Scheeren et al. Ann.

Intensive Care (2021) 11:21

https://doi.org/10.1186/s13613-021-00806-8

RESEARCH Open Access

Current use of inotropes in circulatory shock

Thomas W. L. Scheeren1* , Jan Bakker2,3,4,5, Thomas Kaufmann1, Djillali Annane6, Pierre Asfar7,
E. Christiaan Boerma8, Maurizio Cecconi9,10, Michelle S. Chew11, Bernard Cholley12,13, Maria Cronhjort14,
Daniel De Backer15, Arnaldo Dubin16, Martin W. Dünser17, Jacques Duranteau18, Anthony C. Gordon19,
Ludhmila A. Hajjar20, Olfa Hamzaoui21, Glenn Hernandez22, Vanina Kanoore Edul23, Geert Koster24,
Giovanni Landoni25, Marc Leone26, Bruno Levy27, Claude Martin26^, Alexandre Mebazaa28, Xavier Monnet29,30,
Andrea Morelli31, Didier Payen32, Rupert M. Pearse33, Michael R. Pinsky34, Peter Radermacher35,
Daniel A. Reuter36, Yasser Sakr37, Michael Sander38, Bernd Saugel39, Mervyn Singer40, Pierre Squara41,
Antoine Vieillard‑Baron42,43, Philippe Vignon44,45, Jean‑Louis Vincent46, Iwan C. C. van der Horst47 ,
Simon T. Vistisen48,49 and Jean‑Louis Teboul29,30

Abstract
Background: Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international
survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treat‑
ment of patients with circulatory shock.
Methods: From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs
was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions
focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treat‑
ment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to
formulate recommendations for the use of inotropes based on 11 questions.
Results: A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically
ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes
when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed ade‑
quate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction.
Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts
agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81–90%) agreement.
Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobu‑
tamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate
cardiac output) and stopping criteria (adverse effects and clinical improvement).
Conclusion: Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers.
Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by

*Correspondence: [email protected]
1
Department of Anesthesiology, University of Groningen, University
Medical Center Groningen, Hanzeplein 1, P.O.Box 30.001, 9700 RB
Groningen, The Netherlands
Full list of author information is available at the end of the article
^ Claude Martin participated as expert but deceased before final
submission

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Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 2 of 13

international experts. Future studies should focus on consistent indications for inotrope use and implementation into
a guideline for circulatory shock that encompasses individualized targets and outcomes.
Keywords: Acute circulatory failure, Sepsis, Septic shock, Cardiogenic shock, Resuscitation, Inotropes, Vasoactive
agents, Catecholamines, Levosimendan, PDE-inhibitors, Cardiac output

Background in septic shock [25]. Yet, no large randomized trials

Circulatory shock affects about one-third of patients have provided evidence for a mortality benefit of levosi-
admitted to the intensive care unit (ICU) [1]. Shock mendan over dobutamine in septic shock [26].
is defined as insufficient oxygen and energy supply to Hence, further studies are needed on optimal treat-
organs and is associated with increased mortality [1, 2]. ment with inotropes in circulatory shock states. To aid
Traditionally, four types of circulatory shock have been the design and interpretation of future studies on ino-
distinguished by pathophysiological mechanisms, namely tropes, it is imperative to evaluate current practice and
hypovolemic, cardiogenic, distributive and obstructive therapeutic goals of inotropic treatment of shock states
shock [3]. Critically ill patients present with one or a to establish what is considered standard of care. The aim
combination of these four types of circulatory failure [4]. of the present study was to establish an overall picture of
Treatment of circulatory shock relies on timely initia- the standard of care, which was identified from a survey
tion of adequate fluid resuscitation combined with the among members of the European Society of Intensive
use of vasoactive medication to restore tissue perfusion Care Medicine (ESICM). Furthermore, we developed
[5, 6]. Despite these therapeutic measures, cardiac out- recommendations on the use of inotropes based on a
put (CO) is often inadequate to deliver enough oxygen to subsequent questionnaire and consensus finding by
tissues in patients with circulatory shock [7]. Inotropes international experts in the field.
might improve CO and organ perfusion in patients with
circulatory shock [8, 9]. Several guidelines for differ-
ent types of circulatory shock give different recommen- Methods
dations for the use of inotropes [10–13]. Despite these Survey development
different recommendations and the apparent lack of evi- Survey questions and response options were developed
dence, inotropes are used in daily practice [13, 14]. Data by the leadership of the Cardiovascular Dynamics Sec-
on how inotropes are used in clinical practice are sparse tion of ESICM. The survey consisted of 27 questions on
[15]. Individual registries, observational studies, and tri- the use of vasoactive drugs. The first results on the cur-
als with patients in shock provide insight into the current rent use of vasopressors in septic shock were recently
standard of care. For example, in patients with cardio- published [6]. The present study focused on 14 survey
genic shock, vasopressors and inotropes were adminis- questions related to the use of inotropes in circulatory
tered in 94%, where dobutamine (49%) and levosimendan shock. These questions concerned triggering factors,
(24%) were the most commonly used inotropes [16]. first-line drug choice, dosing, timing, targets, additional
For levosimendan, two systematic reviews with meta- treatment strategies, and effects of inotropes.
analyses and three large randomized trials have shown The Research Committee of the ESICM endorsed the
neutral effects on various outcomes [17–21], while one survey. Data were collected automatically using Survey-
trial reported a possibility of harm (lower likelihood of Monkey Inc. (www.surve​ymonk​ey.com).
successful weaning from mechanical ventilation and a The survey was announced on the ESICM website and
higher risk of supraventricular tachyarrhythmia)[22]. A was open for participation between November 2016 and
recent Cochrane review underlines the low quality of evi- April 2017. Members of the Cardiovascular Dynamics
dence on the use of inotropes in cardiogenic shock with section of the ESICM were additionally encouraged to
levosimendan showing a short-term survival benefit over participate via an email linking to the survey sent to email
dobutamine, while this benefit vanished on long-term addresses in ESICM’s membership database in Novem-
follow-up [23]. In other types of shock, use of inotropes ber 2016 with two subsequent e-mail reminders in Feb-
is less common. Some patients with septic shock may ruary 2017 and March 2017. No incentives were offered
have improved tissue perfusion with inotropic therapy for participation. No personal information was collected,
aimed at increasing oxygen delivery and in this situation, and no log-in was required to participate. Completing
dobutamine is the first-line inotrope [8, 24]. However, a the internal consistency of items was enforced by display-
recent network meta-analysis suggests that levosimendan ing an alert before the questionnaire could be submitted
has the highest probability of being the best treatment and highlighting mandatory but unanswered questions. It
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 3 of 13

