REVIEW

C URRENT
OPINION Inotrope and vasopressor use in cardiogenic shock:
what, when and why?
Kira Hu a and Rebecca Mathew b,c

Purpose of review
Despite increasing interest in the management of cardiogenic shock (CS), mortality rates remain
unacceptably high. The mainstay of supportive treatment includes vasopressors and inotropes. These
medications are recommended in international guidelines and are widely used despite limited evidence
supporting safety and efficacy in CS.
Recent findings
The OptimaCC trial further supports that norepinephrine should continue to be the first-line vasopressor of
choice in CS. The CAPITAL DOREMI trial found that milrinone is not superior to dobutamine in reducing
morbidity and mortality in CS. Two studies currently underway will offer the first evidence of the necessity
of inotrope therapy in placebo-controlled trials: CAPITAL DOREMI2 will randomize CS patients to inotrope
or placebo in the initial resuscitation of shock to evaluate the efficacy of inotrope therapy and
LevoHeartShock will examine the efficacy of levosimendan against placebo in early CS requiring
vasopressor therapy.
Summary
Review of the current literature fails to show significant mortality benefit with any specific vasopressor or
inotropic in CS patients. The upcoming DOREMI 2 and levosimendan versus placebo trials will further
tackle the question of inotrope necessity in CS. At this time, inotrope selection should be guided by
physician experience, availability, cost, and most importantly, individual patients’ response to therapy.
Keywords
cardiogenic shock, inotrope, vasopressor

INTRODUCTION recently updated an expert consensus statement on

Cardiogenic shock (CS) is a primary cardiac disorder of the classification of CS. The stages range from A, those
low cardiac output (CO) resulting in clinical and bio- patients at risk of CS, to E, identifying those patients in
chemical findings of end-organ hypoperfusion [1]. extremis. Patients with class C or higher shock are
Pathophysiological changes include impaired myo- differentiated by evidence of clinical and/or biochem-
cardial contractility and reduced CO, associated with ical hypoperfusion [3]. This classification system
systemic vasoconstriction and coronary ischemia. The standardizes the way in which we communicate about
complex CS spiral can be worsened by concomitant CS, provides prognostic valve across AMI- and non-
systemic inflammation, vasodilation and abnormal AMI CS cohorts, and allows for better assessment of
nitric oxide handling. CS complicates approximately efficacy of interventions in heterogeneous subsets of
5 to 10% of acute myocardial infarction (AMI) pre- CS patients. It is important to recognize the pheno-
sentations [2]. Non-AMI etiologies of CS include acute typic variation of CS patients, and how these etiologies
decompensation of heart failure, severe valvular dis- can impact outcomes. For example, in the CAPITAL
ease, arrhythmias and myocarditis. CS was historically
defined hemodynamically, with persistent hypoten- a
Faculty of Medicine, University of Ottawa, bDivision of Cardiology and
sion of systolic blood pressure less than 90 mmHg c
CAPITAL Research Group, University of Ottawa Heart Institute,
associated with a severe reduction in cardiac index Ottawa, Ontario, Canada
(less than 1.8L/min/m2 without support or less than Correspondence to Rebecca Mathew, HS-407, 40 Ruskin Street,
2.2L/min/m2 with support), and adequate or elevated Ottawa, ON K1Y 4W7 Canada. Tel: +613 696 7406;
filling pressures (left ventricular end-diastolic pressure fax: +613 696 7248; e-mail: [email protected]
of greater than 15–18 mmHg) [1]. The Society for Curr Opin Crit Care 2022, 28:419–425
Cardiovascular Angiography and Interventions (SCAI) DOI:10.1097/MCC.0000000000000957

1070-5295 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Cardiogenic shock

the functions of the sympathetic nervous system.

