest s l
Cardia
Levosi
c
Jrvel 87
68 1 yr mend Placebo 12 12 3 1
surger
an
y
Cardia
Jebeli88 Placebo 35 35 0 2
surger 5 al stay ne
y
Cardiol
ogy 6 Levosi
Jia, 63.
Acute month mend Placebo 80 80 14 18
201489 1
heart s an
failure
Cardiol
ogy 3 Levosi
Jia, 68. Placebo,
Acute month mend 30 60 6 12
201590 6 Nesiritide
heart s an
failure
Cardia
Jo91 Placebo 20 20 0 0
surger 5 al stay ne
y
Cardiol
ogy
Jondeau Chroni 64 28 Enoxi
Placebo 12 12 2 3
92
days mone
c heart
failure
Cardiol
ogy
62. Digoxi Amiodaron
Joseph93 Atrial 48 h 36 79 0 0
9 n e, sotalol
fibrillati
on
Khand94 Cardiol 68. 6 Digoxi Carvedilol 23 24 1 2
ogy 5 month n
Chroni s
c heart
failure
Atrial
fibrillati
on
Methyl
57. 28
Kirov 95
Sepsis ene Placebo 10 10 5 7
3 days
blue
Cardiol
ogy Levosi
60. 12
Kleber*96 Chroni mend Placebo 18 10 0 1
6 weeks
c heart an
failure
Cardia
c
surger
Levosi
Knezevi y Standard
51 1 yr mend 47 47 5 7
c97 Heart treatment
an
transpl
antatio
n
Cardia
Levosi
c 54. ICU
Kodalli 98
surger 2 stay
an
y
Major
non-
cardiac
surger Methyl
Koelzow y 47. 30
ene Placebo 20 18 5 3
99
5 days
Liver blue
transpl
antatio
n
Cardiol
ogy Levosi
64. Standard
Kurt100 Acute 5 days mend 31 29 1 4
1 treatment
heart an
failure
Kwak*101 Cardia 60. Hospit Milrino Placebo 29 33 0 0
c 9 al stay ne
surger
y
Cardia
c
surger 6 Levosi
Lahtinen
y 69 month mend Placebo 99 101 12 12
P102
Acute s an
heart
failure
Cardia
Lassnig c 63. Hospit Dopa Placebo,
42 84 0 5
g103 surger 6 al stay mine furosemide
y
Liver
cirrhosi
52. 2 Vasop Somatostat
Lee104 s 23 20 3 1
8 weeks ressin in
compli
cations
Cardia
Lee*105 Placebo 24 26 0 0
surger 5 al stay ne
y
Cardia
Leppika Levosi
c 75. Hospit
ngas, mend Placebo 12 12 1 0
surger 5 al stay
2011106 an
y
Major
non-
cardiac
Leppika surger Levosi
67.
ngas*, y 5 yr mend Placebo 10 10 4 4
5
2008 107
Vascul an
ar
surger
y
Levin108 Cardia 59. 96 h Methyl Placebo 28 28 0 6
c 9 ene
surger blue
y
Vasopl
egic
syndro
me
Cardia
c 65. Hospit Amrin
Lewis109 Placebo 115 114 3 2
surger 6 al stay one
y
Cardiol
ogy Levosi
Lilleberg 14
Chroni 55 mend Placebo 11 11 0 0
*110 days
c heart an
failure
Cardiol
ogy 6 Levosi
Llorens11 79.
1
2
heart s an
failure
Major
non-
cardiac
surger
y 68. 60 Dobut Standard
Lobo112 25 25 2 7
Haemo 7 days amine treatment
dynami
c
optimiz
ation
Cardiol
ogy
59. 12 Enoxi
Lowes113 Chroni Placebo 70 35 2 4
6 weeks mone
c heart
failure
Shock
Luckner 1
68. ICU Vasop Standard
10 8 8 7
14
Vasodil 9 stay ressin treatment
atory
54. Vasop
Malay115 Sepsis 24 h Placebo 5 5 0 2
5 ressin
Malfatto1 Cardiol 70 1 yr Levosi Furosemid 22 11 4 4
16
ogy mend e
Chroni an
c heart
failure
Liver
Martn-
cirrhosi 3
Llah Terlipr Standard
s 57 month 23 23 17 19
(TAHRS essin treatment
compli s
)117
cations
Cardia
c
surger
Operat Methyl
Maslow y
1
69.
ing ene Placebo 15 15 0 0
18
Vasopl 1
room blue
egic
syndro
me
Cardiol
ogy 6 Levosi
Mavrog 61. Standard
Chroni month mend 25 25 2 8
eni*119 5 treatment
c heart s an
failure
Major
non-
cardiac
surger
McGinle Dopex
y 74 48 h Placebo 12 12 1 1
y120 amine
Vascul
ar
surger
y
Methyl
Memis 52. 28
D121 4 days
blue
1234
Cardiol
month
Metra ogy
s Enoxi
(ESSEN Chroni 62 Placebo 454 450 101 111
(media mone
TIAL-I)122 c heart
n=16
failure
6)
Metra Cardiol 62 1234 Enoxi Placebo 472 478 95 92
(ESSEN ogy month mone
s
Chroni
TIAL- (media
c heart
II)122 n=16
failure
6)
Cardia
Modine* c 61. 1 Dobut
Placebo 16 16 0 0
123
surger 2 month amine
y
Cardiol
Moiseye
ogy Levosi
v VS 67. 180
Acute mend Placebo 402 102 91 32
(RUSSL 2 days
heart an
AN)* 124
failure
Cardia
Mllhoff, c 60. Hospit Milrino
Nifedipine 15 14 1 1
1999125 surger 5 al stay ne
y
Cardia
Mllhoff, c 64. Milrino
1 yr Placebo 11 11 0 0
2002126 surger 4 ne
y
Cardia
c
surger
Morales y
1
60. ICU Vasop
Placebo 17 16 0 1
27
Vasopl 7 stay ressin
egic
syndro
me
Liver
cirrhosi 3
Moreau1 s 54. Terlipr
month Albumin 11 13 2 1
28
3 essin
compli s
cations
Morelli Sepsis 66. ICU Terlipr Standard 40 20 26 14
(DOBU 3 stay essin, treatment
PRESS) dobut
129
amine
+
terlipr
essin
Major
non-
cardiac
surger
Mukhtar1 y 49. Hospit Terlipr
Placebo 15 15 0 0
30
8 al stay essin
Liver
transpl
antatio
n
Cardiol
ogy
Chroni
Nagai c heart
71. Digoxi
(J- failure 2h Landiolol 115 99 0 1
6 n
Land)131 Atrial
fibrillati
on/flutt
er
Cardiol
ogy
62. Dobut
Nanas132 Chroni 2 yr Placebo 16 14 13 13
6 amine
c heart
failure
Cardiol Dobut
Niemine ogy amine,
63. 29 Placebo,
n*, Chroni levosi 115 35 2 0
1 days vehicle
2000133 c heart mend
failure an
Niemine Cardiol
n ogy 210 + Levosi
63.
(PERSI Chroni 14 mend Placebo 205 102 23 6
3
ST), c heart days an
2008134 failure
Cardia
Levosi
Nijhawa c 65.
8h mend Placebo 12 6 0 0
n135 surger 7
an
y
Okamot Cardia 70 30 Vasop Placebo 49 47 0 0
o136 c days ressin
surger
y
Vasopl
egic
syndro
me
Cardiol
ogy 6
Oliva 65. Dobut Standard
Chroni month 19 19 5 3
(DICE)137 5 amine treatment
c heart s
failure
Major
Standard
non-
64. 30 Amrin treatment,
Orii138 cardiac 15 30 0 0
9 days one prostagland
surger
in E1
y
Cardia
O- c Hospit Dobut Standard
63 40 40 0 0
Yurvati surger
139
al stay amine treatment
y
Cardia
c
surger
Methyl
y 65. Hospit Standard
zal140 ene 50 50 0 2
Vasopl 2 al stay treatment
blue
egic
syndro
me
Cardiol
Packer ogy Levosi
58. 90
(REVIV Acute mend Placebo 51 49 4 5
5 days
E-I)141 heart an
failure
Cardiol
Packer ogy Levosi
63. 90
5 days
E-II)141 heart an
failure
Papado Cardia 61 4 days Vasop Placebo 25 25 0 3
poulos142 c ressin
surger
y
Vasopl
egic
syndro
me
Cardiol
ogy Levosi
Parissis Hospit
Acute 65 mend Placebo 42 21 0 0
*143 al stay
heart an
failure
Hepato
biliary Dopa Standard
Parks144 58 5 days 13 10 0 0
surger mine treatment
y
Cardia
Parviain c 52. Hospit Dobut
Placebo 11 11 0 0
en145 surger 5 al stay amine
y
Cardiol
ogy 15 Levosi
Pasqui*1 Acute month mend Placebo 35 32 5 5
46
heart s an
failure
Anaph
Premaw ylaxis 36. Epine
ardhena preven 6 96 h Placebo 56 49 0 0
147 phrine
tion
Intensi
Raplh ve 60. Hospit Dopex Standard
52 50 29 27
CJ148 care 9 al stay amine treatment
unit
Reyad149 Major 41. Hospit Dobut Placebo 40 20 0 2
non- 5 al stay amine
cardiac
surger
y
Haemo
dynami
c
optimiz
ation
Cardia
Levosi
Ristikan c Hospit
kare150 surger al stay
an
y
Major
non-
Epine
cardiac
phrine
surger
54. Hospit ,
Ryu151 y Placebo 64 32 3 1
7 al stay phenyl
Liver
ephrin
transpl
e
antatio
n
Cardia
Santarpi c 62. Hospit Enoxi Methylpred
20 20 0 0
no152 surger 5 al stay mone nisolone
y
Liver
cirrhosi
51. 180 Terlipr
Sanyal153 s Placebo 56 56 32 35
7 days essin
compli
cations
Dopa
Schmoe 54. 28 mine,
Sepsis Placebo 43 21 9 7
lz154 9 days dopex
amine
Liver
cirrhosi Octreotide,
53. 42 Terlipr
Seo 155
s somatostati 345 689 34 59
3 days essin
compli n
cations
Cardia
Levosi
c 63. 30
Shah 156
surger 5 days
an
y
Sharma1 Cardia 54. 30 Levosi Placebo 20 20 1 3
57
c 2 days mend
surger an
y
Cardia Dopa
Sharpe 15
c 60. ICU mine,
Placebo 20 10 0 0
8
surger 4 stay dopex
y amine
Cardia
c Hospit Dopex
Sherry159 54 Placebo 11 9 0 0
surger al stay amine
y
Cardia
6
c 68. Milrino
Shi160 month Placebo 25 24 1 1
surger 9 ne
s
y
Liver
cirrhosi 13
Terlipr
Singh 161
s 47 month Albumin 21 22 0 0
essin
compli s
cations
ICU
Siostrzo Acute ICU Milrino Standard
62 10 10 2 7
nek162 heart stay ne treatment
failure
Cardiol
ogy Levosi
Slawsky Acute 56. 30 mend Placebo 98 48 3 3
163
7 days
heart an
failure
Liver
cirrhosi
Solanki16 51. 15 Terlipr
s Placebo 12 12 7 12
4
5 days essin
compli
cations
Cardia
Song165 Placebo 31 31 1 1
surger 4 al stay ne
y
Sorbello Kidney 53 108 Dopa Fenoldopa 20 20 0 0
*, transpl month mine m
2007 166
antatio s
n
Kidney
Sorbello 58 Standard
transpl 56. Dopa
*, month treatment, 40 80 3 5
antatio 4 mine
2010167 s fenoldopam
n
Dat
Cardia a
Squara16 c not Hospit Enoxi
Nicardipine 20 20 1 0
8
surger rep al stay mone
y orte
d
Cardiol
Prostaglan
ogy
Stanek 52. 1265 Dobut din E1,
Chroni 30 38 1 1
B169 7 days amine prostacycli
c heart
n
failure
Major
non-
cardiac
surger
y 69. Hospit Dopex
Stone170 Placebo 50 50 3 2
Haemo 5 al stay amine
dynami
c
optimiz
ation
Svobod 68. 90 Terlipr Standard
Sepsis 15 17 12 16
a171
Major
non-
cardiac
surger
y 62. Hospit Dopex
Takala172 Placebo 272 140 42 22
dynami
c
optimiz
ation
Taur173 Major 65. 30 Dobut Placebo 20 10 0 0
non- 3 days amine,
cardiac
dopa
surger
mine
y
Cardiol
ogy
Thomas 55. Hospit Digoxi Amiodaron
Atrial 43 97 0 0
*174 8 al stay n e, sotalol
fibrillati
on
Septic
shock
Levosi
Torraco17 68. 30 Standard
Vasopl mend 13 13 6 11
5
7 days treatment
egic an
syndro
me
Cardiol
ogy Levosi
67. 30
Trikas*176 Acute mend Placebo 17 17 2 6
2 days
heart an
failure
Cardiol
Triposki High-dose
ogy
adis 77. Dopa furosemide,
Acute 1 yr 56 105 19 37
(DAD- 7 mine standard
heart
HF II)177 treatment
failure
Cardia
Tritapep Levosi
c Hospit
e*, 68 mend Placebo 12 12 0 0
surger al stay
2006 178
an
y
Cardia
Tritapep Levosi
c 65. 30
e, mend Placebo 53 53 0 0
surger 2 days
2009179 an
y
Cardiol
ogy
63. 24 Digoxi Amiodaron
TseF180 Atrial 7 9 0 0
2 weeks n e
fibrillati
on
Tziakas* Cardiol 66 Hospit Levosi Placebo 30 30 0 0
181
ogy al stay mend
Acute
heart an
failure
Cardia
Standard
Visne c 56. ICU Dobut
treatment, 15 32 0 0
n182
surger 6 stay amine
ranitidine
y
Cardia
van der c 68. Hospit Enoxi
Maaten18 surger 5 Placebo 17 17 0 0
3 al stay mone
y
Cardiol
Van
ogy
Noord 1 Digoxi
Atrial 66 Verapamil 48 49 1 3
(VERDI month n
fibrillati
CT)184
on
Major
non-
cardiac
Epine
surger
phrine
y Hospit Standard
Wilson185 71 , 92 46 3 8
Haemo al stay treatment
dopex
dynami
amine
c
optimiz
ation
Cardia
c 65. Hospit Dopa
Woo186 Placebo 25 25 2 0
surger 5 al stay mine
y
Cardia
Woodho 68. Hospit Epine
c Placebo 94 100 94 100
use187
4 al stay phrine
arrest
Cardia
Yamaur c 61. Hospit Milrino
Placebo 10 10 0 0
a188 surger 5 al stay ne
y
Yavuz, Cardia 56 Hospit Dopa Standard 15 30 0 0
2002a189 c al stay mine treatment,
surger diltiazem
y
Cardia
Yavuz, c 59. Hospit Dopa Standard
11 11 0 0
2002b190 surger 3 al stay mine treatment
y
Cardiol
ogy 3 Levosi
Zemljic19 53. Standard
1
5 treatment
c heart s an
failure
Study Characteristics
The 177 included trials randomized 28 280 patients (14 036 to treatment and 14 244 to control).
The studies analysed 15 different drugs, with levosimendan being the most frequently studied
agent [48/177 trials (27.1%)], followed by dopamine [23/177 (13%)], and milrinone [18/177
(10.2%)]. Twelve studies investigated more than two inotropic/vasopressor comparators (e.g.
levosimendan vs dobutamine vs placebo) ( and ).
Table 1. List of studied drugs together with the number of comparisons performed using
each drug (total number of papers=175; total number of trials=177; total number of
comparisons=189)
Drug Number of studies