was not possible to review and change the given answers income of $12,056 or more [29]. P < 0.05 was considered
after submission. statistically significant. P-values are reported with their
exact value for interpretation and not corrected for mul-
Survey reporting tiple testing in this descriptive reporting.
The questionnaire’s methodology and results are
reported according to the Checklist for Reporting Results
Results
of Internet E-Surveys (CHERRIES) statement [27]. Ethi-
Survey respondents’ characteristics
cal approval for this study was not requested, as no iden-
A total of 839 physicians from 82 countries participated
tifying data were collected and consent was assumed by
in the survey. A firm estimate of response rate could not
participating in the survey.
be calculated as the invitation to the survey was posted
as an open link on the ESICM website. In addition, mem-
Experts’ recommendations
bers of the CD section of the ESICM (n = 10,780 at the
Based on the results of the ESICM members’ survey,
time of the survey) received an email invitation to par-
three authors (TWLS, IVDH and JLT) identified areas
ticipate. From these addressees, 3111 (29%) opened this
of interest and developed 11 questions, including sub-
e-mail (according to Mail Chimp). This corresponds to a
questions and approached a group of 42 experts, who
response rate of 27% (839/3111) of those who opened the
are active members of the Cardiovascular Dynamics
e-mail. Baseline demographic data of respondents and
(CD) section of the ESICM. These experts have all pub-
their ICU and hospitals are presented in Additional file 1:
lished research as first or last author in an international
Table S1 [6].
peer-reviewed journal in articles identified by the Pub-
Med subject headings “inotrope”, and they were asked to
answer the developed experts’ questionnaire in order to Survey results
summarize overall recommendations for the use of ino- All seven questions and answers of the respondents
tropes in circulatory shock based on the ESICM mem- on inotrope use in circulatory shock are summarized
bers’ survey and the experts’ questionnaire. in Table 1. Dobutamine was reported to be used as the
Definitions of the degree of consensus and grades of first-line inotrope in 704 (84%) of questionnaire respond-
recommendations were based on the RAND algorithm ents, followed by PDE-inhibitors (7%), levosimendan
[28]. Excellent agreement (> 90% agreement) and good (5%), dopamine (4%), and dopexamine (0.1%), while epi-
agreement (81–90% agreement) were considered as nephrine was not among the first 5 most used agents.
strong grades of recommendation. A weak agreement First-line use of dobutamine was more common among
was defined when 70–80% of the experts agreed. A Del- non-Europeans than Europeans (88% vs. 82%, p = 0.049).
phi-like process was used to achieve these consensus According to respondents, most inotropes are used
grades. when there are persistent clinical signs of hypoperfusion
(e.g., skin mottling, low urine output) or persistent hyper-
Statistics lactatemia despite a supposed adequate use of fluids and
Data were evaluated as the total distribution of single vasopressors (65%) (Table 1).
answers. Answers to the questionnaire items are reported Mostly, an adequate CO was the preferred target for
as numbers (percentage). Contingency tables and corre- inotropic treatment (44%) (Table 1).
sponding Chi-square statistics were reported to describe The reasons for adding another inotrope when the
the pairwise associations between selected demographic patient did not respond to the first-line inotropic therapy
variables (European vs. non-European ESICM member, varied among respondents (Table 1).
high-income vs. lower-income countries, ICU experi- Most respondents preferred the combination of norepi-
ence more vs. less than 5 years full time, intensive care nephrine plus dobutamine over epinephrine as preferred
as primary specialty vs. other specialties, and university catecholamine in the treatment of circulatory shock
hospital vs. non-university hospital) and the responses (Table 1).
regarding inotrope use. The nature of each question’s Concerning the use of phosphodiesterase (PDE)-
five answer options and their distribution prospectively inhibitors, respondents employed by a university hospi-
defined the answer categories for the subsequent con- tal and more experienced respondents were more likely
tingency tables analyses (2 × 2). In two cases, only three to support PDE-inhibitors in right heart failure than
(question 3) and two (question 7) answer options were non-university or less experienced respondents (52% vs.
used two define the two answer categories for contin- 37%, p < 0.001 and 48% vs. 39%, p = 0.01, respectively)
gency tables. We used the World Bank definition of a (Table 1).
“high-income country,” i.e., a per capita gross national
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 4 of 13