KEY POINTS The alpha-1 receptors are linked to vascular smooth

Vasopressor and inotropes remain the mainstay of muscle activity, and activation produces systemic
supportive treatment in CS, despite limited evidence vasoconstriction, increasing peripheral vascular
supporting its efficacy and safety in CS. resistance and arterial blood pressure. The alpha-2
receptors are located within presynaptic nerve ter-

Norepinephrine is the preferred vasopressor in CS, but
minals and inhibit the release of endogenous nor-
there is no data to support selection of one inotrope
over another in CS. epinephrine. Activation of beta-1 receptors leads to
increased inotropy and chronotropy whereas acti-

Inotrope selection should be guided by individual vation of the beta-2 receptors leads to smooth
patients’ response to therapy and tolerability to muscle and vascular relaxation. Most medications
potential adverse effects.
used in CS resuscitation have both inotropic and

There is an urgent need for randomized trials vasopressor properties and take advantage of exci-
examining inotropes against placebo in CS. tatory and inhibitory effects on the aforementioned
receptors to exert their effects on the heart, periph-
eral vascular system and autonomic nervous system
to augment CO and restore end-organ perfusion
DOREMI cohort, patients with AMI-CS had signifi- [15].
cantly higher rates of all-cause mortality, need for
MCS device and RRT compared to those with non-
AMI-CS, highlighting the need for trials of pharmaco- NOREPINEPHRINE IS PREFERRED OVER
logic and device-based interventions in specific sub- EPINEPHRINE AS FIRST-LINE
&
groups of CS [4 ]. The 2022 SCAI update also included VASOPRESSOR
risk factors beyond shock stage that improved mortal- The most commonly used vasopressor in CS is nor-
ity risk stratification, allowing for additional subgroup epinephrine, a potent vasopressor acting on alpha-1
discrimination and improved prognostic utility. A adrenergic receptors to cause vasoconstriction and
posthoc analysis of the CAPITAL DOREMI trial found on beta-1 adrenergic receptors in the myocardium,
that patients with moderate-to-severe or greater valv- augmenting cardiac contractility [15]. Therapeutic
ular stenosis or regurgitation had higher rates of in- dosing ranges from 0.05 to 1.0 mcg/kg/min [16].
&
hospital mortality [5 ] – whether significant concom- Norepinephrine increases mean arterial pressure
itant valve disease is simply a marker of worsened (MAP) without an associated increase in heart rate,
prognosis or a potential therapeutic target is yet to as outlined in Table 1 [15–17]. This may be due to
be determined. increased afterload from alpha-1 stimulation caus-
The most significant advancement in the care of ing reflex bradycardia. This proves to be potentially
CS patients has been the SHOCK trial, which showed advantageous since tachycardia can worsen myocar-
reduced mortality in AMI-CS with urgent revascula- dial oxygen demand. Furthermore, norepinephrine
rization of culprit coronary artery lesions [6]. Trials does not act on the beta-2 adrenergic receptors,
to explore other therapeutic interventions, includ- preventing the cited epinephrine-induced rise in
ing the intra-aortic balloon pump (IABP) [7] and serum lactate, and allowing lactate to be used as a
nitric oxide synthase inhibitors [8] have not shown more reliable marker of end-organ perfusion [18,19].
benefit and the mortality of CS has plateaued at In contrast, epinephrine has a more potent beta-
greater than 40% over the last two decades [9]. 1 adrenergic effect than norepinephrine, along with
Accordingly, the mainstay of pharmacologic stabi- moderate beta-2 and alpha-1 adrenergic receptor
lization remains with vasopressors and inotropes, effects [15]. Therapeutic dosing ranges from 0.1 to
and these medications are recommended in interna- 1mcg/kg/min [16]. At lower doses, epinephrine
tional guidelines [10,11]. Their use is predominantly increases CO due to its beta-1 adrenergic inotropic
based on expert consensus with limited randomized and chronotropic effects, whereas the alpha-1 adre-
clinical trial data supporting efficacy and safety [12– nergic induced vasoconstriction is balanced by the
14]. Here, we review commonly used inotropes, beta-2 adrenergic vasodilation. At higher doses, the
their mechanisms of action and the data surround- alpha-adrenergic receptor effect predominates,
ing their role in the management of CS. resulting in increased systemic vascular resistance
(SVR) [20]. Epinephrine is not commonly used as
first-line in shock states due to increased risk of
PHYSIOLOGICAL BASIS OF INOTROPES tachyarrhythmias, splanchnic vasoconstriction,
The body’s adrenergic receptors, divided into alpha and hyperlactemia [21]. In a review of several vaso-
and beta receptors, are responsible for performing pressors and inotropes in CS, only epinephrine was

420 www.co-criticalcare.com Volume 28
Number 4
August 2022

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

 Inotrope and vasopressor use in cardiogenic shock Hu and Mathew

Table 1. Commonly used inotropes in CS, with dosing range, receptor binding, hemodynamic effects and adverse effects.