Catecholamines 58
Dobutamine 15
Dopamine 23
Dopexamine 16
Ephedrine 2
Epinephrine 6
Isoproterenol 1
Norepinephrine 0
Phenylephrine 2
Phosphodiesterase-3 inhibitors 32
Amrinone 5
Enoximone 10
Milrinone 18
Vasopressin and analogues 25
Terlipressin 13
Vasopressin 12
Others 64
Digoxin 10
Levosimendan 48
Methylene blue 6
Table 2. Details of the 177 included trials, listed in alphabetic order of first author. ICU,
Intensive Care Unit *data provided by the corresponding author
Pati
Co Con
First ents Longes Inotropes/ Inotropes/
ntr trols
author ' t Study Control vasopress vasopress
Setting ols mor
(Study mea follow- drugs treatment ors ors
pati talit
acronim) n up patients mortality
ents y
age
Cardia
Levosi
Abacillar c 60. Hospit
17
surger 6 al stay
an
y
Liver
cirrhosi
50. Hospit Terlipr
Abid18 s Octreotide 163 161 9 7
3 al stay essin
compli
cations
Cardiol Dobut
ogy 4 amine,
Adamop
Acute 70 month levosi Placebo 46 23 7 4
oulos *19
heart s mend
failure an
Cardia
c 64. Hospit Dopex Placebo,
Adluri20 14 28 0 0
surger 5 al stay amine fenoldopam
y
Altenber Cardiol 69. 24 Levosi Placebo 63 57 1 4
ger ogy 5 weeks mend
(LevoRe Chroni an
p)21 c heart
failure
Major
non-
57. 30 Digoxi
Amar22 cardiac Diltiazem 35 35 5 1
5 days n
surger
y
Cardia
Arbeus23 Placebo 22 22 1 0
surger 5 al stay ne
y
Dat
Cardia a
Levosi
c not Hospit
Asaad24 mend Placebo 10 10 0 0
surger rep al stay
an
y orte
d
Cardia
Bach, c ICU Dopex
65 Placebo 17 16 0 1
199925 surger stay amine
y
Cardia
Placebo,
Bach, c Dopex
63 18 h epidural 13 27 0 1
200226 surger amine
anesthesia
y
Cardiol
Dobut
ogy
61. amine,
Bader27 Chroni 5 days Placebo 89 47 2 0
5 enoxi
c heart
mone
failure
Cardia
c 63. ICU Amrin
Badner28 Placebo 16 14 0 0
surger 9 stay one
y
Baldwin2 Major 66. 5 days Dopa Placebo 18 19 2 0
9
non- 9 mine
cardiac
surger
y
Vascul
ar
surger
y
Cardia
Levosi
c 60. Hospit
Barisin30 mend Placebo 21 10 0 0
surger 9 al stay
an
y
Cardia
Levosi
c 57. 30 Standard
Baysal31 mend 64 64 4 10
surger 5 days treatment
an
y
Intensi
Bellomo ve 3 62. Hospit Dopa
Placebo 163 165 71 68
2
Care 0 al stay mine
Unit
Cardia
Berende c 61. Hospit Dopex
Placebo 30 14 0 0
s33
y
Cardiol
ogy Levosi
Berger 55. Prostaglan
Chroni 1 yr mend 39 36 6 7
*34 6 din E1
c heart an
failure
Major
non-
cardiac
surger
Biancofi 48. Hospit Dopa Placebo,
y 48 92 1 2
ore35
7 al stay mine fenoldopam
Liver
transpl
antatio
n
1238
Cardiol
month
ogy Levosi
26. s
Biteker36 Acute mend Placebo 12 12 3 3
6 (mean
heart an
=20.9
failure
(9)
Bove37 Cardia 68. Hospit Dopa Fenoldopa 40 40 3 4
c 5 al stay mine m
surger
y
Cardia
Brackbill c 63. 30 Milrino
Nesiritide 20 20 0 0
38
surger 9 days ne
y
Cardia
Levosi
Bragado c 67. ICU
ttir39 surger 4 stay
an
y
Intensi
Brienza ve 4 68.
4 days
Dopa Fenoldopa
50 50 1 0
0
Care 8 mine m
Unit
Cardiol
Nesiritide
Burger ogy
14 Dobut (two
(PRECE Acute 61 86 169 2 4
days amine different
DENT)41 heart
doses)
failure
Cardia
Callawa 65. Hospit Vasop
c Placebo 167 158 162 154
y42
5 al stay ressin
arrest
Cardia
Carcoan c 63. Hospit Dopa Placebo,
25 50 0 0
a43 surger 8 al stay mine mannitol
y
Cardiol
Chen ogy
180 Dopa Placebo,
(ROSE) Acute 70
4
days mine nesiritide
122 238 16 34
4
heart
failure
Shock
47. 30 Vasop Standard
Cohn45 38 40 13 11
Traum 2 days ressin treatment
a
Cotter46 Cardiol 71. 72 h Dopa Furosemid 14 6 1 0
ogy 5 mine e
Chroni
c heart
failure
Cardia
Couture c 4
68. Hospit Milrino
Placebo 25 25 2 0
7
surger 5 al stay ne
y
Cardiol
ogy
66. Enoxi
Cowley48 Chroni 1 yr Placebo 75 76 27 18
6 mone
c heart
failure
Cardiol
Cuffe
ogy
(OPTIM 60 Milrino
Acute 66 Placebo 479 472 49 41
E- days ne
heart
CHF)49
failure
Major
non-
cardiac
surger
y Hospit Dopex
Davies50 73 Placebo 60 64 3 3
Haemo al stay amine
dynami
c
optimiz
ation
Major
non-
cardiac
surger
de 60. Hospit Dopa
y Placebo 13 17 0 1
Lasson51 1 al stay mine
Vascul
ar
surger
y
Placebo,
combinatio
Anaph
ns of
de ylaxis 36. Epine
96 h promethazi 123 505 0 7
Silva52 preven 5 phrine
ne and
tion
hydrocortis
one
Cardia
c 63. Hospit Dopex
Dehne53 Placebo 24 24 0 0
y
Major
non-
cardiac
surger
Della 50. Hospit Dopa Fenoldopa
y 21 22 3 2
Rocca54 5 al stay mine m
Liver
transpl
antatio
n
Major
non-
cardiac
surger Sodium
66. Hospit Amrin
Dentz55 y Nitroprussi 10 10 1 0
6 al stay one
Vascul de
ar
surger
y
Major
non-
86. Hospit Ephed
Di Roio56 cardiac Placebo 10 10 0 0
5 al stay rine
surger
y
Digitalis
Cardiol 2858
Investig
ogy month
ation 63. Digoxi 340 119
Chroni s Placebo 3397 1181
Group 4 n 3 4
c heart (mean
(DIG
failure =37)
Trial)57
Cardia
c 30 Milrino
Doolan58 66 Placebo 15 15 0 0
surger days ne
y
Ducros59 Cardia 56 Hospit Vasop Standard 14 30 14 28
c al stay ressin treatment,
arrest nitroglyceri
n+vasopres
sin
Shock
ICU Vasop Standard
Dnser60 68 24 24 17 17
Vasodil stay ressin treatment
atory
Ephed
Cardia
rine,
El- c 37. 30
phenyl Placebo 120 30 2 1
Tahan61 surger 2 days
ephrin
y
e
Cardia
Ensinge c ICU Dobut
59 Placebo 8 8 0 0
r62 surger stay amine
y
Cardia
6 Levosi
c 66.
Erb J63 month mend Placebo 19 18 4 5
surger 5
s an
y
Cardia
Levosi
Eriksson c 31
I64 surger days
an
y
Cardia
Levosi
c 47. Hospit
Ersoy65 mend Placebo 10 10 0 0
surger 6 al stay
an
y
Liver
Escorsel cirrhosi
55. 6 Terlipr Sclerothera
l s 105 114 26 19
5 weeks essin py
(TEST)66 compli
cations
Cardiol
Feldma
ogy
n 26 Enoxi
(EMOTE weeks mone
c heart
)67
failure
Feu68 Liver 57 6 Terlipr Somatostat 80 81 13 13
cirrhosi weeks essin in
s
compli
cations
Cardiol
ogy 3 Levosi
66.
Flevari69 Acute month mend Placebo 30 15 3 1
7
heart s an
failure
Cardia Dopa
Grdeb
c 62. Hospit mine, Standard
ck, 23 12 0 0
surger 3 al stay dopex treatment
199570
y amine
Cardia
Grdeb
c 64. 30 Dopex
ck, Placebo 10 8 1 0
surger 7 days amine
1995b71
y
Cardiol
ogy
Coron 61. Hospit Dopa
Gare M72 Placebo 34 34 0 1
ary 4 al stay mine
angiog
raphy
Cardiol
Giamou
ogy
zis 75. 60 Dopa Furosemid
Acute 30 30 3 3
(DAD- 7 days mine e
heart
HF) 73
failure
Cardia
Gueugni 61. Vasop Standard 145 142
c 1 yr 1442 1424
aud74
5 ressin treatment 2 2
arrest
Cardia
Hadadz c 62. ICU Milrino
Placebo 40 40 1 1
adeh75 surger 4 stay ne
y
Cardia Amrin
Operat
Hamada c 64.
ing
one, Standard
20 10 0 0
76
surger 9 milrino treatment
room
y ne
Hasija77 Cardia 55. Hospit Vasop Placebo 15 32 0 0
c 3 al stay ressin
surger
y
Vasopl
egic
syndro
me
Cardia
Hayashi c Milrino
63 72 h Placebo 12 12 0 0
da78 surger ne
y
Major
non-
cardiac
surger
53. 10 Terlipr Standard
Hong79 y 21 20 0 0
Liver
transpl
antatio
n
Cardiol
ogy
Digoxi Amiodaron
Hou80 Atrial 70 24 h 24 26 0 1
n e
fibrillati
on
Cardiol
Huseby ogy 6 Levosi
e Acute 64 month mend Placebo 30 31 1 4
(LEAF)81 heart s an
failure
Cardia
Levosi
Husedzi c 60. Hospit
novi*82 surger 9 al stay
an
y
Cardiol
ogy 18 Levosi
Ikonomi
Acute 63 month mend Placebo 21 21 0 0
dis*83
heart s an
failure
Innes84 Cardiol 59. 24 h Digoxi Verapamil 22 19 0 0
ogy 8 n + quinidine
Atrial
fibrillati
on
Cardia
64. Hospit Epine
Jacobs 85
c Placebo 272 262 261 257
6 al stay phrine
arrest
Cardia 6 Isopro
Standard
Jaffe 86
c 67 month tereno 37 42 36 40
treatment
arrest s l
Cardia
Levosi
c
Jrvel 87
68 1 yr mend Placebo 12 12 3 1
surger
an
y
Cardia
Jebeli88 Placebo 35 35 0 2
surger 5 al stay ne
y
Cardiol
ogy 6 Levosi
Jia, 63.
201489 1
heart s an
failure
Cardiol
ogy 3 Levosi
Jia, 68. Placebo,
Acute month mend 30 60 6 12
201590 6 Nesiritide
heart s an
failure
Cardia
Jo91 Placebo 20 20 0 0
surger 5 al stay ne
y
Cardiol
ogy
Jondeau Chroni 64 28 Enoxi
Placebo 12 12 2 3
92
days mone
c heart
failure
Joseph93 Cardiol 62. 48 h Digoxi Amiodaron 36 79 0 0
ogy 9 n e, sotalol
Atrial
fibrillati
on
Cardiol
ogy
Chroni
6
c heart 68. Digoxi
Khand94 month Carvedilol 23 24 1 2
failure 5 n
s
Atrial
fibrillati
on
Methyl
57. 28
Kirov 95
3 days
blue
Cardiol
ogy Levosi
60. 12
Kleber*96 Chroni mend Placebo 18 10 0 1
6 weeks
c heart an
failure
Cardia
c
surger
Levosi
Knezevi y Standard
51 1 yr mend 47 47 5 7
c97 Heart treatment
an
transpl
antatio
n
Cardia
Levosi
c 54. ICU
Kodalli 98
surger 2 stay
an
y
Major
non-
cardiac
surger Methyl
Koelzow y 47. 30
ene Placebo 20 18 5 3
99
5 days
Liver blue
transpl
antatio
n
Kurt100 Cardiol 64. 5 days Levosi Standard 31 29 1 4
ogy
Acute mend
1 treatment
heart an
failure
Cardia
Kwak*101 Placebo 29 33 0 0
surger 9 al stay ne
y
Cardia
c
surger 6 Levosi
Lahtinen
y 69 month mend Placebo 99 101 12 12
P102
Acute s an
heart
failure
Cardia
Lassnig c 63. Hospit Dopa Placebo,
42 84 0 5
g103 surger 6 al stay mine furosemide
y
Liver
cirrhosi
52. 2 Vasop Somatostat
Lee104 s 23 20 3 1
8 weeks ressin in
compli
cations
Cardia
Lee*105 Placebo 24 26 0 0
surger 5 al stay ne
y
Cardia
Leppika Levosi
c 75. Hospit
ngas, mend Placebo 12 12 1 0
surger 5 al stay
2011106 an
y
Leppika Major 67. 5 yr Levosi Placebo 10 10 4 4
ngas*, non- 5 mend
2008 107
cardiac an
surger
y
Vascul
ar
surger
y
Cardia
c
surger
Methyl
y 59.
Levin 108
96 h ene Placebo 28 28 0 6
Vasopl 9
blue
egic
syndro
me
Cardia
c 65. Hospit Amrin
Lewis109 Placebo 115 114 3 2
surger 6 al stay one
y
Cardiol
ogy Levosi
Lilleberg 14
Chroni 55 mend Placebo 11 11 0 0
*110 days
c heart an
failure
Cardiol
ogy 6 Levosi
Llorens11 79.
1
2
heart s an
failure
Major
non-
cardiac
surger
y 68. 60 Dobut Standard
Lobo112 25 25 2 7
Haemo 7 days amine treatment
dynami
c
optimiz
ation
Cardiol
ogy
59. 12 Enoxi
Lowes113 Chroni Placebo 70 35 2 4
6 weeks mone
c heart
failure
Luckner1 Shock 68. ICU Vasop Standard 10 8 8 7
14
9 stay ressin treatment
Vasodil
atory
54. Vasop
Malay115 Sepsis 24 h Placebo 5 5 0 2
5 ressin
Cardiol
ogy Levosi
Malfatto1 Chroni 70 Furosemid
1 yr mend 22 11 4 4
16
e
c heart an
failure
Liver
Martn-
cirrhosi 3
Llah Terlipr Standard
s 57 month 23 23 17 19
(TAHRS essin treatment
compli s
)117
cations
Cardia
c
surger
1 y
Operat Methyl
Maslow 69.
ing ene Placebo 15 15 0 0
18
Vasopl 1
room blue
egic
syndro
me
Cardiol
ogy 6 Levosi
Mavrog 61. Standard
eni*119 5 treatment
c heart s an
failure
Major
non-
cardiac
surger
McGinle Dopex
y 74 48 h Placebo 12 12 1 1
y120 amine
Vascul
ar
surger
y
Methyl
Memis 52. 28
D121 4 days
blue
Metra Cardiol 62 1234 Enoxi Placebo 454 450 101 111
month
ogy
s
(ESSEN Chroni
(media mone
TIAL-I)122 c heart
n=16
failure
6)
1234
Cardiol
Metra month
ogy
(ESSEN s Enoxi
TIAL- (media mone
c heart
II)122 n=16
failure
6)
Cardia
Modine* c 61. 1 Dobut
Placebo 16 16 0 0
123
surger 2 month amine
y
Cardiol
Moiseye
ogy Levosi
v VS 67. 180
(RUSSL 2 days
heart an
AN)* 124
failure
Cardia
Mllhoff, c 60. Hospit Milrino
Nifedipine 15 14 1 1
1999125 surger 5 al stay ne
y
Cardia
Mllhoff, c 64. Milrino
1 yr Placebo 11 11 0 0
2002126 surger 4 ne
y
Cardia
c
surger
Morales1 y 60. ICU Vasop
Placebo 17 16 0 1
27
Vasopl 7 stay ressin
egic
syndro
me
Moreau1 Liver 54. 3 Terlipr Albumin 11 13 2 1
28
cirrhosi 3 month essin
s s
compli
cations
Terlipr
essin,
Morelli dobut
(DOBU Sepsis 66. ICU amine
Standard
40 20 26 14
PRESS) 3 stay treatment
129 +
terlipr
essin
Major
non-
cardiac
