Journal of Intensive Medicine 3 (2023) 114–123

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Journal of Intensive Medicine

journal homepage: www.elsevier.com/locate/jointm

Review

The medical treatment of cardiogenic shock

Mickael Lescroart 1,2,3, Benjamin Pequignot 1,2,3, Dany Janah 1,2,3, Bruno Levy 1,2,3,∗
1
Service de Médecine Intensive et Réanimation Brabois, CHRU Nancy, Pôle Cardio-Médico-Chirurgical, Vandoeuvre-les-Nancy 54511, France
2
INSERM U1116, Faculté de Médecine, Vandoeuvre-les-Nancy 54511, France
3
Université de Lorraine, Vandoeuvre-les-Nancy 54000, France

a r t i c l e i n f o a b s t r a c t

Keywords: Cardiogenic shock (CS) is a leading cause of mortality worldwide. CS presentation and management in the cur-
Cardiogenic shock rent era have been widely depicted in epidemiological studies. Its treatment is codified and relies on medical care
Etiology and extracorporeal life support (ECLS) in the bridge to recovery, chronic mechanical device therapy, or trans-
Epidemiology
plantation. Recent improvements have changed the landscape of CS. The present analysis aims to review current
Medical treatment
medical treatments of CS in light of recent literature, including addressing excitation–contraction coupling and
Monitoring
specific physiology on applied hemodynamics. Inotropism, vasopressor use, and immunomodulation are discussed
as pre-clinical and clinical studies have focused on new therapeutic options to improve patient outcomes. Certain
underlying conditions of CS, such as hypertrophic or Takotsubo cardiomyopathy, warrant specifically tailored
management that will be overviewed in this review.

Background ments for inotropy.[ 5 ] Briefly, each action potential drives cal-
cium entry into cardiac myocytes via L-type Calcium ion (Ca2+ )
Cardiogenic shock (CS) is a major worldwide concern occur- channels (LTCC), triggering a greater Ca2+ release from the sar-
ring in 5–7% of patients presenting with acute myocardial in- coplasmic reticulum (SR). Calcium binding troponin C facili-
farction (AMI), with its incidence increasing as life expectancy tates actin–myosin interactions and cardiomyocyte contraction.
rises.[ 1 ] CS is usually defined as a state of organ hypoperfusion Thereafter, Ca2+ diffuses away from troponin C, initiating dias-
related to low cardiac output with normal or elevated filling tolic relaxation. The Ca2+ released from the SR is recaptured
pressure.[ 2 ] While the prognosis of chronic heart failure (HF) by the SR Ca2+ ATPase (SERCA), while the amount of Ca2+
has improved over the decades, the prognosis of CS remains that enters the cell via LTCCs is exported by the Sodium ion
poor.[ 3 , 4 ] The management of CS first relies on inotropic agents (Na+ )/Ca2+ -exchanger (NCX). Stimulation of 𝛽1-adrenergic re-
and vasopressor use to restore oxygen delivery (DO2 ) and main- ceptors (𝛽1-ARs) leads to coupling to G-proteins (Gs ), activation
tain normal ventricular-arterial coupling.[ 4 ] When medical ther- of adenylyl cyclase (AC), and cAMP production. Intracellular
apy is ineffective, extracorporeal life support (ECLS) should be cAMP activates LTCCS, enhances Ca2+ release by the SR after
proposed as rescue therapy in the bridge to recovery, transplan- binding specific ryanodine receptors (RyRs), and decreases tro-
tation, or chronic mechanical support. Pre-clinical studies and ponin calcium affinity driving positive inotropic and lusitropic
clinical trials have recently assessed additional therapies to im- effects. During HF, SERCA expression decreases, Ca2+ efflux
prove outcomes in critically ill patients with CS. This work aims is impaired, and [Na]IC increases, paving the way for failure
to review current treatments for CS management in light of the of underlying compensatory mechanisms (i.e., positive force–
recent literature. frequency relationship and Starling effect). The mechanism of
excitation–contraction coupling is illustrated in Figure 1.
Basic Principles for Applied Hemodynamics The 21st century has also provided significant enhancement
in applied hemodynamics. Guyton[ 6 ] first stated in the 1950s
A better understanding of excitation–contraction coupling that cardiac output mainly relied on the output of systemic
has provided new insights for the development of target treat- venous return, right atrial pressure, and mean systemic pres-

∗
Corresponding author: Bruno Levy, Medical Intensive Care Unit, University Hospital of Nancy, Brabois, Rue du Morvan, Vandoeuvre-Lès-Nancy 54500, France.
E-mail address: [email protected] (B. Levy).

https://doi.org/10.1016/j.jointm.2022.12.001
Received 19 September 2022; Received in revised form 21 November 2022; Accepted 4 December 2022. Managing Editor: Jingling Bao
Available online 19 January 2023
Copyright © 2022 The Author(s). Published by Elsevier B.V. on behalf of Chinese Medical Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
M. Lescroart, B. Pequignot, D. Janah et al. Journal of Intensive Medicine 3 (2023) 114–123

Figure 1. Excitation–contraction coupling.

