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REVIEW ARTICLE

Scandinavian SSAI clinical practice guideline on choice of


inotropic agent for patients with acute circulatory failure
M. H. Møller1 , A. Granholm1 , E. Junttila2 , M. Haney3 , A. Oscarsson-Tibblin4, A. Haavind5,
€ Sverrisson8 and A. Perner1
J. H. Laake6, E. Wilkman7, K. O.
1
Department of Intensive Care 4131, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
2
Department of Anaesthesiology, Tampere University Hospital, Tampere, Finland
3
Anaesthesiology and Intensive Care Medicine, Ume a University, Ume
a, Sweden
4
Department of Anaesthesiology and Intensive Care, Department of Medicine and Health, Linko €ping University, Linko
€ping, Sweden
5
Department of Anaesthesiology and Intensive Care, University Hospital Northern Norway, Tromsø, Norway
6
Division of Critical Care, Oslo University Hospital, Oslo, Norway
7
Division of Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine, Helsinki University Hospital, University of
Helsinki, Helsinki, Finland
8
Department of Anesthesia & Critical Care, Landspitali University Hospital of Iceland, Reykjavik, Iceland

Correspondence Background: Adult critically ill patients often suffer from acute
M. H. Møller, Department of Intensive Care circulatory failure and those with low cardiac output may be treated
4131, Copenhagen University Hospital
with inotropic agents. The aim of this Scandinavian Society of
Rigshospitalet, Blegdamsvej 9, DK - 2100
Copenhagen, Denmark
Anaesthesiology and Intensive Care Medicine guideline was to pre-
E-mail: mortenhylander@gmail.com sent patient-important treatment recommendations on this topic.
Methods: This guideline was developed according to GRADE. We
Conflict of interest assessed the following subpopulations of patients with shock: (1)
The authors declare no relevant conflicts of shock in general, (2) septic shock, (3) cardiogenic shock, (4) hypov-
interest. olemic shock, (5) shock after cardiac surgery, and (6) other types of
shock, including vasodilatory shock. We assessed patient-important
Funding
This guideline was initiated and supported by
outcome measures, including mortality and serious adverse reactions.
the Scandinavian Society of Anaesthesiology Results: For all patients, we suggest against the routine use of any
and Intensive Care Medicine (SSAI). inotropic agent, including dobutamine, as compared to placebo/no treat-
ment (very low quality of evidence). For patients with shock in general,
Submitted 28 December 2017; accepted 3 and in those with septic and other types of shock, we suggest using
January 2018; submission 24 November 2017. dobutamine rather than levosimendan or epinephrine (very low quality
of evidence). For patients with cardiogenic shock and in those with
Citation
Møller MH, Granholm A, Junttila E, Haney M,
shock after cardiac surgery, we suggest using dobutamine rather than
Oscarsson-Tibblin A, Haavind A, Laake JH, milrinone (very low quality of evidence). For the other clinical ques-
€ Sverrisson K, Perner A.
Wilkman E, Orn tions, we refrained from giving any recommendations or suggestions.
Scandinavian SSAI clinical practice guideline on Conclusions: We suggest against the routine use of any inotropic agent
choice of inotropic agent for patients with in adult patients with shock. If used, we suggest using dobutamine
acute circulatory failure. Acta rather than other inotropic agents for the majority of patients, however,
Anaesthesiologica Scandinavica 2018
the quality of evidence was very low, implying high uncertainty on the
doi: 10.1111/aas.13089
balance between the benefits and harms of inotropic agents.

Editorial comment
Failure to generate sufficient cardiac output is a challenge in patients with acute circulatory fail-
ure. This guideline analyzes the available evidence for increasing inotropy, which is scarce. It con-
cludes that no agent should be used on a routine basis, while dobutamine emerges as the drug of
choice when applied with caution to specific patient groups.

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 1

An international journal of anaesthesiology, intensive


care, pain, and critical emergency medicine
M. H. MØLLER ET AL.

Acute circulatory failure or shock is a life-threa- Methods


tening condition that needs prompt and ade-
quate treatment, as it may progress to organ Process
failure and death. Shock is a common condition
The Clinical Practice Committee of SSAI
in critical care medicine, affecting about one
appointed national members of the guideline
third of patients in the intensive care unit
task force for Acute Circulatory Failure (the
(ICU).1
authors of this study). This group identified four
Resuscitation of patients in shock must be
key interventions needing guidelines, including
early and appropriate to prevent or limit vital
fluid resuscitation,2 vasopressor therapy,3 ino-
organ injury. Initial support of the failing cir-
tropic therapy, and cardiovascular diagnostics
culation usually includes fluid resuscitation
and monitoring. This is the group’s third guide-
in combination with the administration of a
line: choice of inotropic agent for adult patients
vasopressor.1 In two recently published Scan-
with acute circulatory failure.
dinavian Society of Anaesthesiology and
We have prepared this guideline according to
Intensive Care Medicine (SSAI) clinical prac-
the AGREE statement.10
tice guidelines, we have proposed recommen-
dations regarding choice of fluid2 and choice
of first-line vasopressor 3 in the management Clinical question
of adult patients with acute circulatory fail-
ure. In collaboration with the Canadian Criti- ‘Which inotropic agent should be used for
cal Care Society, SSAI has also recently adult critically ill patients with acute circula-
issued recommendations for blood pressure tory failure?’
targets in adult critically ill patients with
hypotension.4 Population
Subsets of patients with shock, including
patients with heart failure may, however, The population of interest was adult patients (as
not respond adequately to volume expansion defined in the original trials) with acute circula-
and vasopressors, and additional support, tory failure/shock (as defined in the original tri-
including administration of inotropic agents als) receiving inotropes in a high-dependency
may be required to restore cardiac output setting in hospital, including the emergency
and organ perfusion. Inotropic agents com- department, ICU, operating room, and recovery
monly used include the synthetic cate- room. The following subpopulations were
cholamine dobutamine, the endogenous assessed: patients with (1) shock in general
catecholamine epinephrine, the phosphodi- (any type of shock), (2) septic shock, (3) cardio-
esterase III inhibitor milrinone, and the genic shock, (4) hypovolemic shock, (5) shock
calcium sensitizer levosimendan. 5 Further- after cardiac surgery, and (6) other types of
more, dopamine possesses inotropic proper- shock, including vasodilatory shock.
ties, and is sometimes used as an inotropic Acute circulatory failure and shock are used
agent.6 interchangeably throughout this guideline, and
The Clinical Practice Committee of the SSAI were defined as inadequate/hypoperfusion of
initiated this guideline on choice of inotropic tissue and organs.
agent in adult patients with acute circulatory
failure. The aim was to summarize the available
Intervention(s)
evidence and provide recommendations accord-
ing to current standards for trustworthy guide- We assessed any dose of the following ino-
lines.7–9 tropes: (1) levosimendan, (2) milrinone, (3) epi-
nephrine, (4) dopamine, and (5) placebo/no
treatment.
An electronic version of this guideline can be We defined inotropic agents as drugs with
accessed at www.ssai.info/guidelines/ positive inotropic effect leading to increased
stroke volume and cardiac output.
Acta Anaesthesiologica Scandinavica (2018)
2 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