surger
Mukhtar1 y 49. Hospit Terlipr
Placebo 15 15 0 0
30
8 al stay essin
Liver
transpl
antatio
n
Cardiol
ogy
Chroni
Nagai c heart
71. Digoxi
(J- failure 2h Landiolol 115 99 0 1
6 n
Land)131 Atrial
fibrillati
on/flutt
er
Cardiol
ogy
62. Dobut
Nanas132 Chroni 2 yr Placebo 16 14 13 13
6 amine
c heart
failure
Cardiol Dobut
Niemine ogy amine,
63. 29 Placebo,
n*, Chroni levosi 115 35 2 0
1 days vehicle
2000133 c heart mend
failure an
Niemine Cardiol
n ogy 210 + Levosi
63.
(PERSI Chroni 14 mend Placebo 205 102 23 6
3
ST), c heart days an
2008134 failure
Cardia
Levosi
Nijhawa c 65.
8h mend Placebo 12 6 0 0
n135
surger 7
an
y
Cardia
c
surger
Okamot y 30 Vasop
70 Placebo 49 47 0 0
o136 Vasopl days ressin
egic
syndro
me
Cardiol
ogy 6
Oliva 65. Dobut Standard
Chroni month 19 19 5 3
(DICE)137 5 amine treatment
c heart s
failure
Major
Standard
non-
64. 30 Amrin treatment,
Orii138 cardiac 15 30 0 0
9 days one prostagland
surger
in E1
y
Cardia
O- c Hospit Dobut Standard
63 40 40 0 0
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y
Cardia
c
surger
Methyl
y 65. Hospit Standard
zal140 ene 50 50 0 2
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egic
syndro
me
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5 days
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failure
Packer Cardiol 63. 90 Levosi Placebo 299 301 45 35
ogy
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failure
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c
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61 4 days Placebo 25 25 0 3
poulos142 Vasopl ressin
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surger mine treatment
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en 145
y
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147 phrine
tion
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Raplh ve 60. Hospit Dopex Standard
52 50 29 27
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unit
Reyad149 Major 41. Hospit Dobut Placebo 40 20 0 2
cardiac
surger
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amine
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c 68. Milrino
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s
y
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cations
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62 10 10 2 7
nek162 heart stay ne treatment
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Slawsky Acute 56. 30 mend Placebo 98 48 3 3
163
7 days
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4
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c
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transpl Dopa Fenoldopa
*, 53 month 20 20 0 0
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a171 9 days essin treatment
Takala172 Major 62. Hospit Dopex Placebo 272 140 42 22
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c
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65. 30 amine,
Taur173 cardiac Placebo 20 10 0 0
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mine
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Atrial 43 97 0 0
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8 al stay n e, sotalol
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5
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failure
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ogy
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Acute 1 yr 56 105 19 37
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c Hospit
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c 65. 30
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ogy
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c 65. Hospit Dopa
Woo186 Placebo 25 25 2 0
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c Placebo 94 100 94 100
use187 4 al stay phrine
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c
a188 surger 5 al stay ne
y
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Standard
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56 treatment, 15 30 0 0
2002a189 surger al stay mine
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Cardiol
ogy 3 Levosi
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1
5 treatment
c heart s an
failure
The most frequently studied settings were cardiac surgery [70/177 trials (39.5%)], heart failure
[47/177 (26.5%)], major non-cardiac surgery [21/177 (11.8%)], complications of liver cirrhosis
[10/177 (5.6%)], sepsis [7/177 (3.9%)], and cardiac arrest [6/177 (3.4%)]. Placebo was used as
control in 111 (62.7%) trials while 46 trials (25.9%) randomized more than 100 patients. Fifty-
nine trials [59/177 (33.3%)] reported in-hospital mortality, 35 [35/177 (19.7%)] reported one-
month mortality, and ten [10/177 (5.6%)] reported one-yr mortality (). Quality assessment of
included trials showed that most of the studies were of moderate quality. A total of 60 studies
(33.9%) were judged to carry a low risk of bias, 104 (58.8%) a moderate risk of bias, and 13
(7.3%) a high risk of bias (Supplementary data Table
S5 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1).
Table 3. Results of the main analysis and sub-analysis performed. CI, confidence interval;
RR, risk ratio; OR, odds ratio; PDE-3, phosphodiesterase-3; RD, risk difference. aincluding
acutely decompensated heart failure; bdobutamine, dopamine, dopexamine, epinephrine,
amrinone, enoximone, milrinone, and levosimendan192; cdigoxin, ephedrine, and
isoproterenol; dvalue expressed as odds ratio; evalue expressed as risk difference
95%
Numb Controls P for
Inotropes/vasopre Risk confide P for
Analysis er of mortality heterogen
ssors mortality % ratio nce effect
trials % eity
interval
30
30.3 (4255/14 0.96
Overall 177 (4277/14 0.98 0.23 0.30
046) 1.01
244)
Setting
28 0.61 0.00
Vasoplegia 16 23.2 (87/374) 0.73 0.33
(97/346) 0.88 08
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 25.3 0.60 0.00
14 19.5 (58/298) 0.74 0.38
ors (79/312) 0.91 5
60.4 0.61
Sepsis 7 43.8 (62/141) 0.76 0.02 0.66
(61/101) 0.95
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 64.2 0.62
5 50.8 (33/65) 0.81 0.11 0.85
ors (43/67) 1.05
4.1
Cardiac 0.50
70 2.7 (51/1899) (77/1884 0.70 0.03 0.90
surgery 0.96
)
3.9
0.55
Inotropes 63 3 (51/1700) (65/1671 0.79 0.21 0.94
1.14
)
Vasopress 5.6 0.03 0.00
7 0 (0/199) 0.13 0.90
ors (12/213) 0.56 7
25
23.8 0.93
Heart failure 47 (1778/71 0.98 0.45 0.66
(1800/7566) 1.03
24)
17.5
- 0.90
18 17.7 (383/2158) (406/232 1.02 0.79 0.67
adrenergic 1.15
2)
13.8
Levosimen 0.70
27 12.5 (235/1873) (179/129 0.85 0.07 0.51
dan 1.02
9)
33.9
33.4 0.93
Digoxin 3 (1197/35 0.99 0.74 0.65
(1182/3535) 1.06
26)
11.6
Acute heart 0.78
24 13.5 (293/2161) (275/201 0.91 0.26 0.75
failurea 1.07
6)
Chronic 29.7
28.2 0.92
stable heart 23 (1503/51 0.99 0.73 0.43
(1507/5405) 1.06
failure 08)
97.9
Cardiac 98.3 0.99
6 (2001/20 1.00 0.41 0.45
arrest (1991/2026) 1.01
44)
Major non-
8.5 0.62
cardiac 21 9 (78/871) 0.92 0.67 0.34
(59/697) 1.36
surgery
Vascular 8.8 0.56
5 12.7 (8/63) 1.32 0.52 0.75
surgery (6/68) 3.09
Liver 0.60
6 6.3 (12/189) 4 (8/199) 1.42 0.42 0.99
transplantation 3.38
Haemodyna
12.7 0.26
mic 6 9.8 (53/539) 0.56 0.14 0.07
(44/345) 1.21
optimization
Liver 21.3
0.80
cirrhosis 10 22.1 (143/839) (166/119 0.98 0.85 0.22
1.20
complications 1)
Study drug
22.2
22.4 (2419/11 0.93
Inotropes 145 (2411/10 0.97 0.18 0.69
053) 1.01
959)
16.3
Routinely 16.9 0.89
133 (1171/70 0.95 0.08 0.11
usedb (1194/7214) 1.01
86)
32
Other 31.9 0.93
12 (1240/38 0.99 0.81 0.66
inotropesc (1225/3839) 1.06
73)
56.5
Vasopressor 62.5 0.98
33 (1865/32 1.00 0.78 0.60
s (1821/2915) 1.02
98)
21.2
Catecholami 0.91
58 23.6 (640/2706) (674/317 0.97 0.26 0.58
nes 1.02
1)
Dobutamin 6.7 0.62
15 7.4 (30/402) 0.89 0.53 0.49
e (34/507) 1.28
14.6
0.81
Dopamine 23 15.3 (127/828) (169/115 0.98 0.83 0.97
1.19
6)
Dopexami 13.6 0.70
16 13.1 (86/654) 0.91 0.50 0.84
ne (72/531) 1.19
2.5 0.06
Ephedrine 2 2 (2/100) 0.67 0.74 N/A
(1/40) 7.09
37.5
Epinephrin 0.91
6 57.2 (357/624) (373/994 0.99 0.71 0.0002
e 1.07
)
Isoprotere 95.2 0.94
1 97.3 (36/37) 1.02 0.63 N/A
nol (40/42) 1.11
Norepinep
0 N/A N/A N/A N/A N/A N/A
hrine
Phenyleph 3.2 0.18
2 3.3 (2/61) 1.02 0.98 0.36
rine (2/62) 5.67
14
PDE-3 0.90
32 144 (329/2286) (315/225 1.04 0.61 0.62
inhibitors 1.19
3)
1.1 0.39
Amrinone 5 2.4 (4/166) 1.79 0.45 0.70
(2/178) 8.17
20.6
0.88
Enoximone 10 20.7 (267/1287) (259/125 1.02 0.76 0.31
1.19
5)
6.5 0.75
Milrinone 18 7 (58/833) 1.06 0.75 0.56
(54/830) 1.50
12.4
Levosimend 0.68 0.00
48 11 (263/2395) (227/182 0.80 0.64
an 0.94 8
4)
59.4
Vasopressin 66.5 0.99
25 (1841/31 1.01 0.44 0.64
s (1805/2716) 1.03
00)
15.7
Terlipressi 0.87
13 18.5 (164/887) (195/124 1.02 0.79 0.26
n 1.20
3)
Vasopressi 12 89.7 88.6 1.01 0.99 0.33 0.76
n (1641/1829) (1646/18 1.02
57)
Methylene 16.2 0.37
6 10.1 (14/138) 0.64 0.11 0.28
Blue (22/136) 1.10
31.6
32.1 0.93
Digoxin 9 (1199/37 0.99 0.80 0.47
(1187/3702) 1.06
91)
Follow-up
43.1
43.5 0.99
Hospital stay 59 (1844/42 1.01 0.44 0.88
(1866/4294) 1.03
80)
10.1
0.90
Inotropes 52 10.5 (257/2447) (246/244 1.00 0.97 0.80
1.12
6)
85.7
Vasopress 87.1 1.00
8 (1599/18 1.01 0.18 0.81
ors (1609/1847) 1.02
66)
26.1
0.57
One month 35 20.2 (305/1507) (312/119 0.75 0.04 <0.0001
0.98
7)
10.3 0.51 0.00
Inotropes 28 7.1 (84/1176) 0.67 0.86
(93/901) 0.89 5
59
Vasopress 0.90
8 58.1 (221/380) (220/373 0.98 0.52 0.47
ors 1.05
)
85.8
86.7 0.99
One yr 10 (1496/17 1.00 0.94 0.36
(1475/1704) 1.02
43)
25.4 0.62
Inotropes 9 19.5 (51/262) 0.83 0.22 0.82
(74/291) 1.11
97.9
Vasopress 98.8 1.00
1 (1422/14 1.01 0.08 N/A
ors (1424/1442) 1.02
52)
Additional sensitivity analyses
Studies with 34.3
35.5 (3941/11 0.97
at least 100 46 (3907/11 1.00 0.95 0.48
098) 1.03
patients 389)
Studies with 26.4
24.7 (2479/10 0.94
placebo as 111 (2394/90 0.98 0.36 0.92
026) 1.02
control 80)
20.9
Conventional 19.9 (2118/10 0.91
150 (2092/99 0.96 0.13 0.62
settings 629) 1.01
96)
Therapeutic 37.6
37.8 (4118/10 0.97
drug 80 (4127/10 0.99 0.50 0.33
906) 1.02
administration 964)
Prophylactic 4.7
0.65
drug 97 4.5 (140/3126) (155/327 0.80 0.04 0.89
0.99
administration 6)
Studies with 37.25
0.97
a low risk of 59 38 (3369/8865) (3348/89 1.00 0.76 0.69
1.03
bias 86)
Overall 30
30.3 (4255/14 0.89
analysis using 177 (4277/14 0.96d 0.23 0.77
046) 1.03
ORs 244)
Overall 30
30.3 (4255/14 0.0 0.01
analysis using 177 (4277/14 0.24 0.99
046) 0e 0.00
RDs 244)
Influence
analysis
All 95% CIs of RR<1 and P>0.05
(removing one
study at time)
Quantitative Data Synthesis
The overall analysis showed that mortality in patients receiving inotropes/vasopressors was not
increased when compared with control [4255/14 036 (30.3%) deaths in the treatment group vs
4277/14 244 (30%) deaths in the comparator group, RR=0.98 (0.961.01), P for
effect=0.23, P for heterogeneity=0.30, I 2=6%] ().
Analysis Numb Inotropes/vasopre Controls Risk 95% P for P for