𝛽1-AR: 𝛽1 adrenergic receptors; AC: Adenylate cyclase; Ca2+ : Calcium ion; LTCC: L-type Ca2+ channels; Na+ : Sodium ion; NCX: Na+ /Ca2+ -exchanger; PDE: Phos-
phodiesterase; RyR: Ryanodine receptor; SERCA: SR Ca2+ ATPase; T-tubule: Transversal tubule.

sure (i.e., the residual pressure within the circuitry at zero from LOCS. The European Card Shock study and the Ameri-
flow). In the 1990s, Sunagawa et al.[ 7 ] developed the concept of can registry reported similar in-hospital mortality rates rang-
ventricular-arterial coupling between the left ventricle and the ing from 31% to 39%.[ 10 , 11 ] Although international guidelines
arterial tree, each defined by its own elastic properties. The end- advocate inotropic and vasopressor bi-therapy in CS, substan-
systolic/arterial elastance (Ees/Ea) ratio (Ees for the left ven- tial heterogeneity is found in surveys with norepinephrine use
tricle and Ea for the arterial tree) shows optimal coupling for varying from 53% in the FRENSHOCK study to 92% and 85%
Ea = Ees/2. In this model, a lower inotropism is represented by in the American and European registry, respectively.[ 12 ] Recent
a lower Ees, and the adaptation will be left ventricular (LV) di- efforts by the Society for Cardiovascular Angiography and In-
latation, thus optimizing cardiomyocyte contraction according terventions (SCAI) have been directed toward a more uniform
to Starling’s law (as a result of an immediately increased sen- CS definition with a classification scheme similar to the INTER-
sitivity of troponin C to calcium) and the Anrep effect (caused MACS HF classification.[ 13 ] Based on this new definition, there
by a delayed increase of the intracellular calcium pool). The are five categories, ranging from at-risk, pre-shock to extreme
Windkessel effect converts a pulsatile flow generated by a water CS labeled as A–E. Medical therapy remains central to improv-
hand pump into a continuous flow. This model partly accounts ing tissue DO2 and myocardial recovery.
for the property of the aortic tree to release, during diastole,
the pressure energy accumulated in its walls during the previ-
ous ventricular ejection phase, thus partly dampening the pulse Medical Therapy
pressure generated at the aortic root by the previous ventricular
ejection.[ 8 ] Inotropic agents are still required to treat patients with low
When all of these adaptative mechanisms are overwhelmed, cardiac output with grade IIb-C recommendations for the Eu-
patients may develop CS. Sympathetic activation shifts blood ropean Society of Cardiology (ESC).[ 16 ] Management of CS was
from the unstressed splanchnic circulation to low-capacitance summarized in an international expert consensus statement pub-
vessels, with long-lasting systemic hypoperfusion driving or- lished in 2015.[ 2 ] The aforementioned epidemiological stud-
gan damage, inflammation, and vasoplegia.[ 9 ] Restoring vas- ies highlight that medical treatment of CS mainly relies on
cular tone with norepinephrine (not solely focusing on dobutamine and norepinephrine in the current era. Three cat-
low cardiac output syndrome [LOCS]) improves survival in echolamines have been used to date: epinephrine, dobutamine,
ischemic CS. and dopamine targeting 𝛽-AR, 𝛼-ARs, and D1- and D2-receptors.
One approach when considering medical management is to clas-
Epidemiology and Definition of CS sify drugs according to their inotropic and vasoactive effects. In-
otropic, inopressor, and inodilator therapies may be considered.
CS encompasses a heterogeneous population of patients. The It should be noted that inopressors have failed to improve out-
evolving definition of CS over the last decades is depicted in comes in CS while inotropes and inodilators are still considered
Table 1. Briefly, CS is considered when organ damage results in our clinical practices.

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Table 1
Definition of cardiogenic shock over trials.