Comparator for systematic reviews of randomized clinical tri-


als (RCTs) and RCTs comparing dobutamine
The control inotropic agent was dobutamine
with other inotropic agents on 25 September
(any dose).
2017. No language restriction was employed.
We expected dobutamine to be the most
We used the following search strategies:
widely studied drug, and thus chose dobu-
1. PubMed: (dobutamine OR inotrope* OR inodilat*)
tamine as the comparator and the other ino-
AND (levosimendan OR milrinone OR epinephrine
tropes as experimental interventions.
OR dopamine OR placebo OR ‘control’ OR ‘no
treatment’) AND (shock OR cardiac OR ‘heart
Outcome(s) failure’). Filters: ‘Randomized controlled trials’
‘Systematic reviews’; and ‘Meta-analyses’.
The following patient-important outcome mea-
2. Cochrane Library: ‘shock’ using the
sures11 were assessed at the time of longest fol-
‘Cochrane Review’ filter.
low-up:
3. Epistemonikos: same search as for PubMed
Critical outcomes
adapted and without filters.
1. Short-term mortality (0–90 days, including
in-ICU and in-hospital mortality)
2. Long-term mortality (more than 90 days) Statistics and GRADE
3. Quality of life as defined in the included trials Specific clinical questions were formulated
Important outcomes using the relevant patient population and/or
4. Ischemic events as defined in the included clinical problem (P), the intervention (I) under
trials scrutiny, the comparator (C), and the predefined
5. Use of renal replacement therapy patient-important outcomes (O)12 – PICO ques-
6. Acute kidney injury as defined in the tions (Table 1).
included trials Mantel-Haenszel statistics and random effects
7. Dysrhythmias as defined in the included models were used to generate summary esti-
trials mates/meta-analyses (Review Manager Version
8. Hospital length-of-stay (LOS) 5.3, The Nordic Cochrane Centre, The Cochrane
Collaboration, Copenhagen, Denmark).
We excluded systematic reviews and trials We used trial sequential analysis (TSA) to
done in children, those assessing prophylactic assess the risk of random errors (spurious find-
use of inotropes, those not reporting the prede- ings) due to repetitive testing and sparse data13.
fined patient-important outcome measures, and TSA was applied using an a priori 20% relative
those not comparing dobutamine vs. another risk reduction, an alfa of 5%, beta of 90%, and
inotropic agent, including those comparing a control event proportion according to the
combinations of inotropes or head-to-head results from the included trials. TSA-adjusted
comparison of other inotropes than dobu- 95% confidence intervals (CIs) were estimated
tamine. Systematic reviews and trials allowing (Appendix S1) and are reported in the summary
the use of adjuvant vasopressors were not of finding tables (Appendix S2). If less than 5%
excluded if the vasopressor used was identical of the required information size had been
in both arms. Cross-over trials and trials in accrued, no TSA could be conducted.
which patients were systematically treated We used the Grading of Recommendations
with either the intervention or comparator drug Assessment, Development and Evaluation
prior to or after randomization were also (GRADE) system for formulating clinical ques-
excluded. tions, assessing the quality of evidence, generat-
ing anticipated absolute effects, and for moving
from evidence to recommendations.9 In brief, we
Search strategy
downgraded the quality of evidence (our confi-
We systematically searched PubMed (January dence in the effect estimates) for an intervention
1966 to 25 September 2017), Cochrane Library for identified risks of bias (including baseline
(Issue 4, September 2017), and Epistemonikos imbalance, lack of blinding, academic/financial
Acta Anaesthesiologica Scandinavica (2018)
ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 3
M. H. MØLLER ET AL.

Table 1 Clinical research questions and PICO questions used to assess evidence relevant to this guideline statement.

PICO Question

Clinical question Population (P) Intervention (I) Comparator (C) Outcomes (O)

Should Adult patients with acute 1. Levosimendan Dobutamine 1. Short-term mortality


dobutamine or circulatory failure divided into 2. Milrinone 2. Long-term mortality
other inotropes the following subgroups: 3. Epinephrine 3. Quality of life
be used for adult 1. Shock in general 4. Dopamine 4. Ischemic events
patients with 2. Septic shock 5. Placebo/no treatment 5. Renal replacement therapy
acute circulatory 3. Cardiogenic shock 6. Acute kidney injury
failure? 4. Hypovolemic shock 7. Dysrhythmias
5. Shock after cardiac surgery 8. Length of hospital stay
6. Other types of shock, includ-
ing vasodilatory shock

conflicts of interest, or early termination of trials), recommendation basis (Appendix S3), a peer
inconsistency (unexplained heterogeneity), indi- review process, and a plan for updating of rec-
rectness (including extrapolation from other ommendations. We did not include patient rep-
patient populations or use of surrogate out- resentatives in the guideline process.
comes), imprecision (wide confidence interval
around the effect estimate), or publication bias. Results
Accordingly, the quality of evidence was rated The results and recommendations based on the
from ‘high’ to ‘very low’. We used GradePro v. PICOs are presented below, in Table 2, and in
3.5 to prepare summary of finding tables with the summary of finding tables given in
anticipated relative and absolute effects for the Appendix S2.
outcomes, together with our confidence in the
effect estimates (Appendix S2).
A. Dobutamine vs. other inotropes in
When moving from evidence to recommenda-
patients with shock in general
tions, four factors were considered and integrated:
benefits and harms, quality of evidence, values
and preferences (of patients or their proxies), and
cost considerations. GRADE classifies recommen- 1. We suggest that dobutamine is used as
dations as ‘strong’ when virtually all informed inotropic agent for patients with shock in
patients would choose the recommended manage- general rather than levosimendan (weak
ment strategy. ‘Weak’ recommendations apply recommendation, very low quality of evi-
when fully informed patients would choose dif- dence).
ferent management strategies, and reflects a close
call between benefits and harms, uncertainty
regarding treatment effects, questionable cost No systematic reviews or RCTs reporting our
effectiveness, or variability in values and prefer- predefined patient-important outcome measures
ences.9,14 The author group agreed upon all the have compared the use of dobutamine with that
recommendations in this guideline. Strong recom- of levosimendan in patients with shock in gen-
mendations were given the wording ‘we recom- eral (Fig. 1, Table S1A in Appendix S2). In refer-
mend’, and weak recommendations ‘we suggest’. ence to our recommendation for patients with
We followed standards for trustworthy guide- septic shock, we suggest using dobutamine
lines through use of the GRADE system, (extrapolation).
management of intellectual and financial The quality of evidence was downgraded due
conflicts of interest on a recommendation per to risk of bias, indirectness, and imprecision.

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4 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

Table 2 Key recommendations and quality of evidence.

