Cardiogenic shock (CS) is a state of impaired end-organ perfusion caused by a decrease in cardiac output despite adequate intravascular volume, and is usually associated with the following hemodynamic characteristics: systolic blood pressure of less than 90 mmHg for more than 30 min (in the absence of inotropic or vasopressor support), a reduction of cardiac index (<1.8 l/min/m2 without support and less than 2.2 l/min/m2 with support), and elevated left ventricular (LV) filling pressures (pulmonary capillary wedge pressure >18 mmHg).1,2

The most frequent cause of CS is acute myocardial infarction (AMI), accounting for almost half of cases; it complicates AMI in 5-15% of patients depending on the series.3 Since the SHOCK trial, primary percutaneous coronary intervention (PCI) has been the preferred treatment for AMI patients with CS.4 Advances in treatments, particularly revascularization, have reduced mortality from AMI and the incidence of CS, but CS is still associated with high mortality.3,5,6

Descriptions of the use of inotropes and vasopressors in CS go back to the 1950s,7,8 but there have been few clinical trials in these patients, and so the choice of which drugs to use remains unclear. We analyzed studies in the literature on inotropic and vasopressor agents, with the aim of determining the indications for the use of each drug. Table 1 shows the main drugs used in CS and their characteristics.

Inotropic agents increase myocardial contractility, thereby increasing cardiac output. Many of these drugs also raise heart rate (HR) and thus myocardial oxygen consumption, which may be harmful in some patients. As well as their inotropic properties, they also have vasoconstrictive or vasodilatory effects.

Inotropes are currently used mainly to stabilize patients with acute heart failure (HF).

Epinephrine is a sympathomimetic hormone and drug that binds to α- and β-adrenergic receptors. It increases mean arterial pressure by increasing cardiac output and peripheral vascular tone,9 and is thus used to treat shock. Its effects in septic shock have been tested in clinical trials, in which it showed similar efficacy and impact on mortality to norepinephrine.10,11

In a trial of 30 patients with CS not due to acute coronary syndrome, Levy et al.12 compared epinephrine and combined norepinephrine-dobutamine. Efficacy, as measured by blood pressure (BP), oxygen consumption, improvement in renal function, and mortality were similar in the two groups. Patients treated with epinephrine showed a transient increase in lactate and blood glucose levels and higher HR; three patients in the epinephrine group presented tachyarrhythmias, but none in the norepinephrine-dobutamine group.

Morici et al.13 argue that epinephrine is important for hemodynamic stabilization of patients in CS and that it presents a better profile than other commonly used drugs, since for similar increases in BP, the balance between epinephrine's inotropic and vasoconstrictive effects means that the increase in HR is less marked than with dopamine, while vasoconstriction and hence afterload are less than with norepinephrine.

Dobutamine acts on the myocardium by stimulating β1-adrenergic receptors, increasing contractility, and on smooth muscle, acting on β2 receptors to cause vasodilation.14 It rapidly gained acceptance for the treatment of CS due to its ability to increase cardiac output and to reduce LV filling pressures.15,16

Francis et al.17 compared the hemodynamic effects of dopamine and dobutamine, reporting smaller increases in HR, fewer arrhythmias, less peripheral vasoconstriction and more consistent reductions in LV filling pressures with the latter for similar rises in cardiac output.

Richard et al.18 concluded that an infusion of dopamine and dobutamine achieved similar increases in cardiac output to dopamine alone but with lower oxygen consumption.

The efficacy of dobutamine has been compared to that of milrinone in hospitalized patients awaiting cardiac transplantation, with some authors reporting similar results19 and others favoring milrinone, in terms of mortality20 as well as less need for mechanical ventricular support.21

In a 2012 meta-analysis, Tacon et al.22 analyzed 14 trials with a total of 673 patients with severe HF, comparing dobutamine with placebo or standard care. Higher mortality was seen in patients treated with dobutamine, although without statistical significance.