Trials Definitions of CS

SHOCK Trial, 1999 [ 14 ]

Clinical criteria: SBP <90 mmHg and end organ hypoperfusion
AND
Hemodynamic criteria: CI <2.2 L/min/m2 AND PCWP ≥15 mmHg

IABP-SHOCK II, 2012[ 15 ] SBP <90 mm Hg or catecholamines

AND
Clinical pulmonary congestion
AND
Impaired end-organ perfusion

CARDSHOCK, 2015[ 10 ] Acute cardiac cause

AND
Sustained SBP <90 mmHg or catecholamines + hypoperfusions signs
(lactate >2.0 mmol/L or oliguria or skin mottling)

FRENSHOCK, 2022[ 12 ] SBP <90 mmHg or CI <2.0 L/min/m2 (TTE or right catheterization)
AND
Elevated R/L heart pressure defined by clinic, radiology, biology (BNP), TTE or invasive monitoring
AND
Clinical/biological hypoperfusion
CI: Cardiac index; CS: Cardiogenic shock; ESC: European Society of Cardiology; HF: Heart failure; IABP-SHOCK II: Intra-Aortic Balloon Pump in Cardiogenic Shock
II; LV: Left ventricular; MI: Myocardial infarction; PCWP: Pulmonary capillary wedge pressure; SBP: Systolic blood pressure; SHOCK: Should We Emergently Revas-
cularize Occluded Coronaries for Cardiogenic Shock trial; TTE: Transthoracic echocardiography.

Dobutamine, an inotropic agent while iPDE4 rather increases atrial arrhythmias. Pre-exposure
to 𝛽-adrenergic stimulation modulates the mechanism for in-
Dobutamine is a synthetic catecholamine derived from iso- otropy: under 𝛽-adrenergic stimulation, levosimendan is a Ca2+ -
prosterenol, developed to reduce chronotropic, arrhythmogenic, sensitizer under 𝛽-blockade therapy, conversely inhibits PDE3.
and vascular side effects.[ 17 ] The affinity of dobutamine for 𝛽2- In the initial dose-ranging studies, levosimendan was found to
AR is 10-fold lower than for 𝛽1-ARs and, in particular, its ago- improve hemodynamics and reduce pulmonary capillary wedge
nistic efficacy for 𝛽2-ARs and 𝛼1-ARs is much weaker than for pressures (PCWP) to a greater extent than dobutamine when
𝛽1-ARs. The cardiovascular effect of dobutamine has been as- a loading dose of 6–24 μg/kg/min was followed by an in-
sessed in a dose-ranging study, which revealed a dose-dependent fusion dose of 0.05–0.2 μg/kg/min. The RUSSLAN trial ad-
inotropic and lusitropic action.[ 18 ] Although dobutamine is the dressed its safety and found no difference between levosimen-
most frequently used inotropic agent,[ 18 ] only small compara- dan vs. placebo for clinically relevant hypotension or myocardial
tive trials support its use in clinical practice. A recent expert ischemia[ 24 ] . The LIDO study first compared the Ca2+ -sensitizer
statement recommended avoiding high doses (>20 μg/kg/min) to dobutamine and suggested a benefit for levosimendan as-
since these are associated with excessive tachycardia and an sessed by days alive and out-of-hospital criteria[ 25 ] . However,
increase in metabolism (thermogenic effect, increased glycol- these results were not replicated in either the SURVIVE or
ysis), which may impair oxygen balance. Ultimately, dobu- REVIVE trials[ 26 , 27 ] . There was moreover no improvement in
tamine also improves mitochondrial function in non-infarcted the targeted cardiac surgery population in the CHEETAH or
myocardium, improving oxygen utilization efficiency.[ 19 ] Of LEVO–CTS studies[ 28 , 29 ] . Levosimendan remains to date a drug
note, catecholamines drive the down-regulation of cardiac 𝛽- of interest for 𝛽-blocker intoxication, adrenergic cardiomyopa-
ARs and tachyphylaxis has been observed as early as 3 days after thy, or weaning VA-ECMO. iPDE3 also drives systemic and pul-
exposure.[ 20 ] monary vasodilation that may reduce right ventricular after-
load, although there are concerns raised for end-organ and coro-
Inotropic-vasodilator agents could be considered as an nary perfusion pressure. iPDE5 has been proposed for the treat-
alternative to dobutamine ment of right ventricular HF after LV assistance device therapy
or after heart transplantation for right ventricular primary graft
Levosimendan has been proposed for decades as an al- dysfunction, although remains with marginal indication.[ 30–32 ]
ternative to dobutamine in the treatment of CS. The active Milrinone is a bipyridine derivative synthetized after chemical
metabolite OR 1896 (after acetylation in the colon and liver) modification of amrinone, another inotropic drug. Its plasma
targets the Ca2+ -binding sites in the N-terminal region of tro- half-life averages 100 min and the duration of inotropic action
ponin C (cTNC), improving myofilament shortening[ 21 ] with- is 60 min. Eighty percent of the drug may be recovered intact in
out impairing diastolic relaxation or increasing myocardial the urine after 24 h. Dose ranging studies found that intravenous
oxygen consumption (MVO2 ). With a longer half-life reaching doses of 12.5 μg/kg were efficient to improve CO by 30% and
75–80 h, OR 1896 can improve inotropism for 7–9 days af- reduce PCWP by 20%, while clinically relevant hypotension was
ter infusion.[ 22 ] Levosimendan reduces peripheral vascular re- observed for doses >75.0 μg/kg.[ 33 ] iPDE3 milrinone was also
sistance by inhibiting K+ -channels in vascular smooth muscle, assessed in randomized clinical trials. In 2021, the DOREMI trial
inducing arterial and venous vasodilatation,[ 23 ] and is a po- compared milrinone vs. dobutamine (96 patients in each group)
tent and selective phosphodiesterase 3 (PDE3)-inhibitor. PDE in CS and showed no improvement in outcome.[ 34 ] . To date, mil-
inhibitors (iPDE) increase contractility by increasing [cAMP]IC . rinone remains marginally used by clinicians, with the FREN-
In the human myocardium, only iPDE3 improves contractility SHOCK registry reporting only 1.8% of CS patients having been