Quality of evidence
Strength of the Reason(s) for
Recommendation recommendation Benefits and harms downgrading Comments

A) Use of inotropes in patients with shock in general


1. We suggest using Weak No difference in short-term Very low due to No data available for this
dobutamine rather mortality. Potential imprecision, risk population; data extrapolated
than levosimendan harm of levosimendan25 of bias, and from patients with septic shock.
indirectness The defined daily dose price of
levosimendan is about 22 times
higher than dobutamine

2. Dobutamine vs. None – – No data available; no relevant


milrinone populations to extrapolate
data from.
The defined daily dose price
of milrinone is about 100 times
higher than dobutamine

3. We suggest using Weak No difference in short-term Very low due to No data available for this
dobutamine rather mortality, ischemic imprecision, risk population; data extrapolated
than epinephrine events, and dysrhythmias. of bias, and from patients with septic shock
Excessive vasoconstriction indirectness
and tachycardia of
epinephrine may affect
cardiac output adversely6

4. Dobutamine vs. None – – No data available; no relevant


dopamine populations to extrapolate
data from

5. We suggest against Weak Potential harm of Very low due to No data available for this
the use of dobutamine dobutamine19 serious risk of bias, population; data extrapolated
as compared to and indirectness from patients with septic
placebo/no treatment shock (observational study)

B) Use of inotropes in patients with septic shock


1. We suggest using Weak No difference in short-term Very low due to The defined daily dose price of
dobutamine rather mortality. Potential imprecision, risk levosimendan is about 22 times
than levosimendan harm of levosimendan25 of bias, and higher than dobutamine
indirectness

2. Dobutamine vs. None – – No data available; no relevant


milrinone populations to extrapolate
data from.
The defined daily dose price
of milrinone is about 100 times
higher than dobutamine

3. We suggest using Weak No difference in short-term Very low due to


dobutamine rather mortality, ischemic imprecision, risk
than epinephrine events, and dysrhythmias. of bias, and
Excessive vasoconstriction indirectness
and tachycardia of

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 5
M. H. MØLLER ET AL.

Table 2 (Continued)

Quality of evidence
Strength of the Reason(s) for
Recommendation recommendation Benefits and harms downgrading Comments

epinephrine may affect


cardiac output adversely6

4. Dobutamine vs. None – – No data available; no relevant


dopamine populations to extrapolate
data from

5. We suggest against Weak Potential harm of Very low due to No data available; no relevant
the use of dobutamine dobutamine19 serious risk of RCT populations to extrapolate
as compared to bias, and data from. Observational study
placebo/no treatment indirectness suggests harm from dobutamine

C) Use of inotropes in patients with cardiogenic shock


1. Dobutamine vs. None – – The defined daily dose price of
levosimendan levosimendan is about 22 times
higher than dobutamine

2. We suggest using Weak No difference in short-term Very low due to The defined daily dose price of
dobutamine rather mortality. Unknown imprecision, risk of milrinone is about 100 times
than milrinone balance between the bias, and higher than dobutamine
benefits and harms indirectness
of milrinone15

3. Dobutamine vs. None – – No data available; no relevant


epinephrine populations to extrapolate
data from

4. Dobutamine vs. None – – No data available; no relevant


dopamine populations to extrapolate
data from

5. We suggest against Weak No difference in short-term Very low due to High risk of random errors, which
the use of dobutamine mortality or long-term imprecision, risk of cautions interpretations of the
as compared to mortality in patients bias, and findings in the meta-analyses.
placebo/no treatment treated with dobutamine. indirectness Observational study in patients
with septic shock suggests harm
from dobutamine (extrapolation).

D) Use of inotropes in patients with hypovolemic shock


1. Dobutamine vs. None – – No data available; no relevant
levosimendan populations to extrapolate data from.
The defined daily dose price
of levosimendan is about
22 times higher than dobutamine

2. Dobutamine vs. None – – No data available; no relevant


milrinone populations to extrapolate
data from.
The defined daily dose price of
milrinone is about 100 times
higher than dobutamine

Acta Anaesthesiologica Scandinavica (2018)


6 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

Table 2 (Continued)

Quality of evidence
Strength of the Reason(s) for
Recommendation recommendation Benefits and harms downgrading Comments

3. Dobutamine vs. None – – No data available; no relevant


epinephrine populations to extrapolate
data from

4. Dobutamine vs. None – – No data available; no relevant


dopamine populations to extrapolate
data from

5. We suggest against Weak Potential harm of Very low due to No data available for this
the use of dobutamine dobutamine19 serious risk of bias, population; data extrapolated
as compared to and indirectness from patients with septic shock
placebo/no treatment (observational study)

E) Use of inotropes in patients with shock after cardiac surgery


1. Dobutamine vs. None No reliable differences in – The defined daily dose price of
levosimendan short-term mortality, levosimendan is about 22 times
ischemic events, acute higher than dobutamine.
kidney injury, use Unknown balance between the
of renal replacement benefits and harms of
therapy, and dysrhythmia dobutamine vs. levosimendan
(high risk of random
errors). Potential harm
of levosimendan25

2. We suggest using Weak No difference in acute Very low due to The defined daily dose price of
dobutamine rather kidney injury and imprecision, risk milrinone is about 100 times
than milrinone dysrhythmias. Unknown of bias, and higher than dobutamine
balance between indirectness
the benefits and
harms of milrinone15

3. Dobutamine vs. None – – No data available; no relevant


epinephrine populations to extrapolate
data from

4. Dobutamine vs. dopamine None – – No data available; no relevant


populations to extrapolate
data from

5. We suggest against the Weak Potential harm of Very low due to No data available for this
use of dobutamine as dobutamine19 serious risk of bias, population; data extrapolated
compared to placebo/no and indirectness from patients with septic shock
treatment (observational study)

F) Use of inotropes in patients with other types of shock, including vasodilatory shock
1. We suggest using Weak No difference in short-term Very low due to No data available for this
dobutamine rather mortality. Potential imprecision, risk population; data extrapolated
than levosimendan harm of levosimendan25 of bias, and from patients with septic shock.
indirectness The defined daily dose price of
levosimendan is about 22 times
higher than dobutamine

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 7
M. H. MØLLER ET AL.

Table 2 (Continued)

Quality of evidence
Strength of the Reason(s) for
Recommendation recommendation Benefits and harms downgrading Comments

2. Dobutamine vs. None – – No data available; no relevant


milrinone populations to extrapolate data
from.
The defined daily dose price
of milrinone is about 100 times
higher than dobutamine

3. We suggest using Weak No difference in short-term Very low due to No data available for this
dobutamine rather mortality, ischemic imprecision, risk population; data extrapolated
than epinephrine events, and dysrhythmias. of bias, and from patients with septic shock.
Excessive vasoconstriction indirectness Epinephrine is the drug of
and tachycardia of choice in anaphylactic shock
epinephrine may
affect cardiac output
adversely6

4. Dobutamine vs. dopamine None – – No data available; no relevant


populations to extrapolate
data from

5. We suggest against Weak Potential harm of Very low due to No data available for this
the use of dobutamine dobutamine19 serious risk of bias, population; data extrapolated
as compared to and indirectness from patients with septic
placebo/no treatment shock (observational study)

circulatory failure in general.15 Of note, the


2. Dobutamine vs. milrinone for patients defined daily dose price of milrinone is about
with shock in general: no recommenda- 100 times higher than that of dobutamine.16
tion/suggestion.