Dopamine is a natural precursor of norepinephrine and epinephrine. Its effects are dose-dependent: at low doses (1-2 μg/kg/min) it has a vasodilatory effect, binding to dopaminergic receptors, while at higher doses (5-10 μg/kg/min) it acts as a β1 receptor agonist and thus has inotropic effects. At even higher levels (>10 μg/kg/min) it stimulates α-adrenergic receptors, leading to vasoconstriction and an increase in BP.4,23

For a long time dopamine was thought to have a beneficial effect on renal function, but this was not observed in two trials24,25 and it is now not considered suitable as a treatment for renal dysfunction.

Although long used in CS, its popularity is now waning since a subgroup analysis of the SOAP II trial26 showed that patients with CS treated with dopamine had more arrhythmic events and higher mortality than those treated with norepinephrine. A possible explanation for this difference between norepinephrine and dopamine in shock is the weakened response to indirect agents such as dopamine due to neurotransmitter depletion in CS patients.27 However, a 2009 Portuguese study by Póvoa et al.28 demonstrated that dopamine was associated with lower mortality than norepinephrine in patients in septic shock.

Milrinone is a phosphodiesterase (PDE) inhibitor. By inhibiting PDE3, which degrades cyclic adenosine monophosphate (cAMP), it increases cAMP levels, promoting calcium uptake by cardiomyocytes and increasing myocardial contractility. In vascular smooth muscle, the reduced degradation of cAMP accelerates the removal of intracellular calcium, leading to relaxation and vasodilation.29 Milrinone is thus a positive inotrope and a peripheral vasodilator with lusitropic properties.

The fact that, unlike catecholaminergic agents, milrinone does not raise HR theoretically gives it the advantage of not increasing myocardial oxygen consumption.30

The first studies comparing milrinone with dobutamine31 indicated that the two drugs were equally effective in increasing cardiac output, but that reductions in left and right ventricular (RV) filling pressures and BP were more marked with milrinone.

Milrinone enables catecholamine doses to be reduced in catecholamine-dependent CS patients, facilitating weaning from prolonged catecholamine therapy. In a study by Siostrzonek et al.32 of 20 patients, milrinone improved weaning from catecholamines and enabled earlier discharge from the intensive care unit. However, vasopressor support needed to be increased in some patients.

The largest trial to date on milrinone, OPTIME-CHF,33 compared its efficacy to placebo in patients with acute exacerbation of chronic HF, although patients in shock were excluded. Milrinone was not shown to be superior in length of hospital stay or 60-day mortality and was associated with more cases of hypotension and atrial arrhythmias.

The ADHERE registry,34 the first results of which were published in 2005, showed that inotropes were associated with higher mortality than vasodilators, but only 2.5% of the patients had systolic BP <90 mmHg, so this finding cannot be extrapolated to patients in shock. The inotropes used were dobutamine and milrinone, mortality being higher in those under dobutamine.

In patients with severe HF needing prolonged use of inotropes, oral milrinone therapy on an outpatient basis was associated with an increase in mortality compared with placebo.35 However, milrinone appears to be more effective when association with β-blockers is tolerated.36 A more recent study compared the effectiveness of continuous intravenous infusion of milrinone with that of dobutamine; there was no significant difference in mortality in the two groups.37

The value of milrinone in individuals with reduced RV function and increased pulmonary vascular resistance was demonstrated by Pamboukian et al.38 and confirmed by Eicchorn et al.39 in a trial comparing milrinone with dobutamine, in which the former led to improvement in RV systolic function and reductions in pulmonary artery pressure.

Levosimendan is the most recently available inotrope for the treatment of acute HF. It increases the sensitivity of troponin C to intracellular calcium in the myocardium and thus has inotropic and lusitropic properties.40–42 It also acts on ATP-dependent potassium channels, leading to relaxation of vascular smooth muscle and hence coronary and peripheral vasodilation.34 Levosimendan's effects are dose-dependent and it has a demonstrated impact on the hemodynamic profile of HF patients43; the effects of its active metabolites can last for up to five days after discontinuation of the drug.44

Some studies45–50 have shown that in patients with severe HF levosimendan does not affect mortality compared to placebo, and the results are contradictory when it is compared to other inotropes. In the REVIVE II trial,45 the levosimendan group had rapid symptomatic relief and a reduction in brain natriuretic peptide levels when levosimendan was added to standard treatment, but with a numerically higher risk of death.