Table 1 Survey questions on inotropic use

Frequency Percentage
of response of response

What is your first-line inotrope to increase cardiac pump function?

Dobutamine 706 84%
Dopamine 37 4%
Dopexamine 1 0.1%
Levosimendan 38 5%
Milrinone or any other phosphodiesterase inhibitor 57 7%
What are your most important criteria for using an inotrope to increase cardiac pump function?
­ in−1 m−2)
I measure CO and find it low (e.g., cardiac index < 2.5 L m 189 23%
I measure central venous oxygen saturation and find it low (< 70%) 47 6%
I measure left ventricular ejection fraction and find it low (< 45%) 54 6%
There are persistent clinical signs of hypoperfusion (e.g., skin mottling, low urine output) or persistent hyperlactatemia 184 22%
despite a supposed adequate use of fluids and vasopressors
There are persistent clinical signs of hypoperfusion (e.g., skin mottling, low urine output) or persistent hyperlactatemia 365 44%
despite a supposed adequate use of fluids and vasopressors in the context of low left ventricular ejection fraction
What are your primary therapeutic targets when using an inotrope?
A normal lactate level 155 18%
A normal veno-arterial ­PCO2 difference (< 6 mmHg) 37 4%
An adequate CO 372 44%
An adequate ­ScvO2 173 21%
An adequate urine output 102 12%
When the patient does not respond to your current inotropic therapy, what is your main reason for adding another inotrope/vasoactive agent to the
current therapy?
Although the maximum dose of the 1st choice inotrope has not been reached, previous increases in the inotrope dose 129 15%
were ineffective
By adding a second inotrope although the maximum dose of the 1st choice inotrope has not been reached, I want to 193 23%
limit/reduce the side effects of the first inotrope
I suppose that the mechanism of action of the first inotrope is exhausted (e.g., adrenoceptors down regulation) and 195 23%
want to use a second one with an independent mechanism of action
I want to use synergistic effects of two different mechanisms of action 233 28%
The maximum dose of the 1st choice inotrope has been reached 89 11%
Which of the following statements fits best your opinion on catecholamine use in the treatment of shock?
Although epinephrine (EPI) has the same adrenoceptors profile than the combination norepinephrine (NOR) plus dobu‑ 372 44%
tamine (DOB), the combination NOR plus DOB should be preferred since either component can be titrated individually
Although EPI has the same adrenoceptors profile than the combination NOR plus DOB, EPI should be preferred because 50 6%
of its easiness to be used (single agent)
The combination NOR plus DOB should be preferred over EPI due to a better patient outcome 95 11%
The combination NOR plus DOB should be preferred over EPI since EPI may decrease regional blood flow, particularly in 131 16%
the splanchnic circulation
The combination NOR plus DOB should be preferred over EPI since EPI may increase blood lactate levels and cause 191 23%
cardiac arrhythmias
Which of the following statements fit(s) best your opinion on the use of phosphodiesterase (PDE)-inhibitors in the critically ill?
Because of their prominent vasodilatory effect on the pulmonary circulation, PDE-inhibitors should be preferred in the 365 43%
treatment of predominant right heart failure
Compared to pure vasodilators (e.g., nitroprusside), PDE-inhibitors cause larger increases in CO and smaller decreases in 191 23%
arterial pressure
Compared to ß-adrenoceptor agonists (e.g., dobutamine), PDE-inhibitors have similar effects on CO but additionally 162 19%
decrease the cardiac filling pressures (CVP, PAOP)
PDE-inhibitors should be avoided in the treatment of cardiogenic shock since they are associated with increased mortal‑ 74 9%
ity
PDE-inhibitors should be avoided in the treatment of cardiogenic shock since they may increase the incidence of atrial 47 6%
fibrillation or tachyarrhythmias
Which of the following statements fits best your opinion on the use of levosimendan in the critically ill?
Levosimendan is the only inotrope that does not increase myocardial oxygen demand 354 42%
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 5 of 13

Table 1 (continued)
Frequency Percentage
of response of response

Levosimendan is also a potent vasodilator in the systemic and pulmonary circulation 269 32%
Levosimendan is associated with an increased incidence of atrial fibrillation and ventricular ectopy 83 10%
Levosimendan is the only inotrope that is not associated with an increased mortality 55 7%
Levosimendan may be considered as cardioprotective, as it reduces troponin I release (pleiotropic effect) 78 9%