3. We suggest that dobutamine is used as ino-


No systematic reviews or RCTs reporting our tropic agent for patients with shock in general
predefined patient-important outcome measures rather than epinephrine (weak recommenda-
have compared the use of dobutamine with that tion, very low quality of evidence).
of milrinone in patients with shock in general
(Fig. 1, Table S1B in Appendix S2). We refrain
from giving any recommendations or sugges- No systematic reviews or RCTs reporting our pre-
tions on using dobutamine vs. milrinone for defined patient-important outcome measures have
patients with shock in general, due to the lack compared the use of dobutamine with that of epi-
of data and no relevant populations to extrapo- nephrine in patients with shock in general (Fig. 1,
late from. Importantly, we recommend that if Table S1C in Appendix S2). In reference to our rec-
clinicians prefer to use milrinone rather than ommendation for patients with septic shock, we
dobutamine in this population, they do so in suggest using dobutamine (extrapolation).
the context of high-quality RCTs, given the lack The quality of evidence was downgraded due
of data on the balance between the benefits and to imprecision, risk of bias, and indirectness.
harms of milrinone in patients with acute

Acta Anaesthesiologica Scandinavica (2018)


8 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

A Short-term mortality
No data. 5. We suggest against routine use of dobu-
tamine as inotropic agent for patients
B Long-term mortality with shock in general, as compared to pla-
No data. cebo/no treatment (weak recommenda-
tion, very low quality of evidence).
C Quality of life
No data.
No systematic reviews or RCTs reporting our
D Ischemic events predefined patient-important outcome measures
No data. have compared the use of dobutamine with that
of placebo/no treatment in patients with shock
E Renal replacement therapy in general (Fig. 1, Table S1E in Appendix S2).
No data. Importantly, potential harm of dobutamine has
been suggested in a propensity-matched obser-
F Acute kidney injury vational study in patients with septic shock.19
No data. In reference to our recommendation for patients
with septic shock, we suggest against routine
G Dysrhythmias use of dobutamine (extrapolation).
No data. The quality of evidence was downgraded due
to serious risk of bias and indirectness.
H Hospital length-of-stay
No data. B. Dobutamine vs. other inotropes in
Fig. 1. Forest plot of (A) short-term mortality, (B) long-term mortality,
patients with septic shock
(C) quality of life, (D) ischemic events, (E) renal replacement therapy,
(F) acute kidney injury, (G) dysrhythmias, and (H) hospital length-of-
stay in randomized trials of dobutamine vs. other inotropes for 1. We suggest that dobutamine is used as ino-
patients with shock in general. tropic agent for patients with septic shock
rather than levosimendan (weak recom-
mendation, very low quality of evidence).

4. Dobutamine vs. dopamine for patients In an updated meta-analysis comprising five tri-
with shock in general: no recommenda- als,20–24 we found no statistically significant differ-
tion/suggestion. ence in short-term mortality in patients with septic
shock treated with dobutamine vs. levosimendan
(Fig. 2, Fig. S1A in Appendix S1; Table S2A in
No systematic reviews or RCTs reporting our Appendix S2). None of the other predefined
predefined patient-important outcome measures patient-important outcome measures have been
have compared the use of dobutamine with that of assessed. In the recently published LEOPARDS
dopamine in patients with shock in general trial, in which adult patients with sepsis were ran-
(Fig. 1, Table S1D in Appendix S2). We refrain domized to levosimendan or placebo, levosimendan
from giving any recommendations or suggestions was associated with a lower likelihood of successful
on using dobutamine or dopamine for patients weaning from mechanical ventilation and a higher
with shock in general, due to the lack of data and rate of supraventricular tachyarrhythmia compared
no relevant populations to extrapolate from. to placebo.25 This should caution the use of levosi-
Importantly, we recommend that if clinicians pre- mendan in patients with sepsis, which is why we
fer to use dopamine rather than dobutamine in suggest using dobutamine rather than levosimen-
this population, they do so in the context of high- dan in patients with septic shock. Of note, the
quality RCTs, given the harm associated with use defined daily dose price of levosimendan is about
of dopamine in patients with septic shock.17,18 22 times higher than that of dobutamine.16

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 9
M. H. MØLLER ET AL.

A Short-term mortality

B Long-term mortality

No data.
C Quality of life

No data.
Fig. 2. Forest plot of (A) short-term mortality, (B) long-term mortality, (C) quality of life, (D) ischemic events, (E) renal replacement therapy, (F) acute
kidney injury, (G) dysrhythmias, and (H) hospital length-of-stay in randomized trials of dobutamine vs. other inotropes for patients with septic shock.

The quality of evidence was downgraded due have compared the use of dobutamine with that of
to risk of bias, indirectness, and imprecision. milrinone in patients with septic shock (Fig. 2,
Table S2B in Appendix S2). We refrain from giv-
ing any recommendations or suggestions on using
2. Dobutamine vs. milrinone for patients with dobutamine or milrinone for patients with septic
septic shock: no recommendation/suggestion. shock, due to the lack of data and no relevant pop-
ulations to extrapolate from. Importantly, we rec-
ommend that if clinicians prefer to use milrinone
No systematic reviews or RCTs reporting our
predefined patient-important outcome measures rather than dobutamine in this population, they
do so in the context of high-quality RCTs, given
Acta Anaesthesiologica Scandinavica (2018)
10 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

D Ischemic events

E Renal replacement therapy


No data.
F Acute kidney injury
No data.
Fig. 2. Continued

the lack of data on the balance between benefits A small RCT comprising 60 patients with septic
and harms of milrinone in patients with acute cir- shock found no difference in short-term mortal-
culatory failure in general.15 Of note, the defined ity, ischemic events, and dysrhythmias between
daily dose price of milrinone is about 100 times patients treated with dobutamine vs. epinephrine
higher than that of dobutamine.16 (Fig. 2, Table S2C in Appendix S2).26 None of
our other predefined patient-important outcome
measures have been assessed. As excessive vaso-
3. We suggest that dobutamine is used as ino- constriction and tachycardia may affect cardiac
tropic agent for patients with septic shock output adversely in most patients where an ino-
rather than epinephrine (weak recommen- tropic agent is deemed indicated,6 we suggest
dation, very low quality of evidence). using dobutamine rather than epinephrine in
patients with septic shock.

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 11
M. H. MØLLER ET AL.