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treated with milrinone. According to international guidelines on dynamics among 30 patients in CS. The authors concluded that
CS management, milrinone could be considered in instances of epinephrine was as effective as norepinephrine-dobutamine on
right ventricular-related CS.[ 2 ] global hemodynamic parameters, although epinephrine was as-
Dopamine is an endogenous catecholamine that exerts its sociated with more lactic acidosis, higher heart rate and arrhyth-
dose-dependent effects on the cardiovascular system via its in- mia, and inadequate gastric mucosa perfusion.[ 46 ] In 2018, the
teraction with four different receptors: dopaminergic types 1 nationwide OptimaCC randomized clinical trial conducted in
and 2 and adrenergic 𝛼−1 and 𝛽−1. Its use has been discouraged nine French ICUs compared epinephrine vs. dobutamine + nore-
after the ROSE-AHF[ 35 ] and DAD-HF[ 36 ] trials found no clinical pinephrine among 57 patients in ischemic CS and confirmed ex-
benefit while De Backer et al.[ 37 ] reported frequent atrial and perimental results whereby epinephrine was associated with a
ventricular arrhythmias with dopamine. higher incidence of refractory shock.[ 47 ] It should be noted that
patients under VA-ECMO were excluded. Although mortality
Time for vasopressors in cardiac ICUs and cardiac index (CI) were similar in both groups, epinephrine
was hindered by a decreased lactate clearance, prolonged aci-
Vasopressor therapy is used for improving tissue perfusion in dosis, increased heart rate, and more frequent refractory shocks.
50–90% of patients presenting with CS.[ 38 ] Advanced CS is as- These results were consistent with those reported in the litera-
sociated with low vascular resistance due to the activation of ture. In a meta-analysis including 2583 patients from 16 studies,
inflammatory pathways,[ 39 ] with patients often meeting SIRS Léopold et al.[ 48 ] found that epinephrine in CS was associated
criteria.[ 40 ] Vasopressors are introduced to maintain mean ar- with a 3.33 (2.88–3.94) higher risk for short term mortality.
terial pressure (MAP) >65 mmHg as well as tissue perfusion Only one subgroup analysis, i.e., patients under ECLS, did not
pressure. However, the use of vasopressor treatment at bedside find an excessive risk for short term mortality and should be
remains difficult due to a logical increase in LV afterload with considered for further studies.[ 48 ]
an obstacle to LV ejection as a result of its use. Regarding the pathophysiology of low systemic resistance in
Vasopressors act on vascular myocyte 𝛼1-adrenergic recep- CS, and in line with the results of the main clinical trials, the
tors to increase cytosolic calcium availability, resulting in vaso- ESC guidelines recommend the use of norepinephrine as a first-
constriction and an increase in vascular resistance and MAP.[ 41 ] line vasopressor in CS to maintain MAP >65 mmHg by analogy
Norepinephrine is the most widely used vasopressor in CS.[ 12 ] with septic shock,[ 49 ] with a IIb-B recommendation.[ 50 ] Consid-
Hemodynamic effects of norepinephrine are vasoconstriction ering potential side effects, vasopressors must be used to obtain
and an increase in MAP, albeit with a weak increase in heart optimal organ perfusion, with reduced prescription duration.
rate due to a low 𝛽-adrenergic effect. At low infusion rates, While catecholamines are the cornerstones for relieving pa-
norepinephrine increases cardiac output with a 𝛽1-adrenergic tients from multiple organ failure, diuretics could also poten-