Responses to the use of levosimendan varied among reasons for adding a vasopressor/inotrope if the patient
respondents, with experienced clinicians more likely did not respond to the inotropic agent administered to
selecting levosimendan than less experienced clinicians the patient were virtually uniformly distributed among
(61% vs. 52%, p = 0.01) (Table 1). the respondents, underscoring that balancing maximal
doses, side effects, possible synergistic drug effects, etc.,
Experts’ questionnaire results is challenging for clinicians in late/critical stages of circu-
Forty-two selected experts gave their recommendations latory shock.
for clinical use of inotropes by responding to the expert- The heterogeneous choices of physicians when it comes
opinion questionnaire (Fig. 1), and 40 of them replied to a to inotropes may have various reasons. First, no solid
follow-up questionnaire (Table 2). evidence is available to support choosing one agent over
Experts achieved excellent agreement (95%) on the another [12]. Recently, meta-analyses showed that for
statements that inotropes may be indicated in cardio- many inotropes evidence to support benefit is absent or
genic shock, that inotropes are not indicated in hypov- weak [17, 18, 30]. Moreover, even a statistically signifi-
olemic shock, that dobutamine but not dopamine can cant effect should still be interpreted with caution since
be used for treating circulatory shock in clinical practice, the effects might be small and the clinical relevance
that a low CO can be used as a trigger for starting ino- uncertain. Second, the evidence is sparse and not robust,
tropic treatment, that clinical signs of hypoperfusion can not only because of between-trial heterogeneity, but
be used as a target for inotropic treatment, and to lower also because of high within-trial patient heterogeneity,
or stop inotropic dosing, if patients experience unaccep- combined with little or no individualization in the treat-
table side effects. Other recommendations did not reach ment protocols. In turn, an effect of an inotrope might
excellent agreement and for some the level of agreement be present for certain (groups of ) patients equalized by
was weak. harm of the same inotrope in other (groups of ) patients
In general, experts individually stated that a recom- in the same trial [31]. As part of patient heterogeneity,
mended trigger for inotropic treatment should also be a the underlying pathophysiology and its impact on hemo-
target for the treatment (see Table 3). An exception was dynamics may be incompletely understood and there-
LVEF, where 14 of the 24 experts, who did use low LVEF fore, choosing the right agent might be difficult. Third,
as a trigger for inotropic treatment, did not consider the optimal therapeutic targets for individual patients or
LVEF as a target for the treatment, and three of the 18 groups of patients are unknown. More data have recently
experts, who did not choose low LVEF as a trigger did become available supporting different targets in different
recommend using LVEF as a target for the treatment patients, an example being blood pressure [32]. Further-
(Table 4). more, specific targets for a variable such as CO or car-
diac index might be suboptimal. For one patient, a CO of
Discussion ­ in−1 might be sufficient to maintain organ perfu-
3.0 L m
According to the results of this international survey, pref- sion, for another patient, this level of CO might be asso-
erences around the use of inotropes differ among physi- ciated with organ hypoperfusion and organ dysfunction.
cians. Most physicians (84%) chose dobutamine as their Clearly, bedside titration of inotropes, based on individ-
first-line inotrope, and dopamine, levosimendan, and ual patient responses, seems the most rational approach,
milrinone (or another PDE-inhibitor) were considered but defining what those resuscitation targets should be,
first-line in up to 5% of respondents for patients with remains difficult. Finally, despite being available for many
circulatory shock. Furthermore, the reasons for using years (except for levosimendan in some countries), the
an inotropic agent were diverse. Also, the variation in optimal use of inotropes is incompletely understood, par-
the primary therapeutic target was diverse, where CO, ticularly beyond the choice of the first-line agent. Opti-
­ScvO2, lactate level and urine output were all well-repre- mal treatment concepts for timing, dosing, interaction,
sented answers among the respondents. Furthermore, the and preferred combination of agents remain ill-defined.
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 6 of 13

Fig. 1 Expert answers to the first questionnaire and level of agreement. Answers are visualized as percentages. Positive answers are presented in
green, conditional answers are presented in yellow, negative answers are presented in red. PDE phosphodiesterase, v-a PCO2 veno-arterial ­PCO2
difference, GoR grade of recommendation
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 7 of 13

Table 2 Second round questionnaire to 40 experts on inotrope use

Question Answer

In a terminological sense (when discussing with fellow colleagues and/or researchers), do you refer to norepinephrine as a vasopressor?
Exclusively a vasopressor 65%
It is context dependent and not a fixed term in discussions with fellow colleagues and/or researchers 35%
In your physiological understanding and your treatment approach, do you consider norepinephrine:
Exclusively a vasopressor (i.e., you only use it to modify blood pressure) 42%
A vasopressor and an inotrope (i.e., in your treatment strategy, you consider it a drug to efficiently modify both blood pressure and cardiac 57%
output)
What is your first-line inotrope?
Dobutamine 82%
Epinephrine 5%
Levosimendan 2%
Milrinone 2%
Norepinephrine 8%
Do you recommend a PDE-inhibitor in right ventricular failure?
Yes 65%
No 35%