Agent Therapeutic dosing range Receptor binding Hemodynamic effects Adverse effects

Norepinephrine 0.05--1 mg/kg/min a1þþþ MAP: " " þ contractility Arrhythmias, Increased pulmonary
b1þþ HR: $ or # þþ vasoconstriction vascular resistance, peripheral
CO: " (digital) ischemia
Epinephrine 0.1--1 mg/kg/min a1þþþ MAP: " " þ contractility Ventricular arrhythmias, severe
b1þþþ HR: " " þþ vasoconstriction hypertension, cardiac ischemia
b2þþ CO: " "
Dobutamine 2--20 mg/kg/min b1þþ MAP: $ or # þþ contractility Tachycardia, increased ventricular
HR: " " þ vasodilation response rate in patients with
CO: " " atrial fibrillation, ventricular
arrhythmias, cardiac ischemia,
hypertension, hypotension
Milrinone 0.0625--0.5 mg/kg/min PDE-3 inhibitor MAP: $ or # þþ contractility Ventricular arrhythmias,
HR: " þ vasodilation hypotension, cardiac ischemia,
CO: " " Torsade des pointes
Levosimendan 0.05--2 mg/kg/min Calcium Sensitizer MAP: $ or # þþ contractility Tachycardia, enhanced AV
HR: " " þ vasodilation conduction, hypotension
CO: " "

MAP, mean arterial pressure; CO, cardiac output; HR, heart rate. Adapted from Ref. [15--17].

independently associated with profound worsening specific situations where a pure vasopressor may be
in cardiac and renal biomarkers and increased 90- beneficial, such as in afterload-sensitive situations
day mortality [22]. The advantages of norepinephr- like dynamic left ventricular outflow obstruction
ine over epinephrine were confirmed in the Opti- (LVOTO) and CS [12]. A vasopressor with inotropic
maCC trial, which randomized 57 patients with properties like norepinephrine could be detrimental
AMI-CS to these two agents. Both drugs increased as increasing cardiac contractility would worsen the
MAP, but epinephrine-treated patients showed LVOTO and further compromise forward flow. Addi-
higher rates of lactic acidosis, marked and sustained tionally, vasopressin may be preferentially selected
increases in heart rate, and increased cardiac double in patients with marked right ventricular failure
product – a marker of myocardial oxygen consump- since it is thought to increase SVR without an asso-
tion. Although epinephrine is efficacious in increas- ciated increase in pulmonary vascular resistance
ing MAP, it does so at higher energy costs and lower (PVR), helping to minimize added insult to an
cardiac efficiency. These effects may be due to the already failing RV [24]. This concept is reflected in
differences in receptor affinity, as only epinephrine an RCT where low-dose vasopressin was compared
acts on beta-2 adrenergic receptors. Most impor- to norepinephrine in patients with milrinone-
tantly, patients in the epinephrine group had an induced hypotension during CABG. The results
increased occurrence of refractory shock, but there found that both drugs effectively restored the mil-
was no significant difference in mortality between rinone-induced decrease in SVR, but only low-dose
the two groups (60-day mortality of 52% in the vasopressin decreased the PVR/SVR ratio [25]. With
epinephrine group and 37% in norepinephrine regards to pure vasopressor use specifically in CS, the
group). Several limitations must be taken note of available evidence is experimental in nature with
in OptimaCC, including the small sample size, lack only nonhuman studies published to date. In a pig
of clarification regarding maximum dose reached model of refractory CS complicated by cardiac arrest
and the short duration of follow-up [23]. Although and resuscitated with veno-arterial ECMO, vasopres-
epinephrine is still often used as a ‘push-dose or sin produced quicker lactate clearance, less fluid
bolus-dose vasopressor’ in peri-arrest situation, sus- resuscitation and less pulmonary edema when com-
&
tained infusions for hemodynamic support should pared to norepinephrine [26 ]. An ongoing random-
be avoided among patients with CS. ized trial (NCT02118467) is currently investigating
phenylephrine and vasopressin versus norepinephr-
ine and epinephrine in ICU patients with shock
SECOND-LINE VASOPRESSORS unresponsive to intravenous fluids, hypothesizing
Pure vasopressors such as vasopressin or phenyl- that pure vasopressors will reduce tachyarrhythmias
&
ephrine are typically not the first line in CS as they [27 ]. Since the CS population is so diverse and
have no effect on cardiac contractility. There are heterogeneous in terms of etiology, these findings