G Dysrhythmias

H Hospital length-of-stay
No data.
Fig. 2. Continued

The quality of evidence was downgraded due no relevant populations to extrapolate from.
to imprecision, risk of bias and indirectness. Importantly, we recommend that if clinicians
prefer to use dopamine rather than dobutamine
in this population, they do so in the context of
4. Dobutamine vs. dopamine for patients with high-quality RCTs, given the harm associated
septic shock: no recommendation/suggestion. with use of dopamine in patients with septic
shock.17,18
No systematic reviews or RCTs reporting our
predefined patient-important outcome measures
5. We suggest against routine use of dobu-
have compared use of dobutamine with dopa-
tamine as inotropic agent for patients
mine in patients with septic shock (Fig. 2,
with septic shock, as compared to pla-
Table S2D in Appendix S2). We refrain from giv-
cebo/no treatment (weak recommenda-
ing any recommendations or suggestions on
tion, very low quality of evidence).
using dobutamine or dopamine for patients
with septic shock, due to the lack of data and
Acta Anaesthesiologica Scandinavica (2018)
12 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

No systematic reviews or RCTs reporting our


predefined patient-important outcome measures
have compared use of dobutamine with pla- 2. We suggest that dobutamine is used as
cebo/no treatment in patients with septic shock inotropic agent for patients with cardiogenic
(Fig. 2, Table S2E in Appendix S2). shock rather than milrinone (weak recom-
Importantly, potential harm of dobutamine has mendation, very low quality of evidence).
been suggested in a propensity-matched observa-
tional study in patients with septic shock.19 Conse- A small RCT comprising 30 patients with cardio-
quently, we suggest against routine use of genic shock38 found no difference in short-term
dobutamine as inotropic agent for patients with mortality between patients treated with dobu-
septic shock, as compared to placebo/no treatment. tamine vs. milrinone (Fig. 3, Table S3B in
The quality of evidence was downgraded due Appendix S2). None of our other predefined
to serious risk of bias and indirectness. patient-important outcome measures have been
assessed. As the balance between the benefits and
C. Dobutamine vs. other inotropes in
harms of milrinone in patients with acute circula-
patients with cardiogenic shock
tory failure in general has been sparsely evaluated,
we suggest using dobutamine rather than milri-
none.15 The defined daily dose price of milrinone is
1. Dobutamine vs. levosimendan for
about 100 times higher than that of dobutamine.16
patients with cardiogenic shock: no recom-
The quality of evidence was downgraded due
mendation/suggestion.
to imprecision, risk of bias, and indirectness.

In an updated meta-analysis comprising six


trials, we found no statistically significant dif- 3. Dobutamine vs. epinephrine for patients
ference in short-term mortality,27–32 long-term with cardiogenic shock: no recommenda-
mortality,27,30,31,33–35 ischemic events,30,34 acute tion/suggestion.
kidney injury,31 dysrhythmias,30,36 or hospital
length-of-stay37 in patients with cardiogenic
shock treated with dobutamine vs. levosimen- No systematic reviews or RCTs reporting our
dan (Fig. 3, Fig. S2A, B, D, E in Appendix S1, predefined patient-important outcome measures
Table S3A in Appendix S2). None of our other have compared use of dobutamine with that of
predefined patient-important outcome measures epinephrine in patients with cardiogenic shock
have been assessed. In the recently published (Fig. 3, Table S3C in Appendix S2).26 We refrain
LEOPARDS trial in which adult patients with from giving any recommendations or suggestions
sepsis were randomized to levosimendan or on using dobutamine or epinephrine for patients
placebo, levosimendan was associated with a with cardiogenic shock, due to the lack of data
lower likelihood of successful weaning from and no relevant populations to extrapolate from.
mechanical ventilation and a higher risk of Importantly, excessive vasoconstriction and tachy-
supraventricular tachyarrhythmia compared to cardia increase oxygen consumption and may
placebo.25 Of note, the defined daily dose price affect cardiac output adversely in most patients
of levosimendan is about 22 times higher than where an inotropic agent is deemed indicated.6
dobutamine.16 We recommend that if clinicians
prefer to use levosimendan rather than dobu-
4. Dobutamine vs. dopamine for patients
tamine in this population, they do so in the
with cardiogenic shock: no recommenda-
context of high-quality RCTs, given the lack of
tion/suggestion.
data on the balance between the benefits and
harms of levosimendan in patients with acute
circulatory failure in general, the suggested No systematic reviews or RCTs reporting our
harm of levosimendan in patients with sepsis,25 predefined patient-important outcome measures
and the higher price. have compared use of dobutamine with

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 13
M. H. MØLLER ET AL.

A Short-term mortality

Fig. 3. Forest plot of (A) short-term mortality, (B) long-term mortality, (C) quality of life, (D) ischemic events, (E) renal replacement therapy, (F)
acute kidney injury, (G) dysrhythmias, and (H) hospital length-of-stay in randomized trials of dobutamine vs. other inotropes for patients with
cardiogenic shock.

dopamine in patients with cardiogenic shock patients with cardiogenic shock in the SOAP 2
(Fig. 3, Table S3D in Appendix S2). We refrain trial.39
from giving any recommendations or suggestions
on using dobutamine or dopamine for patients
with cardiogenic shock, due to the lack of data 5. We suggest against routine use of dobu-
and no relevant populations to extrapolate from. tamine as inotropic agent for patients
Importantly, we strongly recommend that if clini- with cardiogenic shock, as compared to
cians prefer to use dopamine rather than dobu- placebo/no treatment (weak recommen-
tamine in this population, they do so in the dation, very low quality of evidence).
context of high-quality RCTs, given the harm
associated with use of dopamine in patients with In an updated meta-analysis, we found no sta-
septic shock17,18 and in a subgroup analysis of
tistically significant difference in short-term

Acta Anaesthesiologica Scandinavica (2018)


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INOTROPES IN ACUTE CIRCULATORY FAILURE

B Long-term mortality

C Quality of life
No data.
Fig. 3. Continued

mortality (1 trial, 199 patients)27 or long-term other predefined patient-important outcome


mortality (2 trials, 245 patients)27,35 in patients measures have been assessed. Importantly, as
with cardiogenic shock treated with dobu- potential harm of dobutamine has been sug-
tamine vs. placebo/no treatment (Fig. 3, gested in patients with septic shock, we sug-
Fig. S2C in Appendix S1, Table S3E in gest against the routine use of dobutamine as
Appendix S2). TSA highlighted high risk of inotropic agent for patients with cardiogenic
random errors due to repetitive testing and shock, as compared to placebo/no treatment
small sample sizes (Fig. S2 in Appendix S1), (extrapolation).
which cautions interpretations of the findings The quality of evidence was downgraded due
in the conventional meta-analysis. None of our to imprecision, indirectness, and risk of bias.

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 15
M. H. MØLLER ET AL.