er of ssors mortality % mortality ratio confide effect heterogen
nce
trials % eity
interval
30
30.3 (4255/14 0.96
Overall 177 (4277/14 0.98 0.23 0.30
046) 1.01
244)
Setting
28 0.61 0.00
Vasoplegia 16 23.2 (87/374) 0.73 0.33
(97/346) 0.88 08
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 25.3 0.60 0.00
14 19.5 (58/298) 0.74 0.38
ors (79/312) 0.91 5
60.4 0.61
Sepsis 7 43.8 (62/141) 0.76 0.02 0.66
(61/101) 0.95
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 64.2 0.62
5 50.8 (33/65) 0.81 0.11 0.85
ors (43/67) 1.05
4.1
Cardiac 0.50
70 2.7 (51/1899) (77/1884 0.70 0.03 0.90
surgery 0.96
)
3.9
0.55
Inotropes 63 3 (51/1700) (65/1671 0.79 0.21 0.94
1.14
)
Vasopress 5.6 0.03 0.00
7 0 (0/199) 0.13 0.90
ors (12/213) 0.56 7
25
23.8 0.93
Heart failure 47 (1778/71 0.98 0.45 0.66
(1800/7566) 1.03
24)
17.5
- 0.90
18 17.7 (383/2158) (406/232 1.02 0.79 0.67
adrenergic 1.15
2)
13.8
Levosimen 0.70
27 12.5 (235/1873) (179/129 0.85 0.07 0.51
dan 1.02
9)
Digoxin 3 33.4 33.9 0.99 0.93 0.74 0.65
(1197/35
(1182/3535) 1.06
26)
11.6
Acute heart 0.78
24 13.5 (293/2161) (275/201 0.91 0.26 0.75
failurea 1.07
6)
Chronic 29.7
28.2 0.92
stable heart 23 (1503/51 0.99 0.73 0.43
(1507/5405) 1.06
failure 08)
97.9
Cardiac 98.3 0.99
6 (2001/20 1.00 0.41 0.45
arrest (1991/2026) 1.01
44)
Major non-
8.5 0.62
cardiac 21 9 (78/871) 0.92 0.67 0.34
(59/697) 1.36
surgery
Vascular 8.8 0.56
5 12.7 (8/63) 1.32 0.52 0.75
surgery (6/68) 3.09
Liver 0.60
6 6.3 (12/189) 4 (8/199) 1.42 0.42 0.99
Haemodyna
12.7 0.26
mic 6 9.8 (53/539) 0.56 0.14 0.07
(44/345) 1.21
optimization
Liver 21.3
0.80
cirrhosis 10 22.1 (143/839) (166/119 0.98 0.85 0.22
1.20
complications 1)
Study drug
22.2
22.4 (2419/11 0.93
Inotropes 145 (2411/10 0.97 0.18 0.69
053) 1.01
959)
16.3
Routinely 16.9 0.89
133 (1171/70 0.95 0.08 0.11
usedb (1194/7214) 1.01
86)
32
Other 31.9 0.93
12 (1240/38 0.99 0.81 0.66
inotropesc (1225/3839) 1.06
73)
56.5
33 (1865/32 1.00 0.78 0.60
s (1821/2915) 1.02
98)
21.2
Catecholami 0.91
58 23.6 (640/2706) (674/317 0.97 0.26 0.58
nes 1.02
1)
Dobutamin 6.7 0.62
15 7.4 (30/402) 0.89 0.53 0.49
e (34/507) 1.28
14.6
0.81
Dopamine 23 15.3 (127/828) (169/115 0.98 0.83 0.97
1.19
6)
Dopexami 13.6 0.70
16 13.1 (86/654) 0.91 0.50 0.84
ne (72/531) 1.19
2.5 0.06
Ephedrine 2 2 (2/100) 0.67 0.74 N/A
(1/40) 7.09
37.5
Epinephrin 0.91
6 57.2 (357/624) (373/994 0.99 0.71 0.0002
e 1.07
)
1 97.3 (36/37) 1.02 0.63 N/A
nol (40/42) 1.11
Norepinep
hrine
Phenyleph 3.2 0.18
2 3.3 (2/61) 1.02 0.98 0.36
rine (2/62) 5.67
14
PDE-3 0.90
32 144 (329/2286) (315/225 1.04 0.61 0.62
inhibitors 1.19
3)
1.1 0.39
Amrinone 5 2.4 (4/166) 1.79 0.45 0.70
(2/178) 8.17
20.6
0.88
Enoximone 10 20.7 (267/1287) (259/125 1.02 0.76 0.31
1.19
5)
6.5 0.75
Milrinone 18 7 (58/833) 1.06 0.75 0.56
(54/830) 1.50
12.4
48 11 (263/2395) (227/182 0.80 0.64
an 0.94 8
4)
59.4
25 (1841/31 1.01 0.44 0.64
s (1805/2716) 1.03
00)
15.7
Terlipressi 0.87
13 18.5 (164/887) (195/124 1.02 0.79 0.26
n 1.20
3)
88.6
Vasopressi 89.7 0.99
12 (1646/18 1.01 0.33 0.76
n (1641/1829) 1.02
57)
Methylene 16.2 0.37
6 10.1 (14/138) 0.64 0.11 0.28
Blue (22/136) 1.10
31.6
32.1 0.93
Digoxin 9 (1199/37 0.99 0.80 0.47
(1187/3702) 1.06
91)
Follow-up
43.1
43.5 0.99
Hospital stay 59 (1844/42 1.01 0.44 0.88
(1866/4294) 1.03
80)
10.1
0.90
Inotropes 52 10.5 (257/2447) (246/244 1.00 0.97 0.80
1.12
6)
85.7
Vasopress 87.1 1.00
8 (1599/18 1.01 0.18 0.81
ors (1609/1847) 1.02
66)
26.1
0.57
One month 35 20.2 (305/1507) (312/119 0.75 0.04 <0.0001
0.98
7)
10.3 0.51 0.00
Inotropes 28 7.1 (84/1176) 0.67 0.86
(93/901) 0.89 5
59
Vasopress 0.90
8 58.1 (221/380) (220/373 0.98 0.52 0.47
ors 1.05
)
85.8
86.7 0.99
One yr 10 (1496/17 1.00 0.94 0.36
(1475/1704) 1.02
43)
25.4 0.62
Inotropes 9 19.5 (51/262) 0.83 0.22 0.82
(74/291) 1.11
97.9
Vasopress 98.8 1.00
1 (1422/14 1.01 0.08 N/A
ors (1424/1442) 1.02
52)
Studies with 34.3
35.5 (3941/11 0.97
at least 100 46 (3907/11 1.00 0.95 0.48
098) 1.03
patients 389)
Studies with 26.4
24.7 (2479/10 0.94
placebo as 111 (2394/90 0.98 0.36 0.92
026) 1.02
control 80)
20.9
Conventional 19.9 (2118/10 0.91
150 (2092/99 0.96 0.13 0.62
settings 629) 1.01
96)
Therapeutic 37.6
37.8 (4118/10 0.97
drug 80 (4127/10 0.99 0.50 0.33
906) 1.02
administration 964)
Prophylactic 4.7
0.65
drug 97 4.5 (140/3126) (155/327 0.80 0.04 0.89
0.99
administration 6)
Studies with 37.25
0.97
a low risk of 59 38 (3369/8865) (3348/89 1.00 0.76 0.69
1.03
bias 86)
Overall 30
30.3 (4255/14 0.89
analysis using 177 (4277/14 0.96d 0.23 0.77
046) 1.03
ORs 244)
Overall 30
30.3 (4255/14 0.0 0.01
analysis using 177 (4277/14 0.24 0.99
046) 0e 0.00
RDs 244)
Influence
analysis
(removing one
study at time)
Sub-analysis in the different clinical settings showed a statistically significant effect of inotropes
or vasopressors in mortality in the settings of vasoplegic syndromes [87/374 (23.2%) vs 97/346
(28%), RR=0.73 (0.610.88), P for effect=0.0008, P for heterogeneity=0.33, I 2=12%, with 16
studies included], sepsis [62/141 (43.8%) vs 61/101 (60.4%), RR=0.76 (0.610.95), P for
effect=0.02, P for heterogeneity=0.66, I 2=0%, with 7 studies included) and cardiac surgery
[51/1899 (2.7%) vs 77/1884 (4.1%), RR=0.70 (0.500.96), P for effect=0.03, P for
heterogeneity=0.90, I 2=0%, with 70 studies included] (). Statistical significance was lost when
analysing only trials with a low risk of bias performed in these settings (Supplementary data
Table S6 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1)
95%
Numb Controls P for
trials % eity
interval
30
30.3 (4255/14 0.96
Overall 177 (4277/14 0.98 0.23 0.30
046) 1.01
244)
Setting
28 0.61 0.00
Vasoplegia 16 23.2 (87/374) 0.73 0.33
(97/346) 0.88 08
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 25.3 0.60 0.00
14 19.5 (58/298) 0.74 0.38
ors (79/312) 0.91 5
60.4 0.61
Sepsis 7 43.8 (62/141) 0.76 0.02 0.66
(61/101) 0.95
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 64.2 0.62
5 50.8 (33/65) 0.81 0.11 0.85
ors (43/67) 1.05
4.1
Cardiac 0.50
70 2.7 (51/1899) (77/1884 0.70 0.03 0.90
surgery 0.96
)
3.9
0.55
Inotropes 63 3 (51/1700) (65/1671 0.79 0.21 0.94
1.14
)
Vasopress 5.6 0.03 0.00
7 0 (0/199) 0.13 0.90
ors (12/213) 0.56 7
25
23.8 0.93
Heart failure 47 (1778/71 0.98 0.45 0.66
(1800/7566) 1.03
24)
17.5
- 0.90
18 17.7 (383/2158) (406/232 1.02 0.79 0.67
adrenergic 1.15
2)
13.8
Levosimen 0.70
27 12.5 (235/1873) (179/129 0.85 0.07 0.51
dan 1.02
9)
33.9
33.4 0.93
Digoxin 3 (1197/35 0.99 0.74 0.65
(1182/3535) 1.06
26)
11.6
Acute heart 0.78
24 13.5 (293/2161) (275/201 0.91 0.26 0.75
failurea 1.07
6)
Chronic 29.7
28.2 0.92
stable heart 23 (1503/51 0.99 0.73 0.43
(1507/5405) 1.06
failure 08)
97.9
Cardiac 98.3 0.99
6 (2001/20 1.00 0.41 0.45
arrest (1991/2026) 1.01
44)
Major non-
8.5 0.62
cardiac 21 9 (78/871) 0.92 0.67 0.34
(59/697) 1.36
surgery
Vascular 8.8 0.56
5 12.7 (8/63) 1.32 0.52 0.75
surgery (6/68) 3.09
Liver 0.60
6 6.3 (12/189) 4 (8/199) 1.42 0.42 0.99
Haemodyna
12.7 0.26
mic 6 9.8 (53/539) 0.56 0.14 0.07
(44/345) 1.21
optimization
Liver 21.3
0.80
cirrhosis 10 22.1 (143/839) (166/119 0.98 0.85 0.22
1.20
complications 1)
Study drug
22.2
22.4 (2419/11 0.93
Inotropes 145 (2411/10 0.97 0.18 0.69
053) 1.01
959)
Routinely 133 16.9 16.3 0.95 0.89 0.08 0.11
usedb (1194/7214) (1171/70 1.01
86)
32
Other 31.9 0.93
12 (1240/38 0.99 0.81 0.66
inotropesc (1225/3839) 1.06
73)
56.5
33 (1865/32 1.00 0.78 0.60
s (1821/2915) 1.02
98)
21.2
Catecholami 0.91
58 23.6 (640/2706) (674/317 0.97 0.26 0.58
nes 1.02
1)
Dobutamin 6.7 0.62
15 7.4 (30/402) 0.89 0.53 0.49
e (34/507) 1.28
14.6
0.81
Dopamine 23 15.3 (127/828) (169/115 0.98 0.83 0.97
1.19
6)
Dopexami 13.6 0.70
16 13.1 (86/654) 0.91 0.50 0.84