1070-5295 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 421

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Cardiogenic shock

emphasize the importance of tailoring decisions to patients with severe heart failure, dobutamine was
individual patient conditions and closely monitor- associated with higher supraventricular and ventric-
ing clinical response. ular arrhythmic burden compared to enoximone
[32]. A retrospective review that included a hetero-
geneous cohort of CS patients found that arryth-
DOPAMINE IS NOT RECOMMENDED IN mias, particularly sinus tachycardia, were more
CARDIOGENIC SHOCK common in the dobutamine compared to milrinone
Dopamine is another commonly used vasopressor in [33]. Nevertheless, dobutamine is widely used and
shock states and acts on beta-1 and alpha-1 adre- the combination of dobutamine-norepinephrine is
nergic receptors. Dosing ranges from 2 to 20mcg/kg/ commonly seen in CS patients requiring both vaso-
min [15]. However, dopamine is not routinely used pressor and inotrope support. A study comparing
in CS, with De Backer et al. finding increased dobutamine-norepinephrine against epinephrine
arrhythmias and 28-day mortality with dopamine found that both interventions were similarly effec-
compared to norepinephrine in the SOAP II trial tive but epinephrine was associated with more
[28]. These results were solidified in a recent meta- adverse events, including transient lactic acidosis,
analysis of randomized control trials (RCT) which increased heart rate and arrhythmias, and inad-
concluded that norepinephrine is associated with equate gastric perfusion [34].
decreased 28-day mortality, fewer arrhythmic Lastly, as a beta-adrenergic agonist, concern has
events, and lower incidence of gastrointestinal reac- been raised about the efficacy of dobutamine with
tions when compared to dopamine in patients with beta-blocker therapy on board. A secondary analysis
CS, regardless of etiology [29]. However, questions of CAPITAL DOREMI trial found no difference in
have been raised regarding the external validity and outcomes between dobutamine and milrinone
applicability of the results as the SOAP II trial did not among patients treated with beta-blocker in the
&&
have a standard definition of CS and included 24 h preceding inotrope initiation [35 ]. In fact,
obstructive, valvular and postcardiotomy states. the beta-blocker cohort demonstrated fewer resus-
The varying hemodynamic profiles may have citated cardiac arrests and deaths, with a trend
resulted in treatment-related differences, which toward fewer ventricular arrhythmias. There may
were not formally evaluated. As a result, van Diepen be a paradoxical protective effect with beta-blocker
et al. suggest that the optimal first-line vasopressor use, and a dedicated clinical trial would help delin-
agent remains unclear [12] but guidelines support eate this finding.
norepinephrine to be the vasopressor of choice due
to its efficacy and lower risk of adverse events.
Further larger scale and high quality randomized MILRINONE
controlled trials are needed to investigate other Milrinone is a positive inotropic agent widely used
agents in different phenotypes of CS, and better in patients with end-stage heart failure and CS.
guide these decisions in an evidence-based manner. Originally approved for use in the 1980s, there is
significant experience and comfort with this agent
[36]. Milrinone is a phosphodiesterase-3 inhibitor,
DOBUTAMINE limiting the breakdown of cyclic adenosine mono-
Dobutamine is one of the most commonly used phosphate (cAMP), increasing activation of protein
inotropes in CS. It is a synthetic catecholamine with kinase A, and transporting calcium intracellularly,
affinity for beta-1 and beta-2 receptors, and produ- which ultimately promotes improved contractility
ces positive inotropic and afterload reducing effects [37]. Dosing ranges from 0.0625 to upwards of
[30]. Dosing ranges from 2 to upwards of 20 mcg/kg/ 0.5 mcg/kg/min, with some clinicians choosing to
min with no need to adjust for renal or hepatic provide a loading dose at initiation, usually reserved
insufficiency [15]. Clinically, dobutamine’s short to its intra-operative use. Amongst decompensated
half-life allows the advantage of a ‘trial’ of inotrope heart failure patients, similar steady-state plasma
therapy, with rapid assessment of its efficacy and levels and hemodynamic benefits were seen regard-
safety [31]. This is particularly important given the less of initial bolus prior to infusion initiation by the
lack of robust data showing meaningful benefit with 3-h mark. Although the bolus group showed hemo-
inotropes combined with the signal of established dynamic benefits earlier, these patients had more
harm, which should temper use until more compel- hypotension and tachycardia compared to the infu-
ling data is available. A concern with dobutamine, sion alone group [38].
particularly in the post-AMI population, is the pur- Milrinone has been most extensively studied in
ported increase in myocardial oxygen consumption, the chronic heart failure population, with random-
ischemia and tachyarrhythmias. Among post-AMI ized data demonstrating no differences in morbidity