D Ischemic events

E Renal replacement therapy


No data.
Fig. 3. Continued

from giving any recommendations or sugges-


D. Dobutamine vs. other inotropes in
tions on using dobutamine or levosimendan for
patients with hypovolemic shock
patients with hypovolemic shock, due to the
lack of data and no relevant populations to
extrapolate from. In the recently published
1. Dobutamine vs. levosimendan for LEOPARDS trial in which adult patients with
patients with hypovolemic shock: no rec- sepsis were randomized to levosimendan or pla-
ommendation/suggestion. cebo, levosimendan was associated with a lower
likelihood of successful weaning from mechani-
cal ventilation and a higher risk of supraventric-
No systematic reviews or RCTs reporting our ular tachyarrhythmia compared to placebo.25
predefined patient-important outcome measures This cautions use of levosimendan in other
have compared use of dobutamine with levosi- patient groups, including patients with hypov-
mendan in patients with hypovolemic shock olemic shock. Of note, the defined daily dose
(Fig. 4, Table S4A in Appendix S2). We refrain price of levosimendan is about 22 times higher
Acta Anaesthesiologica Scandinavica (2018)
16 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

F Acute kidney injury

Fig. 3. Continued

than dobutamine.16 Importantly, adequate fluid extrapolate from. We recommend that if clini-
resuscitation – and not inodilation - should be a cians prefer to use milrinone rather than dobu-
priority in patients with hypovolemic shock. tamine in this population, they do so in the
context of high-quality RCTs, given the lack of
data on the balance between benefits and harms
2. Dobutamine vs. milrinone for patients of milrinone in patients with acute circulatory
with hypovolemic shock: no recommenda- failure in general.15 Of note, the defined daily
tion/suggestion. dose price of milrinone is about 100 times
higher than that of dobutamine.16 Importantly,
No systematic reviews or RCTs reporting our adequate fluid resuscitation – and not inodila-
predefined patient-important outcome measures tion - should be a priority in patients with
have compared use of dobutamine with milri- hypovolemic shock.
none in patients with hypovolemic shock
(Fig. 4, Table S4B in Appendix S2). We refrain
from giving any recommendations or sugges- 3. Dobutamine vs. epinephrine for patients
tions on using dobutamine or milrinone for with hypovolemic shock: no recommenda-
patients with hypovolemic shock, due to the tion/suggestion.
lack of data and no relevant populations to

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 17
M. H. MØLLER ET AL.

G Dysrhythmias

Fig. 3. Continued

No systematic reviews or RCTs reporting


our predefined patient-important outcome 4. Dobutamine vs. dopamine for patients
measures have compared use of dobutamine with hypovolemic shock: no recommenda-
with epinephrine in patients with hypovolemic tion/suggestion.
shock (Fig. 4, Table S4C in Appendix S2).26
We refrain from giving any recommendations or
suggestions on using dobutamine or epinephr- No systematic reviews or RCTs reporting our
ine for patients with hypovolemic shock, due to predefined patient-important outcome measures
the lack of data and no relevant populations to have compared use of dobutamine with dopamine
extrapolate from. Importantly, excessive vaso- in patients with hypovolemic shock (Fig. 4,
constriction and tachycardia increase oxygen Table S4D in Appendix S2). We refrain from giv-
consumption and may affect cardiac output ing any recommendations or suggestions on using
adversely in most patients where an inotropic dobutamine or dopamine for patients with hypov-
agent is deemed indicated.6 Importantly, ade- olemic shock, due to the lack of data and no rele-
quate fluid resuscitation should be a priority in vant populations to extrapolate from. Importantly,
patients with hypovolemic shock. we strongly recommend that if clinicians prefer to

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INOTROPES IN ACUTE CIRCULATORY FAILURE

H Hospital length-of-stay

Fig. 3. Continued

use dopamine rather than dobutamine in this pop- observational study in patients with septic
ulation, they do so in the context of high-quality shock.19 In reference to our recommendation for
RCTs, given the harm associated with use of dopa- patients with septic shock, we suggest against
mine in patients with septic shock17,18 and in a routine use of dobutamine (extrapolation). Of
subgroup analysis of patients with cardiogenic note, adequate fluid resuscitation should be a
shock in the SOAP 2 trial.39 Importantly, adequate priority in patients with hypovolemic shock.
fluid resuscitation should be a priority in patients The quality of evidence was downgraded due
with hypovolemic shock. to serious risk of bias and indirectness.

E. Dobutamine vs. other inotropes in


5. We suggest against routine use of dobu- patients with shock after cardiac surgery
tamine as inotropic agent for patients
with hypovolemic shock, as compared to
placebo/no treatment (weak recommen- 1. Dobutamine vs. levosimendan for
dation, very low quality of evidence). patients with shock after cardiac surgery:
no recommendation/suggestion.
No systematic reviews or RCTs reporting our
predefined patient-important outcome measures In an updated meta-analysis comprising four
have compared use of dobutamine with pla- trials and 470 patients, reduced short-term
cebo/no treatment in patients with hypovolemic mortality,40–43 fewer ischemic events,43 reduced
shock (Fig. 4, Table S4E in Appendix S2). risk of acute kidney injury and use of renal
Importantly, potential harm of dobutamine has replacement therapy,40–43 and reduced risk of
been suggested in a propensity-matched dysrhythmias40,43 were suggested in patients
Acta Anaesthesiologica Scandinavica (2018)
ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 19
M. H. MØLLER ET AL.

A Short-term mortality permitted. Importantly, in the LEOPARDS trial


in which adult patients with sepsis where
No data.
randomized to levosimendan or placebo,
levosimendan was associated with a lower
B Long-term mortality
likelihood of successful weaning from mechan-
No data. ical ventilation and a higher risk of supraven-
tricular tachyarrhythmia, as compared to
C Quality of life placebo.25 Of note, the defined daily dose
No data. price of levosimendan is about 22 times higher
than dobutamine.16 We refrain from giving
D Ischemic events any recommendations or suggestions on using
dobutamine or levosimendan for patients with
No data.
shock after cardiac surgery, due to the
unknown balance between the benefits and
E Renal replacement therapy
harms of these agents in this population.
No data.

F Acute kidney injury


2. We suggest that dobutamine is used as
No data. inotropic agent for patients with shock
after cardiac surgery rather than milrinone
G Dysrhythmias (weak recommendation, very low quality
No data. of evidence).

H Hospital length-of-stay
A small RCT comprising 120 patients with
No data. shock after cardiac surgery 47 found no differ-
ence in acute kidney injury and dysrhythmias
Fig. 4. Forest plot of (A) short-term mortality, (B) long-term mortality,
(C) quality of life, (D) ischemic events, (E) renal replacement therapy,
between patients treated with dobutamine
(F) acute kidney injury, (G) dysrhythmias, and (H) hospital length-of- vs. milrinone (Fig. 5, Table S5B in
stay in randomized trials of dobutamine vs. other inotropes for Appendix S2). None of our other predefined
patients with hypovolemic shock. patient-important outcome measures have
been assessed. As the balance between the
benefits and harms of milrinone in patients
with shock after cardiac surgery treated with with acute circulatory failure in general has
levosimendan, as compared to dobutamine been sparsely evaluated, 15 we suggest using
(Fig. 5, Fig. S3A–C in Appendix S1, dobutamine rather than milrinone. Further-
Table S5A in Appendix S2). However, TSA more, the defined daily dose price of milri-
highlighted high risk of random errors due to none is about 100 times higher than that of
repetitive testing and small sample sizes dobutamine. 16
(Fig. S3 in Appendix S1), which cautions The quality of evidence was downgraded due
interpretations of the findings in the conven- to imprecision, indirectness, and risk of bias.
tional meta-analysis. None of our other prede-
fined patient-important outcome measures have
been assessed. In the recently published 3. Dobutamine vs. epinephrine for patients
LEVO-CTS, CHEETAH, and LICORN trials44–46 with shock after cardiac surgery: no rec-
no difference in outcome between levosimen- ommendation/suggestion.
dan and placebo in patients undergoing
planned cardiac surgery was found. Of note,
levosimendan was studied as a second-line No systematic reviews or RCTs reporting our
inotropic agent in these trials, and other ino- predefined patient-important outcome measures
tropic drugs, such as dobutamine, were have compared use of dobutamine with

Acta Anaesthesiologica Scandinavica (2018)


20 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

A Short-term mortality

B Long-term mortality
No data.