Table 3 Summary of consensus among experts and the degree of recommendations

Degree of consensus Grade
of recommendation

Inotrope indications
1. Inotropes are indicated in septic shock Good Strong
2. Inotropes are indicated in cardiogenic shock Excellent Strong
3. Inotropes are NOT indicated in hypovolemic shock Excellent Strong
Choice of inotrope
4. Dobutamine is the first-line inotrope Good Strong
5. Dopamine is NOT a recommended inotrope Excellent Strong
Triggers
6. Low cardiac output is a trigger for inotropic treatment Excellent Strong
7. Signs of hypoperfusion are a trigger for inotropic treatment Good Strong
Targets
8. Low cardiac output is a target for inotropic treatment Good Strong
9. Signs of hypoperfusion are a target for inotropic treatment Excellent Strong
Dosing should be lowered or stopped when
10. Patients experience unacceptable side effects Excellent Strong
11. Patients show clinical improvement Good Strong

Standard of care or daily practice is obviously not should be optimized by interpreting evidence of studies
uniform among the respondents. Solid meta-analyses on hemodynamic monitoring.
of all inotropes, performed according to contemporary Although primarily being a vasopressor, norepineph-
standards and taking into account bias from funding rine (in combination with dobutamine) was considered
sources, should become available and updated if new a preferred catecholamine for the treatment of circu-
evidence arises [17, 30]. Outcome measures should be latory shock. Even among experts there was disagree-
uniformly defined and incorporate patient-centred out- ment on whether norepinephrine should be considered
comes and not limited to surrogate outcomes such as a pure vasoconstrictor or an agent with combined vaso-
CO. Therefore, triggers and goals/targets for treatment pressor and inotropic effects. Actually, through beta-1
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 8 of 13

Table 4 Answers from 42 experts on questions Q5 and Q6 from Fig. 1, where the view on triggers and targets for inotropic
use are combined. Conditional answers for Q5 in triggers (marked yellow in Fig. 1) are not represented in this table. There
was one conditional Q5 answer for MAP, Bradycardia, and ­ScvO2, and two for v-a ­CO2
MAP used as a Clinical signs used
target as a target

used as trigger
Yes No
MAP used as

Yes No

Clinical signs
trigger

Yes 8 3 Yes 35 2
No 1 29 No 3 2

Bradycardia used Lactate used as a

as a target target
Increased lactate
used as trigger

Yes No used as trigger

Bradycardia

Yes No

Yes 7 4 Yes 22 3
No 0 30 No 3 14

CO used as a target ScvO2 used as target

used as trigger

Yes No
Low CO used

Yes No
as trigger

Low ScvO2

Yes 33 5 Yes 29 1
No 2 2 No 2 9

LVEF used as a v-a CO2 used as a

used as trigger

target target
Low LVEF used

Yes No Yes No
v-a CO2
as trigger

Yes 10 14 Yes 22 1
No 3 15
No 0 17

adrenergic receptor stimulation, norepinephrine has physiological effect, whereas others see it as a vasopres-
been shown to increase systemic and microcircula- sor with clinically relevant inotropic effects that may
tory blood flow along with blood pressure and preload be enough to support contractility as a single agent.
in patients with septic shock [33–36]. Some clinicians The difficult to target inotropic effect (these agents are
might think of norepinephrine and also epinephrine titrated primarily based on their vasopressor effect) and
as pure vasopressors because of their most dominant their potential arrhythmogenic effects at high doses
should be taken into account when these agents are
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 9 of 13