action.[ 42 ] Epinephrine is an 𝛼1 and 𝛽1 agonist, which has tially be considered for treating congestive symptoms, par-
stronger 𝛽2 stimulation than norepinephrine. At low dose, ticularly pulmonary edema. 𝛽-blockers should be discontin-
epinephrine increases cardiac output due to its 𝛽1-adrenergic ued as soon as the diagnosis of CS is confirmed.[ 2 ] When
effect. At high dose, the vasoconstrictive action of epinephrine 𝛽-blocker therapy is responsible for refractory CS in re-
is limited by a 𝛽2-adrenergic activity, and results in paradoxical sponse to standard dobutamine, clinicians should consider
effects on MAP. It has been reported that in patients free of any non-adrenergic inotropic drugs (i.e., levosimendan and mil-
𝛽-blocking agent, the net effect of adding epinephrine on top rinone) and glucagon infusion to stimulate adenylate cy-
of norepinephrine on MAP could be essentially unchanged.[ 43 ] clase and cAMP production independently of 𝛽1-adrenergic
Epinephrine increases cardiac oxygen consumption,[ 44 ] while stimulation.[ 51 ] Non-catecholamine supportive therapy has only
vasopressin stimulates V1a-receptor activation, producing vaso- been scarcely explored in the literature and available data are
constriction. One interesting effect of vasopressin consists in re- not sufficient to provide clear-cut recommendations.
ducing catecholamine requirements in patients with shock. Va- Finally, medical therapy of CS has barely changed over the
sopressin is used in salvage therapy in vasoplegic shock and past decade and primarily relies on inotropic drugs (dobutamine
post-cardiotomy vasoplegia, although no large clinical trials should be preferred) and vasopressor agents (norepinephrine
have studied the effect of vasopressin as a vasoconstrictor in should be preferred). Levosimendan may be considered for
CS.[ 45 ] Phenylephrine is an 𝛼1 agonist without 𝛽-adrenergic ef- treating 𝛽-blocker intoxication or adrenergic cardiomyopathy,
fect, which is not recommended in states of shock.[ 16 ] or for weaning VA-ECMO, and milrinone (iPDE-III) for right
One randomized trial in 2010 compared dopamine and nore- ventricular-related CS. In determining the best timing for initiat-
pinephrine as first line vasopressor therapy in shock. Of 1679 ing inotropic or vasopressor agents, the severity of hypotension
patients, there was no significant difference between the two needs to be considered. In severe hypotension, inotropic and va-
groups in the rate of death at 28 days; however, there were sopressor agents should be initiated simultaneously to enhance
a greater number of arrhythmic events among patients treated cardiac output and restore optimal coronary perfusion pressure.
with dopamine than among those treated with norepinephrine.
A subgroup analysis showed that dopamine, vs. norepinephrine, When CS Deserves Specific Therapy?
was associated with an increased rate of death at 28 days among
patients with CS.[ 37 ] The above-described catecholamine-based management of
Whether epinephrine or norepinephrine-dobutamine should CS has mainly been validated in an ischemic shock popula-
be preferred to improve survival has been intensely debated tion. While these guidelines could potentially be exported to
in the literature. In 2011, Levy et al.[ 46 ] compared the infu- other CS, two conditions deserve specific mention since standard
sion of norepinephrine-dobutamine vs. epinephrine on hemo- amine infusion could worsen the outcome: namely, Takotsubo