C Quality of life
No data.
Fig. 5. Forest plot of (A) short-term mortality, (B) long-term mortality, (C) quality of life, (D) ischemic events, (E) renal replacement therapy, (F)
acute kidney injury, (G) dysrhythmias, and (H) hospital length-of-stay in randomized trials of dobutamine vs. other inotropes for patients with
shock after cardiac surgery.

epinephrine in patients with shock post–cardiac consumption and may affect cardiac output
surgery (Fig. 5, Table S5C in Appendix S2).26 We adversely in most patients where an inotropic
refrain from giving any recommendations or sug- agent is deemed indicated.6
gestions on using dobutamine or epinephrine for
patients with shock after cardiac surgery, due to 4. Dobutamine vs. dopamine for patients
the lack of data and no relevant populations to with shock after cardiac surgery: no rec-
extrapolate from. Importantly, excessive vasocon- ommendation/suggestion.
striction and tachycardia increase oxygen

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 21
M. H. MØLLER ET AL.

D Ischemic events

Fig. 5. Continued

No systematic reviews or RCTs reporting our


predefined patient-important outcome measures 5. We suggest against routine use of dobu-
have compared use of dobutamine with dopa- tamine as inotropic agent for patients with
mine in patients with shock after cardiac sur- shock after cardiac surgery, as compared to
gery (Fig. 5, Table S5D in Appendix S2). We placebo/no treatment (weak recommen-
refrain from giving any recommendations or dation, very low quality of evidence).
suggestions on using dobutamine or dopamine
for patients with shock after cardiac surgery,
due to the lack of data and no relevant popula- No systematic reviews or RCTs reporting our
tions to extrapolate from. Importantly, we rec- predefined patient-important outcome measures
ommend that if clinicians prefer to use have compared use of dobutamine with pla-
dopamine rather than dobutamine in this popu- cebo/no treatment in patients with shock after
lation, they do so in the context of high-quality cardiac surgery (Fig. 5, Table S5E in
RCTs, given the harm associated with use of Appendix S2). Importantly, as potential harm of
dopamine in patients with septic shock17,18 and dobutamine has been suggested in patients with
in a subgroup analysis of patients with septic shock, we suggest against the routine use
cardiogenic shock in the SOAP 2 trial.39 of dobutamine as inotropic agent for patients

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22 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

E Renal replacement therapy

Fig. 5. Continued

with shock after cardiac surgery, as compared to No systematic reviews or RCTs reporting
placebo/no treatment (extrapolation). our predefined patient-important outcome mea-
The quality of evidence was downgraded due sures have compared use of dobutamine with
to serious risk of bias and indirectness. levosimendan in patients with other types of
shock including vasodilatory shock (Fig. 6,
Table S6A in Appendix S2). In reference to our
F. Dobutamine vs. other inotropes in recommendation for patients with septic shock,
patients with other types of shock, including we suggest using dobutamine (extrapolation).
vasodilatory shock The quality of evidence was downgraded due
to risk of bias, indirectness, and imprecision.

1. We suggest that dobutamine is used as ino-


tropic agent for patients with other types of 2. Dobutamine vs. milrinone for patients
shock including vasodilatory shock rather with other types of shock including
than levosimendan (weak recommenda- vasodilatory shock: no recommenda-
tion, very low quality of evidence). tion/suggestion.

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 23
M. H. MØLLER ET AL.

F Acute kidney injury

Fig. 5. Continued

No systematic reviews or RCTs reporting our in general.15 Of note, the defined daily dose price
predefined patient-important outcome measures of milrinone is about 100 times higher than that of
have compared use of dobutamine with milrinone dobutamine.16
in patients with other types of shock including
vasodilatory shock (Fig. 6, Table S6B in
Appendix S2). We refrain from giving any recom- 3. We suggest that dobutamine is used as
mendations or suggestions on using dobutamine inotropic agent for patients with other
or milrinone for patients with other types of shock types of shock including vasodilatory
including vasodilatory shock, due to the lack of shock rather than epinephrine (weak rec-
data and no relevant populations to extrapolate ommendation, very low quality of evi-
from. Importantly, we recommend that if clini- dence).
cians prefer to use milrinone rather than dobu-
tamine in this population, they do so in the No systematic reviews or RCTs reporting our
context of high-quality RCTs, given the lack of predefined patient-important outcome measures
data on the balance between benefits and harms of have compared use of dobutamine with epi-
milrinone in patients with acute circulatory failure nephrine in patients with other types of shock

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24 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

G Dysrhythmias

H Hospital length-of-stay
No data.
Fig. 5. Continued

including vasodilatory shock (Fig. 6, Table S6C No systematic reviews or RCTs reporting our
in Appendix S2). In reference to our recommen- predefined patient-important outcome measures
dation for patients with septic shock, we suggest have compared use of dobutamine with dopa-
using dobutamine (extrapolation). Importantly, in mine in patients with other types of shock
vasodilatory shock caused by anaphylaxis, epi- including vasodilatory shock (Fig. 6, Table S6D
nephrine is the preferred drug of choice. in Appendix S2). We refrain from giving any
The quality of evidence was downgraded due recommendations or suggestions on using dobu-
to risk of bias, indirectness, and imprecision. tamine or dopamine for patients with other types
of shock including vasodilatory shock, due to
the lack of data and no relevant populations to
4. Dobutamine vs. dopamine for patients with extrapolate from. Importantly, we strongly rec-
other types of shock including vasodilatory ommend that if clinicians prefer to use dopamine
shock: no recommendation/suggestion. rather than dobutamine in this population, they

Acta Anaesthesiologica Scandinavica (2018)


ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 25
M. H. MØLLER ET AL.

A Short-term mortality shock, we suggest against routine use of dobu-


No data. tamine (extrapolation).
The quality of evidence was downgraded due
B Long-term mortality to serious risk of bias and indirectness.
No data.