422 www.co-criticalcare.com Volume 28
Number 4
August 2022

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

 Inotrope and vasopressor use in cardiogenic shock Hu and Mathew

or mortality in patients treated with a 48-h milri- cardiac filling pressures and in those patients who are
none infusion compared to placebo. However, mil- on beta-blockers as they act through different phys-
rinone-treated patients had increased rates of new iologic pathways [47]. Levosimendan has been com-
atrial arrhythmias and sustained hypotension pared to dobutamine in several RCTs but patients
requiring intervention [39]. Interestingly, the have been mostly SCAI class A, and not those with
authors noted worse outcomes among milrinone- higher severity of shock. These trials have demon-
treated patients with ischemic cardiomyopathy strated improved hemodynamics and reductions in
compared to nonischemic cardiomyopathy [40] natriuretic peptide levels, but have failed to show
emphasizing the need for dedicated clinicals trials meaningful improvements in mortality [48,49].
segregated by CS etiology. Lewis et al.’s retrospective The results of LevoHeartShock (NCT04020263),
study comparing milrinone to dobutamine as an which will compare the early use of levosimendan
initial inotropic medication in CS patients found against placebo in patients with CS treated with vaso-
that these two inotropes had similar effectiveness pressor therapy (first-line therapy being combined
and safety profiles, but mostly differed in type of norepinephrine-dobutamine), will provide greater
adverse events, with dobutamine-treated patients insight into its efficacy and safety in this unique
&&
reporting more arrhythmias [33]. Most recently, patient population [50 ].
the CAPITAL DOREMI trial compared dobutamine
and milrinone in SCAI class B-E CS, finding that
milrinone was not superior to dobutamine in reduc- CONCLUSION
ing the composite outcome or any of the individual CS continues to carry a high risk of morbidity and
outcomes, including all-cause in-hospital death, mortality. The mainstay of pharmacotherapy lies
need for new renal replacement therapy, need for with vasopressors and inotropes, although dedicated
cardiac transplant or MCS or resuscitated cardiac and comparative evidence in the CS population
arrest. Contrary to retrospective studies previously, remains sparse. Common inotrope agents include
there were no significant differences in heart rate, dobutamine, milrinone and levosimendan, each
MAP or vasoactive-inotropic score (VIS), which is a with their own hemodynamic and clinical benefits
&&
measure of cumulative pharmacologic support [41 ]. and risks. The next most urgent question to be
Serial lactate measurements have diagnostic, thera- answered regarding inotrope therapy is if agents are
peutic and prognostic value in CS, with recent evi- equally effective, ineffective or harmful. We hope to
dence supporting lactate clearance as a surrogate answer this question with our upcoming trial, CAP-
for in-hospital mortality [42]. A posthoc analysis of ITAL DOREMI2, which will randomize SCAI class C/D
the CAPITAL DOREMI trial found that multiple CS to inotrope or placebo in the initial resuscitation of
lactate-parameters, as early as 8 h after enrollment, their shock. Further research is also necessary to
were associated with 30-day mortality, including determine how inotrope therapy fits into a model
complete lactate clearance (CLC), percentage lac- of CS with escalating use of MCS. Ultimately, inotrope
tate clearance and percentage lactate clearance per selection must be guided by physician experience,
hour. However, CLC was the strongest predictor of availability, cost, and most importantly, individual
survival at all time points between 8 and 24 h after patients’ response to therapy.
&
enrollment [43 ].
Acknowledgements
None.
LEVOSIMENDAN
Levosimendan is a calcium-sensitizing agent that Financial support and sponsorship
binds to cardiac troponin C, improving contractility None.
independent of an intracellular rise in calcium [44].
Levosimendan also opens adenosine triphosphate- Conflicts of interest
sensitive potassium channels, resulting in systemic
There are no conflicts of interest.
vasodilation [45]. One of the reasons that levosimen-
dan is preferred in CS is that it has minimal effect on
the beta-adrenergic receptors [44,46], theoretically REFERENCES AND RECOMMENDED
reducing myocardial oxygen demand and attenuat- READING
ing risk of tachyarrhythmias. Dosing ranges from 0.05 Papers of particular interest, published within the annual period of review, have
been highlighted as:
to 0.2 mcg/kg/min [15]. Although not yet available in & of special interest
North America, the European Society of Cardiology && of outstanding interest