ne (72/531) 1.19
2.5 0.06
Ephedrine 2 2 (2/100) 0.67 0.74 N/A
(1/40) 7.09
37.5
Epinephrin 0.91
6 57.2 (357/624) (373/994 0.99 0.71 0.0002
e 1.07
)
1 97.3 (36/37) 1.02 0.63 N/A
nol (40/42) 1.11
Norepinep
hrine
Phenyleph 3.2 0.18
2 3.3 (2/61) 1.02 0.98 0.36
rine (2/62) 5.67
14
PDE-3 0.90
32 144 (329/2286) (315/225 1.04 0.61 0.62
inhibitors 1.19
3)
1.1 0.39
Amrinone 5 2.4 (4/166) 1.79 0.45 0.70
(2/178) 8.17
20.6
0.88
Enoximone 10 20.7 (267/1287) (259/125 1.02 0.76 0.31
1.19
5)
6.5 0.75
Milrinone 18 7 (58/833) 1.06 0.75 0.56
(54/830) 1.50
12.4
48 11 (263/2395) (227/182 0.80 0.64
an 0.94 8
4)
59.4
25 (1841/31 1.01 0.44 0.64
s (1805/2716) 1.03
00)
15.7
Terlipressi 0.87
13 18.5 (164/887) (195/124 1.02 0.79 0.26
n 1.20
3)
88.6
12 (1646/18 1.01 0.33 0.76
n (1641/1829) 1.02
57)
Methylene 16.2 0.37
6 10.1 (14/138) 0.64 0.11 0.28
Blue (22/136) 1.10
31.6
32.1 0.93
Digoxin 9 (1199/37 0.99 0.80 0.47
(1187/3702) 1.06
91)
Follow-up
43.1
43.5 0.99
Hospital stay 59 (1844/42 1.01 0.44 0.88
(1866/4294) 1.03
80)
10.1
0.90
Inotropes 52 10.5 (257/2447) (246/244 1.00 0.97 0.80
1.12
6)
85.7
Vasopress 87.1 1.00
8 (1599/18 1.01 0.18 0.81
ors (1609/1847) 1.02
66)
26.1
0.57
One month 35 20.2 (305/1507) (312/119 0.75 0.04 <0.0001
0.98
7)
10.3 0.51 0.00
Inotropes 28 7.1 (84/1176) 0.67 0.86
(93/901) 0.89 5
59
Vasopress 0.90
8 58.1 (221/380) (220/373 0.98 0.52 0.47
ors 1.05
)
85.8
86.7 0.99
One yr 10 (1496/17 1.00 0.94 0.36
(1475/1704) 1.02
43)
25.4 0.62
Inotropes 9 19.5 (51/262) 0.83 0.22 0.82
(74/291) 1.11
97.9
Vasopress 98.8 1.00
1 (1422/14 1.01 0.08 N/A
ors (1424/1442) 1.02
52)
Studies with 34.3
35.5 (3941/11 0.97
at least 100 46 (3907/11 1.00 0.95 0.48
098) 1.03
patients 389)
Studies with 26.4
24.7 (2479/10 0.94
placebo as 111 (2394/90 0.98 0.36 0.92
026) 1.02
control 80)
20.9
Conventional 19.9 (2118/10 0.91
150 (2092/99 0.96 0.13 0.62
settings 629) 1.01
96)
Therapeutic 37.6
37.8 (4118/10 0.97
drug 80 (4127/10 0.99 0.50 0.33
906) 1.02
administration 964)
Prophylactic 4.7
0.65
drug 97 4.5 (140/3126) (155/327 0.80 0.04 0.89
0.99
administration 6)
Studies with 37.25
0.97
a low risk of 59 38 (3369/8865) (3348/89 1.00 0.76 0.69
1.03
bias 86)
Overall 30
30.3 (4255/14 0.89
analysis using 177 (4277/14 0.96d 0.23 0.77
046) 1.03
ORs 244)
Overall 30
30.3 (4255/14 0.0 0.01
analysis using 177 (4277/14 0.24 0.99
046) 0e 0.00
RDs 244)
Influence
analysis
(removing one
study at time)
Among the different drugs, only levosimendan was associated with a significant improvement in
survival [263/2395 (11%) vs 227/1824 (12.4%), RR=0.80 (0.680.94), P for effect=0.008, P for
heterogeneity=0.64, I 2=0%, with 48 studies included] ().
95%
Numb Controls P for
trials % eity
interval
30
30.3 (4255/14 0.96
Overall 177 (4277/14 0.98 0.23 0.30
046) 1.01
244)
Setting
28 0.61 0.00
Vasoplegia 16 23.2 (87/374) 0.73 0.33
(97/346) 0.88 08
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 25.3 0.60 0.00
14 19.5 (58/298) 0.74 0.38
ors (79/312) 0.91 5
60.4 0.61
Sepsis 7 43.8 (62/141) 0.76 0.02 0.66
(61/101) 0.95
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 64.2 0.62
5 50.8 (33/65) 0.81 0.11 0.85
ors (43/67) 1.05
4.1
Cardiac 0.50
70 2.7 (51/1899) (77/1884 0.70 0.03 0.90
surgery 0.96
)
3.9
0.55
Inotropes 63 3 (51/1700) (65/1671 0.79 0.21 0.94
1.14
)
Vasopress 5.6 0.03 0.00
7 0 (0/199) 0.13 0.90
ors (12/213) 0.56 7
25
23.8 0.93
Heart failure 47 (1778/71 0.98 0.45 0.66
(1800/7566) 1.03
24)
17.5
- 0.90
18 17.7 (383/2158) (406/232 1.02 0.79 0.67
adrenergic 1.15
2)
13.8
Levosimen 0.70
27 12.5 (235/1873) (179/129 0.85 0.07 0.51
dan 1.02
9)
33.9
33.4 0.93
Digoxin 3 (1197/35 0.99 0.74 0.65
(1182/3535) 1.06
26)
11.6
Acute heart 0.78
24 13.5 (293/2161) (275/201 0.91 0.26 0.75
failurea 1.07
6)
Chronic 29.7
28.2 0.92
stable heart 23 (1503/51 0.99 0.73 0.43
(1507/5405) 1.06
failure 08)
97.9
Cardiac 98.3 0.99
6 (2001/20 1.00 0.41 0.45
arrest (1991/2026) 1.01
44)
Major non-
8.5 0.62
cardiac 21 9 (78/871) 0.92 0.67 0.34
(59/697) 1.36
surgery
Vascular 8.8 0.56
5 12.7 (8/63) 1.32 0.52 0.75
surgery (6/68) 3.09
Liver 0.60
6 6.3 (12/189) 4 (8/199) 1.42 0.42 0.99
Haemodyna
12.7 0.26
mic 6 9.8 (53/539) 0.56 0.14 0.07
(44/345) 1.21
optimization
Liver 21.3
0.80
cirrhosis 10 22.1 (143/839) (166/119 0.98 0.85 0.22
1.20
complications 1)
Study drug
Inotropes 145 22.4 (2419/11 22.2 0.97 0.93 0.18 0.69
053) (2411/10 1.01
959)
16.3
Routinely 16.9 0.89
133 (1171/70 0.95 0.08 0.11
usedb (1194/7214) 1.01
86)
32
Other 31.9 0.93
12 (1240/38 0.99 0.81 0.66
inotropesc (1225/3839) 1.06
73)
56.5
33 (1865/32 1.00 0.78 0.60
s (1821/2915) 1.02
98)
21.2
Catecholami 0.91
58 23.6 (640/2706) (674/317 0.97 0.26 0.58
nes 1.02
1)
Dobutamin 6.7 0.62
15 7.4 (30/402) 0.89 0.53 0.49
e (34/507) 1.28
14.6
0.81
Dopamine 23 15.3 (127/828) (169/115 0.98 0.83 0.97
1.19
6)
Dopexami 13.6 0.70
16 13.1 (86/654) 0.91 0.50 0.84
ne (72/531) 1.19
2.5 0.06
Ephedrine 2 2 (2/100) 0.67 0.74 N/A
(1/40) 7.09
37.5
Epinephrin 0.91
6 57.2 (357/624) (373/994 0.99 0.71 0.0002
e 1.07
)
1 97.3 (36/37) 1.02 0.63 N/A
nol (40/42) 1.11
Norepinep
hrine
Phenyleph 3.2 0.18
2 3.3 (2/61) 1.02 0.98 0.36
rine (2/62) 5.67
14
PDE-3 0.90
32 144 (329/2286) (315/225 1.04 0.61 0.62
inhibitors 1.19
3)
1.1 0.39
Amrinone 5 2.4 (4/166) 1.79 0.45 0.70
(2/178) 8.17
20.6
0.88
Enoximone 10 20.7 (267/1287) (259/125 1.02 0.76 0.31
1.19
5)
6.5 0.75
Milrinone 18 7 (58/833) 1.06 0.75 0.56
(54/830) 1.50
12.4
48 11 (263/2395) (227/182 0.80 0.64
an 0.94 8
4)
59.4
25 (1841/31 1.01 0.44 0.64
s (1805/2716) 1.03
00)
15.7
Terlipressi 0.87
13 18.5 (164/887) (195/124 1.02 0.79 0.26
n 1.20
3)
88.6
12 (1646/18 1.01 0.33 0.76
n (1641/1829) 1.02
57)
Methylene 16.2 0.37
6 10.1 (14/138) 0.64 0.11 0.28
Blue (22/136) 1.10
31.6
32.1 0.93
Digoxin 9 (1199/37 0.99 0.80 0.47
(1187/3702) 1.06
91)
Follow-up
43.1
43.5 0.99
Hospital stay 59 (1844/42 1.01 0.44 0.88
(1866/4294) 1.03
80)
10.1
0.90
Inotropes 52 10.5 (257/2447) (246/244 1.00 0.97 0.80
1.12
6)
85.7
Vasopress 87.1 1.00
8 (1599/18 1.01 0.18 0.81
ors (1609/1847) 1.02
66)
26.1
0.57
One month 35 20.2 (305/1507) (312/119 0.75 0.04 <0.0001
0.98
7)
10.3 0.51 0.00
Inotropes 28 7.1 (84/1176) 0.67 0.86
(93/901) 0.89 5
59
Vasopress 0.90
8 58.1 (221/380) (220/373 0.98 0.52 0.47
ors 1.05
)
85.8
86.7 0.99
One yr 10 (1496/17 1.00 0.94 0.36
(1475/1704) 1.02
43)
25.4 0.62
Inotropes 9 19.5 (51/262) 0.83 0.22 0.82
(74/291) 1.11
97.9
Vasopress 98.8 1.00
1 (1422/14 1.01 0.08 N/A
ors (1424/1442) 1.02
52)
Studies with 34.3
35.5 (3941/11 0.97
at least 100 46 (3907/11 1.00 0.95 0.48
098) 1.03
patients 389)
Studies with 26.4
24.7 (2479/10 0.94
placebo as 111 (2394/90 0.98 0.36 0.92
026) 1.02
control 80)
20.9
Conventional 19.9 (2118/10 0.91
150 (2092/99 0.96 0.13 0.62
settings 629) 1.01
96)
Therapeutic 37.6
37.8 (4118/10 0.97
drug 80 (4127/10 0.99 0.50 0.33
906) 1.02
administration 964)
Prophylactic 4.7
0.65
drug 97 4.5 (140/3126) (155/327 0.80 0.04 0.89
0.99
administration 6)
Studies with 37.25
0.97
a low risk of 59 38 (3369/8865) (3348/89 1.00 0.76 0.69
1.03
bias 86)
Overall 30
30.3 (4255/14 0.89
analysis using 177 (4277/14 0.96d 0.23 0.77
046) 1.03
ORs 244)
Overall 30
30.3 (4255/14 0.0 0.01
analysis using 177 (4277/14 0.24 0.99
046) 0e 0.00
RDs 244)
Influence All 95% CIs of RR<1 and P>0.05
analysis
(removing one
study at time)
Additionally, a reduction in mortality in the treatment group was observed when pooling all
studies reporting one-month mortality [305/1507 (20.2%) vs 312/1197 (26.1%), RR=0.75 (0.57
0.98), P for effect=0.04, P for heterogeneity <0.0001, I2=61%, with 35 studies included].
Finally, we found an improvement in survival when study drugs were administered