In the LIDO study,46 levosimendan was compared to dobutamine in patients with low-output HF and need for inotropic support. At 180 days, patients taking levosimendan presented lower mortality and more days to rehospitalization. The LEAF trial47 assessed the efficacy of levosimendan compared to placebo in patients undergoing primary PCI following AMI complicated by HF and revealed improvements in myocardial contractility but no reduction in mortality. Nine patients in this trial had CS but there were no significant differences between them and the other patients.

A Portuguese study on levosimendan, the PORTLAND study,48 which included 129 patients with acute HF and LV dysfunction but excluded those with CS, found that the drug was safe, improved symptoms and reduced readmissions at six-month follow-up. However, this study did not compare levosimendan with other therapies, but only with national data on HF admissions.

Samimi-Fard et al.49 compared outcomes at 12 months in 22 AMI patients with CS after primary PCI treated with levosimendan or dobutamine, and found no significant differences between the groups. Fuhrmann et al.,50 comparing levosimendan and enoximone in 32 CS patients, reported lower mortality at 30 days in the levosimendan group.

In addition to its effects on LV function, levosimendan has also been shown in a small study on 25 patients51 to improve RV function and to reduce pulmonary vascular resistance. It may therefore be useful in AMI patients with CS and RV dysfunction.

Vasopressors are the first-line treatment for patients in shock with low systemic vascular resistance and unresponsive to fluid therapy. In CS, a proinflammatory state may persist that leads to vasoplegia,52 requiring the use of vasopressors to maintain BP. Vasoconstrictive inotropes such as dopamine and epinephrine may be used for this purpose, but the two vasoconstrictors that are most used nowadays are norepinephrine and vasopressin (Table 1). The drug with the greatest impact on mortality in patients with shock is norepinephrine.26

The catecholamine norepinephrine is an α-adrenergic agonist that is used as a vasopressor to increase BP in patients with shock. The first report of a patient with CS following AMI treated with norepinephrine appeared in 1953.7 Although the patient died (from CS complicated by sepsis), hemodynamic improvement had been seen after norepinephrine infusion.

The adverse effects associated with norepinephrine use, such as reduced renal and splanchnic blood flow, especially in patients needing volume expansion, are well known.53

The European Society of Cardiology (ESC) guidelines for the management of ST-segment elevation AMI54 are unclear on treatment for patients in CS, stating that when blood pressure is low, norepinephrine should be the first choice, but gives dopamine a class IIa recommendation, level of evidence C, and norepinephrine class IIb/B.

As stated above, in the SOAP II trial,26 norepinephrine was associated with lower mortality than dopamine in CS patients, and is thus considered the first-line treatment, possibly together with an inotrope.

Vasopressin is a hormone that binds to its own receptors. Binding to V1 receptors causes vasoconstriction due to contraction of vascular smooth muscle,23,55 while V2 stimulation increases renal free water reabsorption.55 In association with norepinephrine, it has been shown to be effective and safe for treating patients in septic shock,23 enabling dosages of other vasopressors to be reduced.55

In situations of cardiopulmonary arrest, vasopressin has similar efficacy to epinephrine for resuscitating patients in ventricular fibrillation or pulseless electrical activity, and is more effective in the presence of asystole.56

A small retrospective study57 of CS patients showed that in those under dopamine therapy, adding vasopressin was not inferior to norepinephrine as assessed by increases in mean BP and other hemodynamic parameters, although no benefit was seen in terms of mortality.

A good response to vasopressin was also observed in hypotensive patients after LV assist device placement, reducing their need for norepinephrine.58

However, to date there have been no randomized clinical trials on vasopressin in CS patients.

The range of studies on the use of these drugs in CS (Table 2) clearly demonstrates the many uncertainties surrounding the subject.

On analysis of these results, no inotropic agent is reported as superior to placebo, although some have beneficial effects compared to other drugs. This may be partly because in placebo-controlled studies, what actually happened was that the drug was added to the center's standard treatment, and the additive effect of inotropes was not shown to reduce mortality in advanced HF.