suggests levosimendan, or other phosphodiesterase 1. Reynolds HR, Hochman JS. Cardiogenic shock. Circulation 2008;
type III inhibitors, may be preferred as they reduce 117:686–697.

1070-5295 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 423

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Cardiogenic shock

2. Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest 26. Klein T, Grandmougin D, Liu Y, et al. Comparison of vasopressin versus
hemodynamic correlate of mortality in cardiogenic shock: a report from the & norepinephrine in a pig model of refractory cardiogenic shock complicated by
SHOCK trial registry. J Am Coll Cardiol 2004; 44:340–348. cardiac arrest and resuscitated with Veno-arterial ECMO. Shock 2021;
3. Naidu SS, Baran DA, Jentzer JC, et al. SCAI SHOCK Stage Classification 56:473–478.
Expert Consensus Update: a review and incorporation of validation studies. J The first experimental look at pure vasopressor versus inopressor therapy speci-
Am Coll Cardiol 2022; 79:933–946. fically in the CS population.
4. Jung RG, Di Santo P, Mathew R, et al. Implications of myocardial infarction on 27. University of Chicago. A Randomized Double Blind Trial of Vasoactive Drugs
& management and outcome in cardiogenic shock. J Am Heart Assoc 2021; 10: & for the Management of Shock in the ICU [Internet]. clinicaltrials.gov; 2020
e021570. Nov [cited 2022 Jan 23]. Report No.: NCT02118467. Available from: https://
This study outlines a heterogeneity of outcomes between AMI and non-AMI CS clinicaltrials.gov/ct2/show/NCT02118467
patients, supporting that future trials should consider studying interventions in An ongoing clinical trial comparing pure vasopressor vs inopressor therapy in a
specific subgroups of CS. generalized shock population. If a cardiogenic shock subgroup included, it would
5. Parlow S, Weng W, Di Santo P, et al. Significant valvular dysfunction and be interesting to evaluate the efficacy of pure vasopressor therapy, since these
& outcomes in cardiogenic shock: insights from the randomized DOREMI trial. medications are generally not used in cardiogenic shock.
Can J Cardiol 2022. S0828-282X (22)00220-3. 28. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and
This study finds significant valvular dysfunction is associated with poorer outcomes norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779–789.
in CS, highlighting how different etiologies of CS impact outcomes. 29. Rui Q, Jiang Y, Chen M, et al. Dopamine versus norepinephrine in the
6. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute treatment of cardiogenic shock. Medicine 2017; 96:e8402.
myocardial infarction complicated by cardiogenic shock. SHOCK Investiga- 30. Jentzer JC, Hollenberg SM. Vasopressor and inotrope therapy in cardiac
tors. Should We Emergently Revascularize Occluded Coronaries for Cardio- critical care. J Intensive Care Med 2021; 36:843–856.
genic Shock. N Engl J Med 1999; 341:625–634. 31. Ashkar H, Adnan G, Makaryus AN. Dobutamine. In: StatPearls. Treasure
7. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for Island (FL): StatPearls Publishing; 2022. [cited 2022 Jan 24]. Available from:
myocardial infarction with cardiogenic shock. N Engl J Med 2012; http://www.ncbi.nlm.nih.gov/books/NBK470431/.
367:1287–1296. 32. Caldicott LD, Hawley K, Heppell R, et al. Intravenous enoximone or dobuta-
8. TRIUMPH Investigators. Alexander JH, Reynolds HR, Stebbins AL, et al. mine for severe heart failure after acute myocardial infarction: a randomized
Effect of tilarginine acetate in patients with acute myocardial infarction and double-blind trial. Eur Heart J 1993; 14:696–700.
cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA 2007; 33. Lewis TC, Aberle C, Altshuler D, et al. Comparative effectiveness and safety
297:1657–1666. between milrinone or dobutamine as initial inotrope therapy in cardiogenic
9. Thiele H, Ohman EM, Desch S, et al. Management of cardiogenic shock. Eur shock. J Cardiovasc Pharmacol Ther 2019; 24:130–138.