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syndrome (TTS) and obstructive hypertrophic cardiomyopathy halting disease progression. LVOTO should be treated with 𝛽-
(HCM). blockers (atenolol, propranolol) and fluid loading, which im-
prove LV filling. Propranolol has exhibited beneficial effects
TTS in this indication.[ 63 ] If 𝛽-blockers are contraindicated, vera-
pamil can be considered. Disopyramide, which is a class IA anti-
TTS was first described in 1990, and is defined as an acute arrhythmic with negative inotropic properties, can be used if
and reversible LV dysfunction associated with LV wall motion 𝛽-blockers are not sufficient, together with QT monitoring.[ 64 ]
abnormalities that are not limited to an epicardial artery terri- Digoxin should be avoided due to inotropic effects.[ 65 ] If med-
tory. These LV kinetic disorders typically concern the LV apex ical treatments fail and the patient remains symptomatic with
with an apical ballooning and basal hyperkinesis,[ 52 ] in the ab- LVOTO >50 mmHg and NYHA dyspnea III or IV, septal alcohol
sence of culprit epicardial coronary artery disease.[ 53 ] ablation or surgical myomectomy are potential alternatives.[ 60 ]
This syndrome is due to an increase in circulating cate- CS without LVOTO must be treated with the usual drugs.
cholamines sufficient to trigger stress cardiomyopathy in predis- There is a lack of data on patients with HCM developing
posed patients, followed by impaired microvascular perfusion, CS. Due to LVOTO and microvascular ischemia, some patients
myocardial inflammation, and electrophysiological abnormali- present with features suggesting acute coronary syndrome, with
ties. normal coronary angiograms. A small study on 14 HCM patients
There are no randomized clinical trials to support spe- in CS with LVOTO showed improvement after 𝛽-blocker infu-
cific treatment for stress cardiomyopathy. Regular echocar- sion with metoprolol or esmolol, with phenylephrine to support
diographic monitoring is needed. In patients with hemody- blood pressure, thereby reducing SAM and LVOTO gradients.[ 66 ]
namically significant left ventricular outflow tract obstruction This counterintuitive medical management in obstructive
(LVOTO) >40 mmHg, 𝛽-blockers may be considered. As to the HCM should be kept in mind by critical care physicians who
pathophysiology of TTS, cessation of sympathomimetic drugs should track LVOTO and SAM, to avoid catecholamine infusion
appears to be necessary. and perform fluid loading.
In patients with acute failure symptoms and altered LVEF,
levosimendan, a non-catecholamine inotrope that does not in- Post Shock Management
crease oxygen consumption, can accelerate recovery.[ 54 ] In in-
stances of CS and absence of access to emergency mechanical Expert guidelines currently rely on sparse literature. The best
support, levosimendan is probably preferable to conventional timing to initiate cardioprotective drug titration after CS re-
inotropes or vasopressors.[ 55 ] mains unclear and should be individualized. New SGLT2 in-
In patients with severe CS, the use of inotropes or vasopres- hibitors are not burdened by hypotension and could be initi-
sors should be avoided.[ 56 ] These drugs can further activate cat- ated after catecholamine removal. However, the benefit of early
echolamine pathways and worsen the clinical prognosis.[ 57 ] At introduction of iSGLT2 after CS has yet to be established. Re-
a stage of end-organ dysfunction, options include mechanical cent publications suggest empaglifozin and dapaglifozin could
support such as temporary LV assist devices and extracorpo- be introduced early after MI.[ 67 ] For the other cardioprotective
real membrane oxygenation (ECMO) in the “bridge to recovery” drugs, the rule should be: “start low, go slow.” Although cur-
with a high probability for full recovery,[ 58 , 59 ] although no ev- rent guidelines suggest that only targeting doses of cardiopro-
idence currently exists. A possible alternative is the combined tective drugs are effective, low drug doses for HF with reduced
use of short half-life selective 𝛽1-blockers such as landiolol with ejection fraction yield substantial benefits in reducing morbid-
a post-receptor inotrope such as levosimendan or milrinone plus ity and mortality. Clinicians should remember that the addition
a vasopressor in situations of hypotension. of a new drug class yields benefits that are greater in magnitude
than up-titration of existing drug classes.[ 68 ] Experts recommend
HCM that 𝛽-blockers should be introduced only several days after IV
drug discontinuation. In patients with troublesome hypotension
HCM is the most frequent inherited cardiomyopathy, and is (i.e., systolic arterial pressure <100 mmHg), mineralocorticoid
diagnosed in transthoracic echocardiography (TTE) as a wall antagonists (MRA) and iSGLT2 should first be introduced.[ 68 ]
thickness >15 mm in one or more LV myocardial segments, and Whether the patient could be considered for heart transplan-
unexplained by loading conditions.[ 60 ] Sixty percent of cases in- tation or ventricular assistance device implantation should be
volve an autosomic dominant gene mutation targeting sarcom- assessed early as it may help to stratify the need for VA-ECMO.
ere proteins, while non-genetic etiologies are metabolic disor-
ders, mitochondrial diseases, infiltrative diseases with amyloi- Perspectives for CS
dosis, or neuromuscular disease.[ 61 ]
Critical care physicians should track LVOTO, defined by an The prognosis of CS has scarcely improved over the past
LV outflow tract gradient ≥30 mmHg at rest or ≥50 mmHg decade and its management, aside from catecholamine therapy,
provoked and mitral regurgitation due to systolic anterior mo- has remained broadly similar. New treatments targeting inflam-
tion (SAM).[ 62 ] Identification of LVOTO and SAM is crucial mation, vasoplegia, or inotropism are currently proposed to im-
for medical management as catecholamine infusion increases prove the outcome. Table 2 summarizes target populations as
inotropism, LVOTO, and SAM and subsequently worsens the well as main results of recently published major clinical trials.
condition.[ 62 ] Immunomodulation has failed to improve outcomes in CS to
Large randomized trials are currently lacking in HCM. Ob- date. In 2007, the TRIUMPH trial assessed the non-selective NOS
jectives or treatments are aimed at reducing symptoms and inhibitor L-N-monomethylarginine (L-NMMA) in myocardial in-