Nevertheless, in the absence of alternatives, inotropes and vasopressors continue to be essential in the management of patients in CS,59 in order to prevent tissue hypoperfusion and the resulting organ dysfunction by maintaining a mean arterial pressure of 65-70 mmHg.60

The ESC guidelines on HF61 recommend the use of an inotrope such as dobutamine for hypotensive (‘shocked’) patients (class IIa recommendation) and a vasopressor (e.g. norepinephrine or dopamine) in patients under inotrope therapy to increase blood pressure and improve vital organ perfusion (class IIb). In the American College of Cardiology Foundation/American Heart Association (ACC/AHA) HF guidelines,62 inotropic support is recommended (class I) for patients with CS, while the use of vasopressors is mentioned in the text without class of recommendation; in neither case are specific drugs recommended.

At present, the use of drugs in CS varies according to the experience of physicians and the conditions in each center, as demonstrated by Pei et al.,63 who suggest that medical training in vasoactive agent use for shock management needs to be improved and treatment should be standardized.

In view of all of the above and in light of current knowledge, the authors believe that inotropes and vasopressors should be used in CS at minimum doses and for only as long as absolutely necessary, in accordance with the therapeutic scheme outlined in Figure 1.

Figure 1.

Proposed therapeutic scheme for patients in cardiogenic shock unresponsive to fluid therapy. CI: cardiac index; LVEF: left ventricular ejection fraction; MAP: mean arterial pressure; RV: right ventricular.

(0.11MB).

As suggested in the ESC guidelines54 and following publication of the results of the SOAP II trial,26 norepinephrine should be the first-line drug for CS patients with hypotension and vasoplegia. Adding vasopressin should be considered in those needing high doses of norepinephrine and in those with an unstable heart rhythm, in whom raising the norepinephrine dose would be unsafe.

Inotropes should be reserved for short-term treatment in cases of low cardiac output. Dobutamine should be used in patients with isolated LV dysfunction, while those with elevated pulmonary resistance and RV dysfunction appear to benefit from a phosphodiesterase inhibitor such as milrinone or levosimendan. These two drugs are also the best option in patients under beta-blocker therapy, since their action is independent of β-adrenergic receptors.

Epinephrine can also be used in CS and is equally safe, and so may be added to the above drugs if they do not achieve a rise in BP.

Dopamine appears to have the most adverse effects and is of little apparent benefit, and so its role in shocked patients is increasingly limited; the ACC/AHA guidelines on ST-elevation myocardial infarction64 do not suggest any specific inotrope or vasopressor, but do emphasize that dopamine should be avoided.

The ideal inotrope would increase cardiac output and reduce ventricular filling pressures, have no adverse effects and reduce mortality. The search continues for such a drug for the treatment of CS.65 Omecamtiv mecarbil is a promising new drug for stable HF that exerts inotropic effects by activating cardiac myosin.29 Gene therapy is another area in which innovatory treatments for HF are being developed, with promising results in phase II trials.66 Further results of these new approaches are awaited.

In the IABP-SHOCK II trial,67 mortality in patients with CS complicating AMI was around 40% despite inotropic and vasopressor therapy, even with the benefit of intra-aortic balloon counterpulsation. Mortality in CS patients occurs mainly in the first three days,6,67 and so as well as medical therapy, mechanical circulatory support devices should be considered as soon as possible. The results of studies on such devices68 are promising in hemodynamic terms and they are recommended for patients in persistent shock after inotropic and vasopressor therapy. Even so, mortality in these patients remains high, implying that this approach does not always deliver the intended benefits.69,70 Trials are under way to determine which are the best devices for particular situations and when they should be implanted.

In 2009 data from the Portuguese national acute coronary syndromes registry were published,71 including 22482 patients between 2002 and 2008. In this registry, 7% of patients were medicated with catecholamines, 50% of them for CS. Although precise data on the use of mechanical support devices in Portugal are lacking, the number of patients with access to this therapy is small, and there would undoubtedly be benefits from the establishment of referral networks for CS.

The only treatment shown to reduce mortality in CS is emergent revascularization.

The choice of drugs to treat CS is still controversial and more randomized trials in this area are needed.

Patients in CS refractory to medical therapy have a poor prognosis and some may benefit from mechanical circulatory support.

The authors have no conflicts of interest to declare.