prophylactically [140/3,126 (4.5%) vs 155/3276 (4.7%), RR=0.80 (0.650.99), P for
effect=0.04, P for heterogeneity=0.89, I 2=0%, with 97 studied included] ().
95%
Numb Controls P for
trials % eity
interval
30
30.3 (4255/14 0.96
Overall 177 (4277/14 0.98 0.23 0.30
046) 1.01
244)
Setting
28 0.61 0.00
Vasoplegia 16 23.2 (87/374) 0.73 0.33
(97/346) 0.88 08
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 25.3 0.60 0.00
14 19.5 (58/298) 0.74 0.38
ors (79/312) 0.91 5
60.4 0.61
Sepsis 7 43.8 (62/141) 0.76 0.02 0.66
(61/101) 0.95
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 64.2 0.62
5 50.8 (33/65) 0.81 0.11 0.85
ors (43/67) 1.05
Cardiac 70 2.7 (51/1899) 4.1 0.70 0.50 0.03 0.90
(77/1884
surgery 0.96
)
3.9
0.55
Inotropes 63 3 (51/1700) (65/1671 0.79 0.21 0.94
1.14
)
Vasopress 5.6 0.03 0.00
7 0 (0/199) 0.13 0.90
ors (12/213) 0.56 7
25
23.8 0.93
Heart failure 47 (1778/71 0.98 0.45 0.66
(1800/7566) 1.03
24)
17.5
- 0.90
18 17.7 (383/2158) (406/232 1.02 0.79 0.67
adrenergic 1.15
2)
13.8
Levosimen 0.70
27 12.5 (235/1873) (179/129 0.85 0.07 0.51
dan 1.02
9)
33.9
33.4 0.93
Digoxin 3 (1197/35 0.99 0.74 0.65
(1182/3535) 1.06
26)
11.6
Acute heart 0.78
24 13.5 (293/2161) (275/201 0.91 0.26 0.75
failurea 1.07
6)
Chronic 29.7
28.2 0.92
stable heart 23 (1503/51 0.99 0.73 0.43
(1507/5405) 1.06
failure 08)
97.9
Cardiac 98.3 0.99
6 (2001/20 1.00 0.41 0.45
arrest (1991/2026) 1.01
44)
Major non-
8.5 0.62
cardiac 21 9 (78/871) 0.92 0.67 0.34
(59/697) 1.36
surgery
Vascular 8.8 0.56
5 12.7 (8/63) 1.32 0.52 0.75
surgery (6/68) 3.09
Liver 0.60
6 6.3 (12/189) 4 (8/199) 1.42 0.42 0.99
Haemodyna 6 9.8 (53/539) 12.7 0.56 0.26 0.14 0.07
mic (44/345) 1.21
optimization
Liver 21.3
0.80
cirrhosis 10 22.1 (143/839) (166/119 0.98 0.85 0.22
1.20
complications 1)
Study drug
22.2
22.4 (2419/11 0.93
Inotropes 145 (2411/10 0.97 0.18 0.69
053) 1.01
959)
16.3
Routinely 16.9 0.89
133 (1171/70 0.95 0.08 0.11
usedb (1194/7214) 1.01
86)
32
Other 31.9 0.93
12 (1240/38 0.99 0.81 0.66
inotropesc (1225/3839) 1.06
73)
56.5
33 (1865/32 1.00 0.78 0.60
s (1821/2915) 1.02
98)
21.2
Catecholami 0.91
58 23.6 (640/2706) (674/317 0.97 0.26 0.58
nes 1.02
1)
Dobutamin 6.7 0.62
15 7.4 (30/402) 0.89 0.53 0.49
e (34/507) 1.28
14.6
0.81
Dopamine 23 15.3 (127/828) (169/115 0.98 0.83 0.97
1.19
6)
Dopexami 13.6 0.70
16 13.1 (86/654) 0.91 0.50 0.84
ne (72/531) 1.19
2.5 0.06
Ephedrine 2 2 (2/100) 0.67 0.74 N/A
(1/40) 7.09
37.5
Epinephrin 0.91
6 57.2 (357/624) (373/994 0.99 0.71 0.0002
e 1.07
)
1 97.3 (36/37) 1.02 0.63 N/A
nol (40/42) 1.11
Norepinep
hrine
Phenyleph 3.2 0.18
2 3.3 (2/61) 1.02 0.98 0.36
rine (2/62) 5.67
14
PDE-3 0.90
32 144 (329/2286) (315/225 1.04 0.61 0.62
inhibitors 1.19
3)
1.1 0.39
Amrinone 5 2.4 (4/166) 1.79 0.45 0.70
(2/178) 8.17
20.6
0.88
Enoximone 10 20.7 (267/1287) (259/125 1.02 0.76 0.31
1.19
5)
6.5 0.75
Milrinone 18 7 (58/833) 1.06 0.75 0.56
(54/830) 1.50
12.4
48 11 (263/2395) (227/182 0.80 0.64
an 0.94 8
4)
59.4
25 (1841/31 1.01 0.44 0.64
s (1805/2716) 1.03
00)
15.7
Terlipressi 0.87
13 18.5 (164/887) (195/124 1.02 0.79 0.26
n 1.20
3)
88.6
12 (1646/18 1.01 0.33 0.76
n (1641/1829) 1.02
57)
Methylene 16.2 0.37
6 10.1 (14/138) 0.64 0.11 0.28
Blue (22/136) 1.10
31.6
32.1 0.93
Digoxin 9 (1199/37 0.99 0.80 0.47
(1187/3702) 1.06
91)
Follow-up
43.1
43.5 0.99
Hospital stay 59 (1844/42 1.01 0.44 0.88
(1866/4294) 1.03
80)
10.1
0.90
Inotropes 52 10.5 (257/2447) (246/244 1.00 0.97 0.80
1.12
6)
Vasopress 8 87.1 85.7 1.01 1.00 0.18 0.81
(1599/18
ors (1609/1847) 1.02
66)
26.1
0.57
One month 35 20.2 (305/1507) (312/119 0.75 0.04 <0.0001
0.98
7)
10.3 0.51 0.00
Inotropes 28 7.1 (84/1176) 0.67 0.86
(93/901) 0.89 5
59
Vasopress 0.90
8 58.1 (221/380) (220/373 0.98 0.52 0.47
ors 1.05
)
85.8
86.7 0.99
One yr 10 (1496/17 1.00 0.94 0.36
(1475/1704) 1.02
43)
25.4 0.62
Inotropes 9 19.5 (51/262) 0.83 0.22 0.82
(74/291) 1.11
97.9
Vasopress 98.8 1.00
1 (1422/14 1.01 0.08 N/A
ors (1424/1442) 1.02
52)
Studies with 34.3
35.5 (3941/11 0.97
at least 100 46 (3907/11 1.00 0.95 0.48
098) 1.03
patients 389)
Studies with 26.4
24.7 (2479/10 0.94
placebo as 111 (2394/90 0.98 0.36 0.92
026) 1.02
control 80)
20.9
Conventional 19.9 (2118/10 0.91
150 (2092/99 0.96 0.13 0.62
settings 629) 1.01
96)
Therapeutic 37.6
37.8 (4118/10 0.97
drug 80 (4127/10 0.99 0.50 0.33
906) 1.02
administration 964)
Prophylactic 4.7
0.65
drug 97 4.5 (140/3126) (155/327 0.80 0.04 0.89
0.99
administration 6)
Studies with 37.25
0.97
a low risk of 59 38 (3369/8865) (3348/89 1.00 0.76 0.69
1.03
bias 86)
Overall 30
30.3 (4255/14 0.89
analysis using 177 (4277/14 0.96d 0.23 0.77
046) 1.03
ORs 244)
Overall 30
30.3 (4255/14 0.0 0.01
analysis using 177 (4277/14 0.24 0.99
046) 0e 0.00
RDs 244)
Influence
analysis
(removing one
study at time)
No difference between treatments was found when analysing studies randomizing more than
100 patients, studies comparing inotropes/vasopressors with placebo, studies performed in
'conventional' settings, studies carrying a low risk of bias, studies with therapeutical drug
administration, and by changing analysis methods. Removing each study, each setting and
each agent and reanalysing the remaining data set did not determine major changes in direction
or magnitude of statistical findings (). No subgroup analysis showed an increased mortality
associated to the use of inotropes/vasopressors. Begg test and Egger's test excluded presence
of a publication bias (P=0.14 and P=0.81, respectively). Funnel plot is presented as
Supplementary data Figure S1 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1.
95%
Numb Controls P for
trials % eity
interval
30
30.3 (4255/14 0.96
Overall 177 (4277/14 0.98 0.23 0.30
046) 1.01
244)
Setting
28 0.61 0.00
Vasoplegia 16 23.2 (87/374) 0.73 0.33
(97/346) 0.88 08
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 14 19.5 (58/298) 25.3 0.74 0.60 0.00 0.38
ors (79/312) 0.91 5
60.4 0.61
Sepsis 7 43.8 (62/141) 0.76 0.02 0.66
(61/101) 0.95
52.9 0.35
Inotropes 2 26.8 (15/56) 0.58 0.04 0.79
(18/34) 0.98
Vasopress 64.2 0.62
5 50.8 (33/65) 0.81 0.11 0.85
ors (43/67) 1.05
4.1
Cardiac 0.50
70 2.7 (51/1899) (77/1884 0.70 0.03 0.90
surgery 0.96
)
3.9
0.55
Inotropes 63 3 (51/1700) (65/1671 0.79 0.21 0.94
1.14
)
Vasopress 5.6 0.03 0.00
7 0 (0/199) 0.13 0.90
ors (12/213) 0.56 7
25
23.8 0.93
Heart failure 47 (1778/71 0.98 0.45 0.66
(1800/7566) 1.03
24)
17.5
- 0.90
18 17.7 (383/2158) (406/232 1.02 0.79 0.67
adrenergic 1.15
2)
13.8
Levosimen 0.70
27 12.5 (235/1873) (179/129 0.85 0.07 0.51
dan 1.02
9)
33.9
33.4 0.93
Digoxin 3 (1197/35 0.99 0.74 0.65
(1182/3535) 1.06
26)
11.6
Acute heart 0.78
24 13.5 (293/2161) (275/201 0.91 0.26 0.75
failurea 1.07
6)
Chronic 29.7
28.2 0.92
stable heart 23 (1503/51 0.99 0.73 0.43
(1507/5405) 1.06
failure 08)
97.9
Cardiac 98.3 0.99
6 (2001/20 1.00 0.41 0.45
arrest (1991/2026) 1.01
44)
Major non- 21 9 (78/871) 8.5 0.92 0.62 0.67 0.34
cardiac
(59/697) 1.36
surgery
Vascular 8.8 0.56
5 12.7 (8/63) 1.32 0.52 0.75
surgery (6/68) 3.09
Liver 0.60
6 6.3 (12/189) 4 (8/199) 1.42 0.42 0.99
Haemodyna
12.7 0.26
mic 6 9.8 (53/539) 0.56 0.14 0.07
(44/345) 1.21
optimization
Liver 21.3
0.80
cirrhosis 10 22.1 (143/839) (166/119 0.98 0.85 0.22
1.20
complications 1)
Study drug
22.2
22.4 (2419/11 0.93
Inotropes 145 (2411/10 0.97 0.18 0.69
053) 1.01
959)
16.3
Routinely 16.9 0.89
133 (1171/70 0.95 0.08 0.11
usedb (1194/7214) 1.01
86)
32
Other 31.9 0.93
12 (1240/38 0.99 0.81 0.66
inotropesc (1225/3839) 1.06
73)
56.5
33 (1865/32 1.00 0.78 0.60
s (1821/2915) 1.02
98)
21.2
Catecholami 0.91
58 23.6 (640/2706) (674/317 0.97 0.26 0.58
nes 1.02
1)
Dobutamin 6.7 0.62
15 7.4 (30/402) 0.89 0.53 0.49
e (34/507) 1.28
14.6
0.81
Dopamine 23 15.3 (127/828) (169/115 0.98 0.83 0.97
1.19
6)
Dopexami 13.6 0.70
16 13.1 (86/654) 0.91 0.50 0.84
ne (72/531) 1.19
2.5 0.06
Ephedrine 2 2 (2/100) 0.67 0.74 N/A
(1/40) 7.09
37.5
Epinephrin 0.91
6 57.2 (357/624) (373/994 0.99 0.71 0.0002
e 1.07
)
1 97.3 (36/37) 1.02 0.63 N/A
nol (40/42) 1.11
Norepinep
hrine
Phenyleph 3.2 0.18
2 3.3 (2/61) 1.02 0.98 0.36
rine (2/62) 5.67
14
PDE-3 0.90
32 144 (329/2286) (315/225 1.04 0.61 0.62
inhibitors 1.19
3)
1.1 0.39
Amrinone 5 2.4 (4/166) 1.79 0.45 0.70
(2/178) 8.17
20.6
0.88
Enoximone 10 20.7 (267/1287) (259/125 1.02 0.76 0.31
1.19
5)
6.5 0.75
Milrinone 18 7 (58/833) 1.06 0.75 0.56
(54/830) 1.50
12.4
48 11 (263/2395) (227/182 0.80 0.64
an 0.94 8
4)
59.4
25 (1841/31 1.01 0.44 0.64
s (1805/2716) 1.03
00)
15.7
Terlipressi 0.87
13 18.5 (164/887) (195/124 1.02 0.79 0.26
n 1.20
3)
88.6
12 (1646/18 1.01 0.33 0.76
n (1641/1829) 1.02
57)
Methylene 16.2 0.37
6 10.1 (14/138) 0.64 0.11 0.28
Blue (22/136) 1.10
31.6
32.1 0.93
Digoxin 9 (1199/37 0.99 0.80 0.47
(1187/3702) 1.06
91)
Follow-up
43.1
43.5 0.99
Hospital stay 59 (1844/42 1.01 0.44 0.88
(1866/4294) 1.03
80)
10.1
0.90
Inotropes 52 10.5 (257/2447) (246/244 1.00 0.97 0.80
1.12
6)
85.7
Vasopress 87.1 1.00
8 (1599/18 1.01 0.18 0.81
ors (1609/1847) 1.02
66)
26.1
0.57
One month 35 20.2 (305/1507) (312/119 0.75 0.04 <0.0001
0.98
7)
10.3 0.51 0.00
Inotropes 28 7.1 (84/1176) 0.67 0.86
(93/901) 0.89 5
59
Vasopress 0.90
8 58.1 (221/380) (220/373 0.98 0.52 0.47
ors 1.05
)
85.8
86.7 0.99
One yr 10 (1496/17 1.00 0.94 0.36
(1475/1704) 1.02
43)
25.4 0.62
Inotropes 9 19.5 (51/262) 0.83 0.22 0.82
(74/291) 1.11
97.9
Vasopress 98.8 1.00
1 (1422/14 1.01 0.08 N/A
ors (1424/1442) 1.02
52)
Studies with 34.3
35.5 (3941/11 0.97
at least 100 46 (3907/11 1.00 0.95 0.48
098) 1.03
patients 389)
Studies with 26.4
24.7 (2479/10 0.94
placebo as 111 (2394/90 0.98 0.36 0.92
026) 1.02
control 80)
20.9
Conventional 19.9 (2118/10 0.91
150 (2092/99 0.96 0.13 0.62
settings 629) 1.01
96)
Therapeutic 80 37.8 (4118/10 37.6 0.99 0.97 0.50 0.33
drug 906) (4127/10 1.02
administration 964)
Prophylactic 4.7
0.65
drug 97 4.5 (140/3126) (155/327 0.80 0.04 0.89
0.99
administration 6)
Studies with 37.25
0.97
a low risk of 59 38 (3369/8865) (3348/89 1.00 0.76 0.69
1.03
bias 86)
Overall 30
30.3 (4255/14 0.89
analysis using 177 (4277/14 0.96d 0.23 0.77
046) 1.03
ORs 244)
Overall 30
30.3 (4255/14 0.0 0.01
analysis using 177 (4277/14 0.24 0.99
046) 0e 0.00
RDs 244)
Influence
analysis
(removing one
study at time)
Meta-regression analyses did not find a significant effect of disease severity (slope=0.0003,
95% CI 0.0010.0005, P=0.44; Supplementary data Fig.
S2 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1), duration of treatment
(slope=0.00001, 95% CI 0.000070.0001, P=0.77; Supplementary data Fig.
S3 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1), and age (slope=0.004, 95% CI
0.010.001, P=0.13; Supplementary data Fig.
S4 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1), on our results. Forest plots of the
main analysis and sub-group analyses with a statistically significant result are available as
supplementary material (Supplementary data Fig. S5
11 http://bja.oxfordjournals.org/content/115/5/656/suppl/DC1).
Discussion
The most important finding of this study is that, according to published randomized evidence,
inotropic and vasoconstrictors have no detrimental effect on survival. This is important for
clinicians who routinely use these drugs in critically ill patients to stabilize haemodynamics and
might surprise some who are aware that a few RCTs reported a detrimental effect on survival.[6
8,193]
Notably, the most relevant of these randomized trials showing a poor outcome in patients
receiving inotropic agents (e.g. the PROMISE study[6] and the Xamoterol in Severe Heart Failure
study[7]) were done in the setting of chronic, stable heart failure. In our study we did not find an
increase in mortality in this setting with the use of inotropes; however, several studies on
inotrope use in chronic heart failure, such as the above mentioned, were published before 1994
and were therefore excluded in our analysis. In the last 20 yr, the largest studies published in
this setting were the Digitalis Investigation Group (DIG) trial (1997),[57] the Vesnarinone Trial
(1998)[8] and the ESSENTIALs trials (2009).[122] The DIG trial enrolled 6,800 patients and is, to
the best of our knowledge, the largest RCT ever performed on an inotrope; it compared digoxin
with placebo and found that, although digoxin reduced the rate of hospitalizations, it did not
affect all-cause mortality.[57] The Vesnarinone Trial (3,833 patients, the second largest trial on
inotropes ever performed) found that vesnarinone (a mild phosphodiesterase inhibitor with
several effects on intracellular ion balance) increased mortality in a dose-dependent manner.
[8]
In the two ESSENTIAL trials 1854 patients were randomized to low-dose oral enoximone or
placebo; enoximone treatment did not affect mortality nor improved major clinical outcomes.
[122]
Of note, all the above mentioned trials evaluated daily oral administration of inotropic agents.
Because of the results of these and earlier trials, treatment with inotropes in stable heart failure
is currently contraindicated and can be considered only when palliative or bridge therapy is
required.[194,195] A possible exception might be intermittent i.v. levosimendan administration in
patients with advanced heart failure. In recent meta-analyses levosimendan improved survival in
both cardiology and cardiac surgery settings[14] and pulsed levosimendan has been showed to
reduce mid-term mortality in advanced heart failure.[196]
If we specifically consider acute or decompensated heart failure, the effect of inotropes is less
defined. There are some evidences from observational studies that inotropes in general and
catecholamines in particular could increase mortality.[79]Moreover, in a meta-regression analysis,
Thackray and colleagues[11] found a non-significant increase in mortality associated with i.v.
inotropes use, as compared with placebo or non-inotropic control. On the other hand, no
randomized study has yet demonstrated a clear positive or negative effect of inotropic drugs on
survival. In the largest trial, the OPTIME-CHF study, patients with acutely decompensated heart
failure were randomized to a 48-h infusion of milrinone or placebo.[49] The investigators found no
difference in 60-day mortality rate; however, they found an increase in early adverse events
related to arrhythmias or hypotension in the milrinone-treated group.[49] A post-hoc analysis of
this trial suggested that milrinone might be harmful in patients with ischaemic heart failure,
whereas it could be beneficial in patients with non-ischaemic cardiomyopathy.[197] The authors
hypothesized that this effect could be as a result of the accelerated apoptosis, and thus heart
failure progression, in the chronically ischaemic, hibernating myocardium, mediated by the
adrenergic signaling pathways.[197,198] The recent ROSE trial investigated the effect of dopamine,
nesiritide and placebo on renal function in decompensated heart failure patients (360 patients
randomized); the authors reported no difference in mortality at 180-days follow-up; however
dopamine was used at low-dose (2 g kg1 min1) and mortality was not the primary endpoint of
the study.[44] Most of the other major trials in the setting of acute or decompensated heart failure
evaluated levosimendan, and these trials showed controversial results, with levosimendan
having either a beneficial or neutral effect on survival. In our study, that includes the major trials
performed on patients with acute heart failure, we found no difference in mortality between
patients treated with inotropes and control patients in this particular setting.
In cardiac surgery, inotropes are used in 2090% of patients, depending on the preoperative
state, complexity of procedure, patient's response to surgery and physician attitude.[12,13,199] The
most common reason to administer inotropes in this setting is to prevent or treat postoperative
low-cardiac output syndrome, a complication that increases both morbidity and mortality.
[192]
Some observational trials reported increased mortality associated with inotropes use in the
setting of cardiac surgery;[12,13]however others found no difference in major clinical outcomes
between patients who received inotropes and those who did not.[199] We found that inotropes do
not seem to increase mortality in cardiac surgery. On the contrary, treatment with inotropic and
vasopressor drugs was associated with improved survival.
Unfortunately, despite being so widely used in the perioperative period, large, randomized trials
focusing on clinically relevant endpoints are lacking.[192]
In our systematic review we found no study randomizing patients with severe vasodilatory shock
to norepinephrine or no vasopressor therapy. Nonetheless, we found trials investigating the
effect of non-catecholaminergic vasopressors (i.e. vasopressin, terlipressin and methylene blue)
vs placebo or standard treatment. Because of the possible side-effects of catecholamines,[2
5]
interest in new vasopressors acting through pathways other than the adrenergic pathway has
recently developed.[200] Interestingly, we found that treatment with these agents in patients with
or at risk for vasoplegia and vasodilatory shock might be associated with a significant increase
in survival. It is worth noticing that the recent VASST trial found no difference in mortality
between patients with septic shock treated with norepinephrine or vasopressin,[201] while a recent
meta-analysis, including also the VASST trial, suggested that vasopressin and terlipressin might
reduce mortality in patients with vasodilatory shock.[201] Further researches on the topic are
therefore recommended.
If we consider the different drugs, we found that levosimendan is the only drug that significantly
improved survival. This result is consistent with a previous meta-analysis.[14] However, despite
being a promising and extensively studied agent, levosimendan has not yet been shown to
improve survival in large, multicenter randomized clinical trials. Three additional trials on
levosimendan use in the setting of cardiac surgery (HSR-LEVO, NCT00994825 LICORN,
P110138 LEVO-CTS, NCT02025621) and one in the setting of sepsis (LeoPARDS
ISRCTN12776039) are currently ongoing, and are expected to better define the role of
levosimendan in treatment of critically ill patients.[202204]
The finding of an improved one-month survival in patients receiving inotrope or vasopressor