C Quality of life Discussion


No data.
We were able to use existing systematic reviews
D Ischemic events and RCTs to answer some of the clinical ques-
No data. tions concerning choice of inotropic agents in
patients with septic shock, cardiogenic shock,
E Renal replacement therapy and in those with shock after cardiac surgery.
No data. However, for patients with shock in general,
and those with hypovolemic shock, and other
F Acute kidney injury
types of shock, the quantity and quality of evi-
No data.
dence was very limited.
G Dysrhythmias
The most widely studied comparison was
No data. dobutamine vs. levosimendan, whereas dobu-
tamine vs. milrinone, dobutamine vs. epinephr-
H Hospital length-of-stay ine, and dobutamine vs. placebo/no treatment
No data. have been sparsely assessed. No trials have
compared dobutamine vs. dopamine in any of
Fig. 6. Forest plot of (A) short-term mortality, (B) long-term mortality,
the six predefined subpopulations.
(C) quality of life, (D) ischemic events, (E) renal replacement therapy,
(F) acute kidney injury, (G) dysrhythmias, and (H) hospital length-of-
We propose no strong recommendations, as
stay in randomized trials of dobutamine vs. other inotropes for the quantity and quality of evidence was very
patients with other types of shock, including vasodilatory. low with large uncertainty about the direction
and magnitude of effect.
For all the six predefined subpopulations, we
do so in the context of high-quality RCTs, given suggest against the routine use of dobutamine,
the harm associated with use of dopamine in as compared to placebo/no treatment (very low
patients with septic shock17,18 and in a subgroup quality of evidence). There are no data support-
analysis of patients with cardiogenic shock in ing that inotropic agents offer benefit as com-
the SOAP 2 trial.39 pared to placebo or no treatment, and in
patients with septic shock, dobutamine has been
associated with adverse outcome.
5. We suggest against routine use of dobu- For patients with shock in general and those
tamine as inotropic agent for patients with septic shock and other types of shock, we
with other types of shock including suggest using dobutamine over levosimendan
vasodilatory shock, as compared to pla- (very low quality of evidence). This was based
cebo/no treatment (weak recommenda- on an overall low confidence of benefit from
tion, very low quality of evidence). levosimendan, and importantly, potential harm,
as suggested in the LEOPARDS trial, in which
adult patients with sepsis randomized to treat-
No systematic reviews or RCTs reporting our ment with levosimendan had lower likelihood
predefined patient-important outcome measures of successful weaning from mechanical ventila-
have compared use of dobutamine with pla- tion and a higher rate of supraventricular tach-
cebo in patients with other types of shock yarrhythmia, as compared to placebo.25
including vasodilatory shock (Fig. 6, For patients with shock in general and in
Table S6E in Appendix S2). In reference to those with septic and other types of shock, we
our recommendation for patients with septic suggest using dobutamine over epinephrine, as

Acta Anaesthesiologica Scandinavica (2018)


26 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

excessive vasoconstriction and tachycardia may for trustworthy guidelines, including the
affect oxygen consumption and cardiac output GRADE methodology which support a system-
adversely in most patients where an inotropic atic and transparent process,9 and use of TSA to
agent is deemed indicated (very low quality of assess the risk of random errors.13 The limita-
evidence). tions include the reliance upon existing system-
For patients with cardiogenic shock and those atic reviews for some recommendations, including
with shock after cardiac surgery, we suggest the risk of trial heterogeneity, indirectness, and
using dobutamine over milrinone (very low bias. Also, we did not include time to resolution
quality of evidence). This was based on overall of shock or days free of inotropic support as out-
low confidence of benefit and insufficient comes, as we did not expect that any trials had
knowledge on harms from milrinone,15 and a assessed these otherwise patient-important out-
considerably higher defined daily dose price of comes. Furthermore, not all of the included sys-
milrinone. tematic reviews and trials have been designed as
Because of no available data, no reliable data a direct comparison between dobutamine and
on the balance between the benefits and harms, another inotropic agent, as some trials have used
or no relevant patient groups to extrapolate adjuvant vasopressors. Consequently, some of the
from, we were not able to provide recommenda- benefits and harms observed may partly be
tions/suggestions for (1) dobutamine vs. milri- caused by other adjuvant agents used and/or
none/dopamine in patients with shock in induced changes in dosing of the inotropic agent
general, and for those with septic and other assessed. Our recommendations have been
types of shock, (2) dobutamine vs. levosimen- restricted to those that can be based on findings
dan/epinephrine/dopamine for patients with from RCTs exclusively, however, observational
cardiogenic shock and those with shock after studies may – although seldom and often biased -
cardiac surgery, and for (3) dobutamine vs. provide evidence to help form some recommenda-
levosimendan/milrinone/epinephrine/dopamine tions.52 Finally, our guideline group did not
in patients with hypovolemic shock. include critical care nurses or other relevant stake-
As witnessed by the very low quality of evi- holders such as patients, relatives, and representa-
dence supporting the suggestions of this guide- tives of regulatory bodies and hospital owners.
line, there is large uncertainty on the balance
between the benefits and harms when using
inotropic agents in adult patients with acute cir-
Conclusion
culatory failure.48 Several interventions, which
are common practice in the ICU, have been For all adult patients with shock, we suggest
adopted based on the perception of improved against the routine use of dobutamine as com-
physiological parameters and physiological rea- pared to placebo/no treatment. If inotropic
soning. This has the eminent risk of overestimat- agents are used, we suggest using dobutamine
ing benefit and underestimating harm.49 In a rather than levosimendan or epinephrine in
recently published systematic review, eight criti- patients with shock in general, and in those
cal care interventions used in clinical practice with septic and other types of shock. In patients
were shown to increase mortality.50 Furthermore, with cardiogenic shock and in those with shock
there is empirical evidence within critical care after cardiac surgery, we suggest using dobu-
that research results based on data from trials tamine rather than milrinone. For the remaining
with lower quality have changed direction once clinical questions, we refrained from giving any
higher quality trials were published.51 Conse- recommendations or suggestions. In general, the
quently, we highly recommend that clinicians quality of evidence was very low, implying high
who are using inotropic agents in patients with uncertainty on the balance between the benefits
acute circulatory failure, consider doing this in and harms when using inotropes in adult
the context of high-quality RCTs with low risk patients with acute circulatory failure. Conse-
of bias-assessing patient-important outcomes. quently, RCTs with low risk of bias should be a
The strengths of this clinical practice guide- high research priority in settings where ino-
line include the application of current standards tropes are used.
Acta Anaesthesiologica Scandinavica (2018)
ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 27
M. H. MØLLER ET AL.

Acknowledgements 11. Jammer I, Wickboldt N, Sander M, Smith A,


Schultz MJ, Pelosi P, Leva B, Rhodes A, Hoeft A,
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low ejection fraction undergoing coronary artery
bypass grafting with cardiopulmonary bypass: the Appendix S1. Trial sequential analyses.
LICORN randomized clinical trial. JAMA 2017; Fig. S1. Trial sequential analysis of dobutamine
318: 548–56. vs. other inotropes in patients with septic shock.
Acta Anaesthesiologica Scandinavica (2018)
30 ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
INOTROPES IN ACUTE CIRCULATORY FAILURE

Fig. S2. Trial sequential analysis of dobutamine Table S3. Summary of findings for patients with
vs. other inotropes in patients with cardiogenic cardiogenic shock.
shock. Table S4. Summary of findings for patients with
Fig. S3. Trial sequential analysis of dobutamine hypovolemic shock.
vs. other inotropes in patients with shock after car- Table S5. Summary of findings for patients with
diac surgery. shock after cardiac surgery.
Appendix S2. GRADE summary of findings Table S6. Summary of findings for patients with
tables. other types of shock, including vasodilatory
Table S1. Summary of findings for patients with shock.
shock in general. Appendix S3. Conflicts of interest on a recom-
Table S2. Summary of findings for patients with mendation per recommendation basis per co-
septic shock. author.

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ª 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation 31