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Table 2
Perspective treatment for cardiogenic shock.

Treatment Pathophysiology and benefits Study population Main results

Adrecizumab Endovascular chelation of adrenomedullin CS defined as low SBP + clinical pulmonary On day-30, number of days free from any
ACCOST HH[ 70 ] to enhance its vascular and myocardial congestion + organ dysfunction (lactate, CV support (vasopressor, inotropes,
protective effects oliguria, altered mental status, clammy skin mechanical circulatory support) Failed to
and limbs) Exclusion criteria: cardiac arrest improve CV support free survival days.
with CPR >60 min, sustained bradycardia or
tachycardia.
OM ATOMIC Cardiac myosin activator. Increases Elevated BNP/NTBNP and reduced LVEF and Primary outcome: dyspnea relief after OM
HF[ 74,75 ] systolic ejection time and inotropism dyspnea refractory to IV loop diuretics infusion vs. placebo. Only the highest
without increasing MVO2 Exclusion criteria: eGFR <20 mL/min/m2 , dose (targeting blood concentration ≈
stenotic valvular disease, recent AMI (<30 310 ng/mL) improved dyspnea relief at
day), uncontrolled blood pressure 48 h
iDPP3 Increased DPP3 found in CS DPP3 Pre-clinical studies only –
injection in murine models induces
myocardial depression Murine model of
isuprel induced heart failure, injection of
iDPP3 resolve cardiac function
Istaroxime SEISMIC Positive stimulation of SERCA Ca2+ SCAI stage B pre-CS: acute HF + LVEF Primary outcome: AUC of SBP along the
trial[ 79 ] re-uptake and Na/K ATPase plasmatic <40% + SBP <75–90 mmHg Exclusion first 6 h of infusion was significantly
membrane pump Increases inotropism and criteria: recent AMI < 3 months; IV drugs; higher in the Istaroxime group TTE ΔCO
lusitropism without increased heart rate. venous lactate >2 mmol/L; eGFR improvement: +0.2 L/min/m2 Adverse
<30 mL/min/m2 ; Tp° >38 °C; recent stroke. events: nausea, vomiting
ΔCO: Cardiac output variations; AMI: Acute myocardial infarction; AUC: Area under the curve; BNP: Type natriuretic peptide; CPR: Cardiopulmonary resuscitation;
CS: Cardiogenic shock; CV: Cardiovascular; eGFR: Estimated glomerular filtration rate; iDPP3: Dipeptidyl peptidase 3 inhibitor; IV: Intravenous; LVEF: Left ventricular
ejection fraction; MVO2 : Myocardial oxygen consumption; NTBNP: N-terminal pro B-type natriuretic peptide; OM: Omecamtiv mecarbil; SBP: Systolic blood pres-
sure; SCAI: Society for Cardiovascular Angiography and Interventions; SERCA: Sarcoendoplasmic reticulum calcium ATPase; Tp: Temperature; TTE: Transthoracic
echocardiography.