therapy, should be considered with caution, as only 17% of trials reported one-month mortality
and this trend was diluted when including one-yr follow-up data. It is worth noting that although
concerns regarding the safety of inotropes have been raised, particularly towards their effect on
long-term mortality, unfortunately, only 5.6% of studies reported this information. The need for a
systematic report of long-term outcome have been also highlighted by recently published
guidelines from the European Society of Anaesthesiology/European Society of Intensive Care
Medicine for reporting outcome of trials in perioperative medicine.[205]
Finally, we found that inotrope or vasopressor therapy may improve survival when administered
prophylactically, a finding which is in contrast with the general agreement that these drugs
should be reserved for critically ill patients. Indeed, preemptive haemodynamic optimization
(which usually imply administration of inotropes and fluids) seems to improve survival in high-
risk surgical patients.[206] On the contrary, it has not shown efficacy in critically ill patients,
[193,207]
and even the concept of early goal-directed therapy for septic shock,[208] a mainstay of
sepsis treatment, has been recently challenged by recent large trials.[209211]
Limitations
Our study has several limitations. First of all, we investigated heterogeneous settings ranging
from septic patients to those undergoing cardiac surgery to those suffering from complications
of liver cirrhosis such as hepatorenal syndrome. Patients' follow-up also varies widely among
the different studies. In addition, we investigated the effect of a large number of different drugs,
with different mechanisms of actions, indications and side-effects. Nonetheless, all sub-analyses
confirmed magnitude and direction of our main results. Another important limitation we have to
acknowledge is that it is likely that statistically significant results have been influenced by trials
investigating levosimendan, (the only drug associated with a statistically significant survival
benefit), which consisted of 27% of all included trials. Therefore, these results should be
interpreted with caution. Furthermore, we excluded trials investigating drugs that are not
anymore available for prescription, usually because of negative results of the trials. Examples of
such agents include vesnarinone, pimobendan, ibopamine and tilargine acetate.
A strength of our study is that we included only trials published after 1st January 1994. Even if,
as a consequence, several trials were excluded, the most important of which is probably the
PROMISE study from 1991,[6] this adds modernity to our meta-analysis. It is likely that, including
also the early-1990s trials on inotropes use in chronic stable heart failure, we would have found
that inotropes increase mortality in this subset of patients. On the contrary, we are not aware of
other large, randomized trials performed in other clinical settings before 1994 that might have
importantly influenced our results.
Conclusions
Our study shows that in the overall analyses and in different clinical settings, inotropes and
vasopressor use was not associated with an increase in mortality, according to published
randomized evidences. On the contrary, vasoactive agents administration in vasodilatory shock
and cardiac surgery, and prophylactic administration of vasoactive agents, might improve
survival. We also observed a beneficial overall effect of inotropic and vasoconstrictors at one-
month follow-up. It is worth noting that we found no randomized study comparing treatment with
an inotropic/vasopressor drug and no treatment at all with such medications in critically ill,
unstable patients, nor are we aware of any trial with such a design published before 1994 or
ongoing. This may reflect the fact that, despite concerns expressed in observational studies,
clinicians' belief is that inotropic/vasopressor drugs improve patients' survival, when used
appropriately. Our study suggests that inotropes are not detrimental per se; as for many other
drugs, accurate evaluation of benefits and risks and selection of the correct agent is required in
every clinical setting.
Sidebar
Editor's Key Points
Vasoactive therapies are intended to improve end-organ perfusion but complexity and
side-effects limit their use
Clinical trials of inotropic therapy in heart failure have shown worse survival
Selective vasoactive therapy in appropriate settings is likely to benefit some patients
Vasoactive therapy seems to be beneficial in vasodilatory shock and at least some