Heart J 2015; 36:1223–1230. 34. Levy B, Perez P, Perny J, et al. Comparison of norepinephrine-dobutamine to
10. Ibanez B, James S, Agewall S, et al. ESC Guidelines for the management of epinephrine for hemodynamics, lactate metabolism, and organ function vari-
acute myocardial infarction in patients presenting with ST-segment elevation: ables in cardiogenic shock. A prospective, randomized pilot study. Crit Care
The Task Force for the management of acute myocardial infarction in patients Med 2011; 39:450–455.
presenting with ST-segment elevation of the European Society of Cardiology 35. Di Santo P, Mathew R, Jung RG, et al. Impact of baseline beta-blocker use on
(ESC). Eur Heart J 2018; 39:119–177. && inotrope response and clinical outcomes in cardiogenic shock: a subgroup
11. Levy B, Bastien O, Karim B, et al. Experts’ recommendations for the manage- analysis of the DOREMI trial. Crit Care 2021; 25:289.
ment of adult patients with cardiogenic shock. Ann Intensive Care 2015; 5:52. The subgroup analysis shows a paradoxical protective effect of beta-blocker use. It
12. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of raises the question of whether baseline beta-blocker use may actually improve
cardiogenic shock: a scientific statement From the American Heart Associa- response to inotropic therapy and clinical outcomes. With many cardiac patients
tion. Circulation 2017; 136:e232–e268. on a baseline beta-blocker, this would be an important question to answer with a
13. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the dedicated control trial.
diagnosis and treatment of acute and chronic heart failure: The Task Force for 36. Tariq S, Aronow WS. Use of inotropic agents in treatment of systolic heart
the diagnosis and treatment of acute and chronic heart failure of the European failure. Int J Mol Sci 2015; 16:29060–29068.
Society of Cardiology (ESC)Developed with the special contribution of the 37. Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the
Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; treatment of congestive heart failure. Mechanisms of action and recent clinical
37:2129–2200. developments. 2 N Engl J Med 1986; 314:349–358.
14. Zeymer U, Bueno H, Granger CB, et al. Acute Cardiovascular Care Associa- 38. Baruch L, Patacsil P, Hameed A, et al. Pharmacodynamic effects of milrinone
tion position statement for the diagnosis and treatment of patients with acute with and without a bolus loading infusion. Am Heart J 2001; 141:266–273.
myocardial infarction complicated by cardiogenic shock: A document of the 39. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for
Acute Cardiovascular Care Association of the European Society of Cardiol- acute exacerbation of chronic heart failure: a randomized controlled trial.
ogy. Eur Heart J Acute Cardiovasc Care 2020; 9:183–197. JAMA 2002; 287:1541–1547.
15. Overgaard CB, Džavı́k V. Inotropes and vasopressors. Circulation 2008; 40. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response
118:1047–1056. to milrinone in decompensated heart failure: results from the OPTIME-CHF
16. Levy B, Buzon J, Kimmoun A. Inotropes and vasopressors use in cardiogenic study. J Am Coll Cardiol 2003; 41:997–1003.
shock: when, which and how much? Curr Opin Crit Care 2019; 41. Mathew R, Di Santo P, Jung RG, et al. Milrinone as compared with dobu-
25:384–390. && tamine in the treatment of cardiogenic shock. N Engl J Med 2021;
17. Levy B, Klein T, Kimmoun A. Vasopressor use in cardiogenic shock. Curr Opin 385:516–525.
Crit Care 2020; 26:411–416. The most recent high-quality look at milrinone vs dobutamine as initial inotropic
18. Levy B, Bollaert PE, Charpentier C, et al. Comparison of norepinephrine and therapy in CS patients. With results showing no differences in clinical outcomes
dobutamine to epinephrine for hemodynamics, lactate metabolism, and between the two inotropes, this outlines the need for a placebo-based trial to