used in this context. Epinephrine was hardly cited, pos- value of cardiac index or ­SvO2 or an improvement in
sibly due to studies indicating safety concerns [37, 38]. a given variable (lactate, capillary refill time, micro-
Another interesting result is that most experts recom- circulation variables, etc.). It should be determined
mended using more than one inotropic agent in the same whether these triggers and targets should be identi-
patient. Reasons for this might be synergistic effects by cal for all patients or individualized based on cardiac
adding an independent mechanism of action, e.g., in case function, organ perfusion, and underlying patient
of adrenoceptor downregulation, or the wish to limit the condition establishing an individualized benefit/risk
dose and side effects of each agent [6]. profile.
The majority of the respondents of the survey as well 2. Determine pharmacokinetics and pharmacodynam-
as the experts chose dobutamine as preferred inotrope in ics of inotropes in shock.
patients with hypoperfusion to increase CO, which is in Little is known about the pharmacokinetics and
accordance with current guidelines [8, 9, 24]. More evi- pharmacodynamics (e.g., clearance) of available
dence might come from the ongoing ADAPT multicenter inotropes in the presence of shock. Information on
trial (ClinicalTrials.gov ID: NCT04166331), which tests clearance and uptake of inotropes in shock may have
the hypothesis that dobutamine will reduce tissue hypop- implications for specific aspects related to the timing
erfusion and associated organ dysfunctions in patients of interventions, the weaning of these drugs, limiting
with septic shock and associated septic cardiomyopathy. the risk of delayed hemodynamic failure or rebound
Since clinicians prefer having recommendations effects. This might also include research on the con-
accompanying evidence summaries in the context of low comitant use of other medication (e.g., beta-blockers)
certainty of evidence [39], we asked international experts and the effects of the various inotropes on the host
in the field to draft and agree on recommendations (inflammatory or immune) response [41]. Finally,
regarding inotropic treatment. In general, experts agreed the individual variation in responses to inotropic
that a recommended trigger for starting inotropic treat- drugs related to genetic related alterations in recep-
ment should also be a therapeutic target, except for LVEF. tors and/or signaling pathways should be evaluated.
Less than half of the experts using LVEF as a trigger for 3. Compare and combine available inotropic agents and
the use of an inotrope, also considered LVEF as the tar- identify new, safer inotropes.
get for this use. This might be due to LVEF not being a Further multicenter randomized controlled trials
continuously available variable, and its value is consid- (with adaptive designs) are needed to compare dif-
ered less reliable since it is mostly based on rough estima- ferent inotropic agents (a vs. b) and their combina-
tion of echocardiographic images (eyeballing) rather than tions (a + b vs. a or b alone) on different outcomes
exact measurements in clinical practice. such as organ function, adverse effects and survival.
In view of the lack of evidence on the use of inotropes For instance, combining two inotropic agents acting
in circulatory shock, we suggest the following research through different mechanisms or receptors (e.g., dob-
agenda for the coming years: utamine + levosimendan) could permit minimizing
the doses of each drug, thus reducing the incidence
1. Determine univocal and personalized triggers and of adverse effects and increasing safety. The choice
targets to start inotrope therapy in circulatory shock of combination should be based on the pharmaco-
states. logic properties of the different agents (see point 2).
Current evidence and expert opinion differ on the New, non-catecholamine inotropic agents that are
initial triggers to start and then guide inotrope ther- not associated with side effects such as arrhythmia or
apy as targets in patients with circulatory shock. hypotension should be identified and tested.
Consensus needs to be established on which triggers 4. Combine inotrope therapy with personalized care
and target endpoints to use, ideally based on data bundle.
rather than on expert opinion alone. These could be While inotrope use needs to be personalized in
macro-hemodynamic values (e.g., cardiac output), future research, the other mainstays of circulatory
surrogates of regional (organ) blood flow, or micro- shock treatment must be employed in a similar per-
circulatory values (tissue perfusion, peripheral circu- sonalized manner to improve comparability. For
lation) [40]. instance, optimal MAP targets in circulatory shock
As an example, interventional trials have used vari- and the role of fluid therapy should ideally be estab-
ous triggers to initiate inotropic therapy such as lished as these will influence inotrope therapy. How-
“shock”, “low ejection fraction”, “low cardiac index” or ever, this in itself will be challenging as there is no
“low ­SvO2 not responding to fluids”. Also, some trials current consensus on types of fluid, monitoring and
use a fixed dose while others attempt to reach a given other interventions being delivered, nor on how to
