REVIEW URRENT C OPINION

Pharmacologic therapies for acute cardiogenic shock Jose Nativi-Nicolau a,b, Craig H. Selzman c, James C. Fang a, and Josef Stehlik a,b

Purpose of review The natural history of cardiogenic shock has improved significantly with the utilization of revascularization and mechanical circulatory support. Despite the interest in identifying new pharmacological agents, the medical therapy to restore perfusion is limited by their side-effects and no solid evidence about improving outcomes. In this article, we review the current pharmacological agents utilized during cardiogenic shock. Recent findings Inotropes and vasopressors are widely used to improve hemodynamics acutely; however, reliable information regarding comparative efficacy of individual agents is lacking. A subanalysis of a prospective randomized trial suggested that norepinephrine may be preferred over dopamine in patients with cardiogenic shock. Levosimendan is a new inotrope with calcium sensitization properties that improves acute hemodynamics, but with uncertain effects in mortality. Diuretics are used to decongest patients; however, mortality data are not available. Inhibition of inflammation during cardiogenic shock seems to be a potential therapeutic target; however, initial clinical studies in this area have not shown benefit. Summary The current pharmacological treatment for cardiogenic shock includes inotropes, vasopressors and diuretics. The information about comparative effective outcomes is limited and their use should be limited as a temporary measure as a bridge to recovery, mechanical circulatory support or heart transplantation. Keywords inotropes, shock, vasopressors

INTRODUCTION Cardiogenic shock is a stage of heart failure characterized by decreased tissue perfusion from cardiac pump failure. Clinically, cardiogenic shock presents with an evidence of congestion (dyspnea, orthopnea, high jugular venous pressure, rales, edema, ascites) and low perfusion (hypotension, narrow pulse pressure, pulsus alternans, cool forearms and legs, obtunded mental status, oliguria), a clinical scenario commonly described as a ‘wet and cold’ patient [1]. Hemodynamically, cardiogenic shock is defined as persistent hypotension (systolic blood pressure a

2–15 mg/kg/min

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Milrinone

PDE-3 inhibitor

0.375–0.75 mg/kg/min

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Levosimendan

Calcium sensitizer

0.05–0.2 mg/kg/min

0

0

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Epinephrine

b1 ¼ b2 > a

0.01–0.03 mg/kg/min, max 0.1–0.3 mg/kg/min

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Norepinephrine

b1 > a > b2

0.01–0.03 mg/kg/min, max 0.1 mg/kg/min

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0

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Dopamine

Moderate dose b

2–5 mg/kg/min

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0 or #

Dopamine

High dose a

5–15 mg/kg/min

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Phenylephrine

a1

40–60 mg/min

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Vasopressin

V1

0.01–0.04 units/min

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0

0

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BP, blood pressure; CO, cardiac output; HR, heart rate; PDE, phosphodiesterase; SVR, systemic vascular resistance.

scenarios, including intermittent [6] and continuous intravenous (i.v.) infusions [7]. The recommended dose is from 2 to 15 mg/kg/min [8] and does not require renal adjustment.

and should be adjusted for renal insufficiency. A loading dose of 50 mg/kg can be used to accelerate the onset of milrinone’s hemodynamic effects.

Milrinone

Levosimendan is a calcium-sensitizing agent that binds to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect in the vascular smooth muscle by opening adenosine triphosphate-sensitive potassium channels. Several trials have evaluated the effects of levosimendan in severe decompensated heart failure [10–13]. The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial compared levosimendan with dobutamine in 1327 patients with decompensated heart failure. After 180 days, there was no difference in all-cause mortality [12]. The Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy trial randomized 600 patients to 24-h levosimendan infusion vs. placebo. At 5 days after randomization patients in the levosimendan group had better symptoms, lower serum B-type natriuretic peptide levels and shorter length of hospital stay compared with placebo. However, at 90 days after randomization, patients assigned to levosimendan experienced more hypotension, cardiac arrhythmias and higher mortality (14 vs. 11% deaths, P ¼ 0.29) [13]. As hypotension was an exclusion criterion in these trials, the role of levosimendan in cardiogenic shock remains uncertain and limited to case reports describing successful outcomes of patients with refractory cardiogenic shock treated with levosimendan [14–17]. Delle Karth et al. [18] reported on the hemodynamic effects of levosimendan 0.1 mg/kg/min in 10 patients with refractory cardiogenic shock. At 24 h, cardiac index increased from 1.8  0.4 to 2.4  0.6 l/min/m2, P ¼ 0.023, and SVR decreased from 1559  430 to 1109  202 dyn/s/ cm5, P ¼ 0.001. There were no changes in heart rate

Milrinone is a phosphodiesterase-3 inhibitor that prevents the degradation of cyclic adenosine monophosphate (cAMP). In the myocardium, elevated levels of cAMP activate protein kinase A, which then phosphorylates calcium channels, increasing the influx of calcium into the cardiomyocyte, and promotes contractility. In the smooth muscle, elevated cAMP inhibits myosin light chain kinase, producing arterial and venous vasodilation. In patients with heart failure, milrinone increases heart rate, stroke volume and cardiac output. It is also likely to decrease mean arterial pressures, SVR and left ventricular filling pressures [4]. Milrinone increases myocardial oxygen consumption, but to a lesser degree than dobutamine (Fig. 1) Although milrinone improves hemodynamics acutely, there are concerns regarding its safety as far as longer-term outcomes. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure study randomized 951 patients with decompensated heart failure (not in shock) to milrinone vs. placebo for a total of 48 h. There was no significant difference in the primary endpoint of cumulative days of hospitalisation; however, there was a nonsignificant increase in inhospital mortality in the milrinone group vs. the placebo group (3.8 vs. 2.3%, P ¼ 0.19). There were also more adverse events in the milrinone group compared with placebo, including new atrial fibrillation or flutter (4.6 vs. 1.5%, P ¼ 0.004) and sustained hypotension (10.7 vs. 3.2%, P ¼