gastric tonometric variables in septic shock: a prospective, randomized study. determine efficacy of the individual inotropes
Intensive Care Med 1997; 23:282–287. 42. Fuernau G, Desch S, de Waha-Thiele S, et al. Arterial lactate in cardiogenic
19. Levy B, Gibot S, Franck P, et al. Relation between muscle NaþKþ ATPase shock: prognostic value of clearance versus single values. JACC Cardiovasc
activity and raised lactate concentrations in septic shock: a prospective study. Interv 2020; 13:2208–2216.
Lancet 2005; 365:871–875. 43. Marbach JA, Di Santo P, Kapur NK, et al. Lactate clearance as a surrogate for
20. Allwood MJ, Cobbold AF, Ginsburg J. Peripheral vascular effects of nora- & mortality in cardiogenic shock: insights from the DOREMI Trial. J Am Heart
drenaline, isopropylnoradrenaline and dopamine. Br Med Bull 1963; Assoc 2022; 11:e023322.
19:132–136. This post hoc analysis of the DOREMI trial finds complete lactate clearance as a
21. Russell JA. Vasopressor therapy in critically ill patients with shock. Intensive significant predictor of in-hospital mortality in CS patients. These results empha-
Care Med 2019; 45:1503–1517. size the utility of serial lactate measurements.
22. Tarvasmäki T, Lassus J, Varpula M, et al. Current real-life use of vasopressors 44. Kaheinen P, Pollesello P, Hertelendi Z, et al. Positive inotropic effect of
and inotropes in cardiogenic shock – adrenaline use is associated with levosimendan is correlated to its stereoselective Ca2þ-sensitizing effect
excess organ injury and mortality. Crit Care 2016; 20:208. but not to stereoselective phosphodiesterase inhibition. Basic Clin Pharmacol
23. Levy B, Clere-Jehl R, Legras A, et al. Epinephrine versus norepinephrine for Toxicol 2006; 98:74–78.
cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2018; 45. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. The novel calcium
72:173–182. sensitizer levosimendan activates the ATP-sensitive Kþ channel in rat ven-
24. Wallace AW, Tunin CM, Shoukas AA. Effects of vasopressin on pulmonary tricular cells. J Pharmacol Exp Ther 1997; 283:375–383.
and systemic vascular mechanics. Am J Physiol-Heart Circ Physiol 1989; 46. Haikala H, Kaheinen P, Levijoki J, Lindén IB. The role of cAMP- and cGMP-
257:H1228–H1234. dependent protein kinases in the cardiac actions of the new calcium sensi-
25. Jeon Y, Ryu JH, Lim YJ, et al. Comparative hemodynamic effects of vaso- tizer, levosimendan. Cardiovasc Res 1997; 34:536–546.
pressin and norepinephrine after milrinone-induced hypotension in off-pump 47. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the
coronary artery bypass surgical patients. Eur J Cardiothorac Surg 2006; diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;
29:952–956. 42:3599–3726.

424 www.co-criticalcare.com Volume 28
Number 4
August 2022

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

 Inotrope and vasopressor use in cardiogenic shock Hu and Mathew

48. Follath F, Cleland JGF, Just H, et al. Efficacy and safety of intravenous 50. Effect of Early Use of Levosimendan Versus Placebo on Top of a Conventional
levosimendan compared with dobutamine in severe low-output heart failure && Strategy of Inotrope Use of a Combined Morbidity-mortality Endpoint in Patients
(the LIDO study): a randomised double-blind trial. Lancet 2002; 360: with Cardiogenic Shock. ClinicalTrials.gov identifier: NCT04020263. Updated
196–202. July 18, 2019. [cited 2022 Jan 23]. https://clinicaltrials.gov/ct2/show/
49. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for NCT04020263
patients with acute decompensated heart failure: the SURVIVE Randomized An upcoming clinical trial providing the first look at the potential efficacy of levosi-
Trial. JAMA 2007; 297:1883–1891. mendan, a widely used inotrope in heart failure, in the cardiogenic shock population.

1070-5295 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 425

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.