farction CS (MI-CS) and found no improvement for the primary fraction to OM (using pharmacokinetic-guided doses of 25 mg,
endpoint of 30-day all-cause mortality.[ 69 ] Adrenomedullin 37.5 mg, or 50 mg twice daily) or placebo and found a lower
blood concentration has been identified as a risk factor for incidence of a composite of heart-failure event or death from
mortality in CS.[ 70 ] Circulating adrenomedullin binding to en- cardiovascular causes (37% vs. 39%, respectively).[ 74 , 75 ] The
dovascular receptors improves vascular function while intersti- ATOMIC-AHF trial specifically assessed OM in acute HF and
tial adrenomedullin drives inflammation and capillary leakage. found a dose-dependent improvement for dyspnea.[ 76 ]
Adrecizumab binds to adrenomedullin and prolongs its vascu- Recently, dipeptidyl peptidase 3 (DPP3) has been proposed
lar half-life but does not act as an inhibiting antibody. In the as a new biomarker in CS.[ 77 ] DPP3 is a metallopeptidase in-
ACCOST-HH trial, 77 patients (51%) were randomly assigned to volved in cleavage of proteins such as angiotensin II (ATII). De-
adrecizumab and 73 (49%) to placebo. Mortality did not differ niau et al.[ 78 ] recently reported that DPP3 should be not only
between groups at 30 days (hazard ratio[HR]=0.99, 95% con- a biomarker but also, more importantly, a causal myocardial
fidence interval [CI]: 0.60–1.65; P=0.98) or 90 days (HR=1.10, depressant agent and could represent a bio-target in CS. In a
95% CI: 0.68–1.77; P=0.70).[ 70 ] Whether non-specific anti- murine model of isoproterenol-induced HF, the DPP3 inhibitor
inflammatory therapy could benefit CS patients remains un- procizumab restored normal hemodynamics while DPP3 infu-
known. The ongoing “low dose corticosteroids for CS in Adult sion resulted in a profound negative inotropic action in healthy
patients” (COCCA) trial is designed to assess the hemodynamic mice. In a previous pre-clinical study, DPP3 infusion affected
effects of early low-dose corticosteroid therapy (with hydro- hemodynamics only in ATII-infused mice. While the mechanism
cortisone and fludrocortisone) on CS reversal, as defined by for myocardial improvement remains unknown, DPP3 inhibitor
catecholamine-free days at day 7, while 28- and 90-day over- and its therapeutic potential will be of interest in coming years.
all survival will be analyzed as secondary outcomes.[ 71 ] Istaroxime, a new molecule targeting both inotropism
Current treatments targeting inotropism raise myocyte cal- (Na+ /K+ ATPase pump activation) and lusitropism (through di-
cium concentrations and increase myocardial contractility but astolic Ca2+ reuptake in the SERCA), has been developed. Ani-
at the cost of increased heart rate and oxygen consumption. mal models confirmed this favorable mechanism with a dose-
Omecamtiv mecarbil (OM) is a selective cardiac myosin activa- dependent cardiac unloading and inotropism effect, while not
tor accelerating the transition rate of myosin into the strongly hampered by an increased heart rate. The HORIZON–HF trial as-
actin-bound force-generating state and generating an increased sessed the effects of istaroxime in a randomized controlled trial
systolic ejection time (SET) without increasing heart rate or in non-shock patients hospitalized with acute HF: unlike dobu-
MVO2 .[ 5 ] Nagy et al.[ 72 ] found that OM improved isometric tamine or milrinone, this agent was found to decrease heart rate,
force in response to increasing Ca2+ contraction in an in vitro ex- shorten the QTC interval, and demonstrated no pro-arrhythmic
perimental study. Bakkehaug et al.[ 73 ] reported an improvement effects.[ 79 ] The phase II SEISMIC trial recently validated the
in ejection fraction under OM in an ischemic porcine model of safety and efficacy of istaroxime in a pre-CS population.[ 80 ] Fur-
acute HF. Large clinical trials have assessed the outcomes for ther studies are needed to implement istaroxime in clinical prac-
OM in chronic and acute HF.[ 74 ] Although OM failed to im- tice.
prove exercise capacity at 20 weeks in the METEORIC–HF trial, Similarly, ATII infusion has been proposed in refractory CS.
GALACTIC–HF randomized 8256 patients with reduced ejection Under VA-ECMO, the significant proportion of blood bypass-

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M. Lescroart, B. Pequignot, D. Janah et al. Journal of Intensive Medicine 3 (2023) 114–123

Figure 2. Central illustration. Definition, monitoring, and medical treatment of CS.

ALT: Alanine aminotransferase; AMI: Acute myocardial infarction; BPM: Beats per minute; CI: Cardiac index; CMP: Cardiomyopathy; CO: Cardiac output; CS: Car-
diogenic shock; IABP: Intra-Aortic balloon pump; LV: Left ventricle; LVOT: Left ventricular outflow tract; MAP: Mean arterial pressure; PCWP: Pulmonary capillary
wedge pressure; PDE-3: Phosphodiesterase 3; RAP: Right atrial pressure; SBP: Systolic blood pressure; ScvO2 : Venous blood oxygen saturation.

120
M. Lescroart, B. Pequignot, D. Janah et al. Journal of Intensive Medicine 3 (2023) 114–123

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