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 10 of 13

adopt an optimal personalized approach. For exam- 9. Better define the interaction between IV fluids and
ple, a one-size-fits-all approach for MAP targets can- vasoactive agents.
not be optimal. The physiologic interplay between vasoactive agents
5. Develop and implement core outcome sets for and intravenous fluids is evident, but the scientific
patients with circulatory shock. evidence in terms of comparative effectiveness tri-
Core outcome sets (i.e., standardized collection of als (fluids vs. early vasopressor use, addition of ino-
outcomes measured and reported in all trials for a tropes, etc.) is scarce. For instance, inotropic agents
specific clinical area) should be developed for circu- can only increase myocardial contractility, lusitropy,
latory shock research due to established inconsisten- and heart rate. They do not primarily increase car-
cies in trial outcome selection. Any new trial assess- diac output. For cardiac output to increase there
ing the benefit/risk of inotropes should include the also needs to be sufficient blood volume and vas-
selection of an adequately targeted study population cular tone, as known from the poor impact of ino-
to improve the “noise/signal ratio” inherent to heter- tropic agents in hemorrhagic shock and profound
ogeneous cohorts (in terms of hemodynamic profile). vasoplegia. Therefore, the optimal vasopressor/fluid/
6. Evaluate the impact of prolonged (> 72 h) inotropic inotrope ratio remains to be determined at the indi-
therapy on myocardial energetics. vidual level.
Experimental and clinical data on inotrope use dem-
onstrate direct effects of inotropes on myocardial Ongoing and upcoming studies such as ADAPT
injury, energetics and modulation of the immune/ (NCT04166331: Effects of dobutamine on tissue hypop-
inflammatory response. The relevance of this to fur- erfusion and associated organ dysfunctions in patients
ther organ injury and patient outcomes needs to be with septic shock and associated septic cardiomyopathy)
established. Data from experimental and clinical and LevoHeartShock (NCT04020263: Early use of levosi-
studies in chronic heart failure suggest that long-term mendan versus placebo on top of conventional inotropes
inotropic therapy leads to interstitial calcinosis, myo- in patients with cardiogenic shock) will probably provide
cardial fibrosis and contraction band necrosis [42]. important answers to some of these questions.
Does this also apply to the context of shock where
the duration of inotropic stimulation is expected
Limitations
to be shorter (less than one month)? What is the
The number of responses is considered high (correspond-
maximal duration of intravenous inotropic therapy
ing to 27% of ESICM members who opened the e-mail
before receptor down regulation, diastolic dysfunc-
invite), but the methods used to invite individuals to
tion, myocardial injury, and persistent arrhythmias
respond did not allow us to report a conclusive response
develop in this setting?
rate. Therefore, response bias might be present, in which
7. Establish specific use of inotropes in patients under
case, external validity could be somewhat hampered.
mechanical circulatory support.
The results presented in this manuscript come from
The use of inotropic agents should be adapted in
an online survey. Online surveys have limitations like
patients under mechanical circulatory support for
potential multiple responses by a single person. We did
cardiogenic shock secondary to acute myocardial
not use cookies or log-file/IP address analyses to prevent
infarction. When are these agents indicated in this
multiple responses. On the other hand, individual per-
specific setting, and which hemodynamic targets
sons are unlikely to spend time answering a survey more
should be used? The purpose of inotropic stimulation
than once. Another limitation is the multiple-choice
and the choice and doses of the inotropic agent may
character of our survey, limiting answers to those offered.
not be identical at the initiation of mechanical cir-
In addition, studies published after the survey was per-
culatory support, during the maintenance phase, or
formed [38, 43–46] might have altered the answers of
during the weaning process.
the respondents. Nevertheless, after careful analysis of
8. Evaluate the best hemodynamic strategy in predomi-
the results of those studies we believe that the experts’
nant right ventricular failure.
recommendation would not have changed significantly.
In patients with circulatory shock, which is predomi-
Furthermore, the recommendations of experts can only
nantly associated with right ventricular failure, the
reach excellent agreement if the available evidence is
question should be answered by comparative effec-
solid and clear. The evidence for inotropes in circulatory
tiveness trials if inotropic agents or vasopressors
shock lack this evidence for many questions raised. Fur-
(e.g., norepinephrine to increase coronary perfusion
thermore, both patients and studies show high heteroge-
pressure) should be preferred.
neity. Therefore, recommendations should be interpreted
with caution.
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 11 of 13