cardiac surgery
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The Effect of Inotropes and Vasopressors On Mortality

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The Effect of Inotropes and Vasopressors on

Abstract and Introduction

Drug Number of studies

Flow diagram for the selection of studies.

Excluded papers are available in the Supplementary data

Drug Number of studies

Analysis Numb Inotropes/vasopre Controls Risk 95% P for P for

Finally, we found an improvement in survival when study drugs were administered

The finding of an improved one-month survival in patients receiving inotrope or vasopressor

Selective vasoactive therapy in appropriate settings is likely to benefit some patients

Vasoactive therapy seems to be beneficial in vasodilatory shock and at least some

9. Mebazaa A, Parissis J, Porcher R, et al. Short-term survival by treatment among patients

14. Landoni G, Biondi-Zoccai G, Greco M, et al. Effects of levosimendan on mortality and

23. Arbeus M, Axelsson B, Friberg O, Magnuson A, Bodin L, Hultman J. Milrinone increases

25. Bach F, Silomon M, Grundmann U, Strner J, Graeter T, Larsen R. [Effects of

26. Bach F, Grundmann U, Bauer M, et al. Modulation of the inflammatory response to

29. Baldwin L, Henderson A, Hickman P. Effect of postoperative low-dose dopamine on renal

31. Baysal A, Yanartas M, Dogukan M, Gundogus N, Kocak T, Koksal C. Levosimendan

32. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Lowdose dopamine in patients

33. Berendes E, Mllhoff T, Van Aken H, et al. Effects of dopexamine on creatinine

34. Berger R, Moertl D, Huelsmann M, et al. Levosimendan and prostaglandin E1 for

39. Bragadottir G, Redfors B, Ricksten SE. Effects of levosimendan on glomerular filtration

46. Cotter G, Weissgarten J, Metzkor E, et al. Increased toxicity of high-dose furosemide

62. Ensinger H, Rantala A, Vogt J, Georgieff M, Takala J. Effect of dobutamine on splanchnic

71. Grdebck M, Settergren G, Ohquist G, Tirn C. Effect of dopexamine on calculated low

76. Hamada Y, Kawachi K, Yamamoto T, et al. Effects of single administration of a

77. Hasija S, Makhija N, Choudhury M, Hote M, Chauhan S, Kiran U. Prophylactic

78. Hayashida N, Tomoeda H, Oda T, et al. Inhibitory effect of milrinone on cytokine

82. Husedzinovi I, Barisin S, Bradi N, Barisin A, Sonicki Z, Milanovi R. Levosimendan as

83. Ikonomidis I, Parissis JT, Paraskevaidis I, et al. Effects of levosimendan on coronary

86. Jaffe R, Rubinshtein R, Feigenberg Z, et al. Evaluation of isoproterenol in patients

87. Jrvel K, Maaranen P, Sisto T, Ruokonen E. Levosimendan in aortic valve surgery:

92. Jondeau G, Dubourg O, Delorme G, et al. Oral enoximone as a substitute for

102. Lahtinen P, Pitknen O, Plnen P, Turpeinen A, Kiviniemi V, Uusaro A.

103. Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of

107. Leppikangas H, Tenhunen JJ, Lindgren L, Salenius JP, Ruokonen E. Effects of

110. Lilleberg J, Laine M, Palkama T, Kivikko M, Pohjanjousi P, Kupari M. Duration of

111. Llorens P, Mir , Romn F, Zapater P, Carbajosa-Dalmau J, Llanos L. Efficacy

113. Lowes BD, Higginbotham M, Petrovich L, et al. Low-dose enoximone improves

116. Malfatto G, Della Rosa F, Villani A, et al. Intermittent levosimendan infusions in

119. Mavrogeni S, Giamouzis G, Papadopoulou E, et al. A 6-month follow-up of

120. McGinley J, Lynch L, Hubbard K, McCoy D, Cunningham AJ. Dopexamine

121. Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The influence of

123. Modine T, Decoene C, Al-Ruzzeh S, et al. Dobutamine improves thoracic aortic

129. Morelli A, Ertmer C, Lange M, et al. Effects of short-term simultaneous infusion of

133. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral

140. Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue administration in

141. Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term

142. Papadopoulos G, Sintou E, Siminelakis S, Koletsis E, Baikoussis NG,

143. Parissis JT, Papadopoulos C, Nikolaou M, et al. Effects of levosimendan on

145. Parviainen I, Ruokonen E, Takala J. Dobutamine-induced dissociation between

146. Pasqui AL, Maffei S, Di Renzo M, Pompella G, Auteri A, Puccetti L.

149. Reyad AR, Elkharboutly W, Wahba A, Elmorshedi M, Hasaneen NA. Effect of

150. Ristikankare A, Pyhi R, Eriksson H, Valtonen M, Leino K, Salmenper M.

152. Santarpino G, Caroleo S, Onorati F, et al. Inflammatory response to

153. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-

154. Schmoelz M, Schelling G, Dunker M, Irlbeck M. Comparison of systemic and

156. Shah B, Sharma P, Brahmbhatt A, et al. Study of levosimendan during off-pump

157. Sharma P, Malhotra A, Gandhi S, Garg P, Bishnoi A, Gandhi H. Preoperative

162. Siostrzonek P, Koreny M, Delle-Karth G, Haumer M, Koller-Strametz J, Heinz G.

166. Sorbello M, Morello G, Paratore A, et al. Fenoldopam vs dopamine as a

167. Sorbello M, Morello G, Parrinello L, et al. Effect of N-acetylcysteine (NAC) added