Conclusions Sanofi, Roche, Abbott, and 4TEEN4. The other authors have no competing
interest to declare regarding this paper.
In conclusion, the use of inotropes in critically ill
patients is quite heterogeneous as reported by indi- Author details
1
vidual caregivers. International experts recommend Department of Anesthesiology, University of Groningen, University Medical
Center Groningen, Hanzeplein 1, P.O.Box 30.001, 9700 RB Groningen, The
the use of inotropes in septic and cardiogenic shock Netherlands. 2 New York University Medical Center, New York, USA. 3 Columbia
(but not in hypovolemia), using an inadequate CO and University Medical Center, New York, USA. 4 Erasmus MC University Medi‑
signs of tissue hypoperfusion as triggers and targets for cal Center Rotterdam, Rotterdam, The Netherlands. 5 Pontificia Universidad
Católica de Chile, Santiago, Chile. 6 School of Medicine Simone Veil, Raymond
treatment, and adverse effects and clinical improve- Poincaré Hospital (APHP), Department of Intensive Care Medicine, University
ment as stopping/weaning criteria. While experts rec- of Versailles- University Paris Saclay, Garches, France. 7 Département de Méde‑
ommend using dobutamine as the first-line agent, they cine Intensive‑Réanimation Et de Médecine Hyperbare, Centre Hospitalier
Universitaire Angers; and Institut MITOVASC, CNRS UMR 6215, INSERM U1083,
recommend against the use of dopamine. Future stud- Angers University, Angers, France. 8 Medical Centre Leeuwarden, Department
ies reporting patient-centred outcomes should focus of Intensive Care, Leeuwarden, the Netherlands. 9 Department of Anesthesia
on specific subpopulations based on prespecified and and Intensive Care, IRCCS Humanitas Research Hospital, Via Manzoni 56, Milan,
Italy. 10 Department of Biomedical Sciences, Humanitas University, Via Rita Levi
measurable triggers, targets, and with clear stopping Montalcini, Milan, Italy. 11 Department of Anaesthesiology and Intensive Care,
criteria in order to ensure comparability across trials. Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
12
This would allow a better summary of the evidence and Department of Anaesthesiology & Intensive Care Medicine, AP-HP, Hôpital
Européen Georges Pompidou, Paris, France. 13 Université de Paris, Paris, France.
its implementation in future guidelines. 14
Section of Anaesthesiology and Intensive Care, Department of Clinical
Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm,
Supplementary Information Sweden. 15 Department of Intensive Care, CHIREC Hospitals, Université Libre
de Bruxelles, Brussels, Belgium. 16 Cátedra de Farmacología Aplicada, Facultad
The online version contains supplementary material available at https​://doi.
de Ciencias Médicas, Universidad Nacional de La Plata Y Servicio de Terapia
org/10.1186/s1361​3-021-00806​-8.
Intensiva, Sanatorio Otamendi, Buenos Aires, Argentina. 17 Department
of Anesthesiology and Intensive Care Medicine, Kepler University Hospital
Additional file 1: Table S1. Baseline characteristics of survey respondents. and Johannes Kepler University Linz, Linz, Austria. 18 Department of Anaesthe‑
sia and Intensive Care, Assistance Publique Des Hopitaux de Paris, Hôpitaux
Universitaires Paris-Saclay, Université Paris-Saclay, Hôpital de Bicêtre, Le Krem‑
Abbreviations lin‑Bicêtre, France. 19 Division of Anaesthetics, Pain Medicine and Intensive
ABP: Arterial blood pressure; CHERRIES: Checklist for Reporting Results of Inter‑ Care, Imperial College London, London, UK. 20 Department of Cardiopneumol‑
net E-Surveys; CO: Cardiac output; CVP: Central venous pressure; ESICM: Euro‑ ogy, Instituto Do Coracao, Universidade de São Paulo, Hospital SirioLibanes,
pean Society of Intensive Care Medicine; ICU: Intensive care unit; IC: Intensive São Paulo, Brazil. 21 Assistance Publique-Hôpitaux de Paris, Paris Saclay
care; LVEF: Left ventricular ejection fraction; MAP: Mean arterial pressure; NE: University Hospitals, Antoine Béclère Hospital, Paris, France. 22 Departamento
Norepinephrine; PDE: Phosphodiesterase; PAOP: Pulmonary artery occlusion de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica
pressure; SSC: Surviving Sepsis Campaign; ScvO2: Central venous oxygen satu‑ de Chile, Santiago, Chile. 23 Servicio de Terapia Intensiva, Hospital Fernández,
ration; v-a ­PCO2: Venous-to-arterial carbon dioxide pressure difference. Buenos Aires, Argentina. 24 Department of Critical Care, University of Gron‑
ingen, University Medical Center Groningen, Groningen, the Netherlands.
25
Acknowledgement Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific
This work has received the endorsement of the European Society of Intensive Institute, Vita-Salute San Raffaele University, Milan, Italy. 26 Aix Marseille Uni‑
Care Medicine. The authors would like to thank Hannah Wunsch and Anders versité, Assistance Publique Hôpitaux de Marseille, Service D’Anesthésie Et de
Perner, who provided their expertise as experts but abstained from being Réanimation CHU Nord, Marseille, France. 27 Service de Réanimation Médicale
listed as co-author of this paper. Brabois Et Pôle Cardio‑Médico‑Chirurgical. CHRU Brabois, INSERM U1116,
Université de Lorraine, Vandoeuvre les NancyNancy 54500, France. 28 Depart‑
Authors’ contributions ment of Anesthesia, Burn and Critical Care, APHP Hôpitaux Universitaires Saint
TWLS and JLT developed the survey. TWLS, IVDH and JLT developed the ques‑ Louis LariboisièreUniversité Paris DiderotU942 Inserm, Paris, France. 29 Medical
tions to experts. SVT analyzed the data. TWLS, IVDH, STV, MD, MS and JLT were Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Paris-Saclay Uni‑
major contributors in writing the manuscript. All authors read and approved versity Hospitals, Bicêtre hospital, Le Kremlin‑Bicêtre, France. 30 INSERM UMR_S
the final manuscript. 999, FHU SEPSIS, Le Kremlin‑Bicêtre, France. 31 Department of Clinical Internal,
Anesthesiological and Cardiovascular Science, Sapienza University of Rome,
Funding Rome, Italy. 32 University Paris 7 Denis Diderot; INSERM 1160 and Hôpital Lari‑
No funding. boisière, APHP, Paris, France. 33 William Harvey Research Institute, Queen Mary
University of London, London EC1M 6BQ, UK. 34 Department of Critical Care
Availability of data and materials Medicine, University of Pittsburgh, Pittsburgh, USA. 35 Institut Für Anästhesi‑
The data of the survey are available from the corresponding author upon ologische Pathophysiologie Und Verfahrensentwicklung, Universitätsklinikum
reasonable request. Ulm, Ulm, Germany. 36 Department of Anesthesiology and Intensive Care
Medicine, Rostock University Medical Centre, Rostock, Germany. 37 Depart‑
Ethics approval and consent to participate ment of Anesthesiology and Intensive Care, Uniklinikum Jena, Jena, Germany.
38
Not applicable. Department of Anesthesiology, Intensive Care Medicine and Pain Therapy,
University Hospital Giessen, UKGM, Justus-Liebig University Giessen, Gies‑
Consent for publication sen, Germany. 39 Department of Anesthesiology, Center of Anesthesiology
Not applicable. and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany. 40 Bloomsbury Institute of Intensive Care Medicine, Divi‑
Competing interest sion of Medicine, University College London, London, UK. 41 ICU Department,
A.M. received speaker’s honoraria from Novartis, Orion, and Servier and fees Réanimation CERIC, Clinique Ambroise Paré, Neuilly, France. 42 Assistance
as a member of the advisory board or steering committee from Adrenomed, Publique-Hôpitaux de Paris, University Hospital Ambroise Paré, intensive care
unit, Boulogne‑Billancourt, France. 43 INSERM U-1018, CESP, Team 5, University
of Versailles Saint-Quentin en Yvelines, Villejuif, France. 44 Medical‑Surgical
Scheeren et al. Ann. Intensive Care (2021) 11:21 Page 12 of 13

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