Inotropes have a generally disputed place in heart failure therapy. They have marked acute hemodynamic effects. Thus, intravenous infusion of dobutamine and/or phosphodiesterase (PDE) inhibitors was considered a therapy of choice for acute and acute-on-chronic heart failure. However, long-term therapy had no sustained benefit and was even associated with increased mortality. Dopamine, dobutamine, and milrinone are the drugs generally used to sustain severely impaired hemodynamics in advanced heart failure.
Dopamine activates pre- and postsynaptic adrenoceptors directly or indirecdy via the release of norepinephrine. Its inotropic and chronotropic effects result from postsynaptic myocardial (3,-receptor activation at dosages from 5 |ig/kg/min to 15 fig/kg/min; at lower dosages (0.5 |ig/kg/min to 2.5 |ig/kg/min), it acts on postsynaptic dopaminergic receptors (Dj vascular receptors), without concomitant adrenoceptor stimulation. At intermediate and high dosages, its cardiac action releases endogenous cardiotropic norepinephrine. At low dosages, Dj vascular receptor activation predominates, with vasodilatation of the renal vascular bed enhancing the glomerular filtration rate, renal blood flow, and sodium excretion, which is useful in heart failure. At still higher dosages, dopamine-dependent norepinephrine release activates (i-adrenoceptors, causing vasoconstriction. In heart failure, dopamine is often administered at low dosages, combined with dobutamine and vasodilators.
Two studies have investigated this dopamine-like synthetic sympathomimetic vs placebo in 63 patients with chronic heart failure (cardiac index [Cl] 2.5 L/min/m2,
pulmonary wedge pressure 15 mm Hg; n=45) or acute left ventricular failure (n=18) due to hypertrophic cardiomyopathy, valvular heart disease, angina pectoris, and inflammatory disease. Dopexamine 1 mg/kg/min to 4 mg/kg/min improved the hemodynamic profile 1 and 8 hours after infusion. Progressive cardiac norepinephrine depletion may attenuate the cardiovascular effects.
Dobutamine is a direct-acting sympathomimetic with potent P-adrenergic and a-adrenergic activity; p2 stimulation generally causes a mild decrease in systemic vascular resistance and a significant increase in cardiac output. Thus, dobutamine can be considered a vasodilator inotrope. It does not usually influence’ heart rate at dosages from 2 pg/kg/min to 5 pg/kg/min titrated to optimal hemodynamic effect. Higher doses, eg, 15 pg/kg/min, are often associated with arrhythmia. Dobutamine is being increasingly used in critically ill patients as a continuous infusion often combined with dopamine, PDE inhibitors, and/or vasodilators. Most efficacy and safety studies have been conducted vs active comparators rather than placebo. Overall, dobutamine has not proved superior either to vasodilators, such as nitrates or nesiritide, or to other inotropes such as levosimendan. It has also been tested as intermittent outpatient therapy.
PDE inhibitors are potent vasodilator inotropes whose use has grown sharply in recent years. Whereas extensive p-blockade in chronic heart failure can depress the response to sympathomimetics during acute episodes, the effect of PDE inhibitors under such conditions remains unimpaired, since these drugs
act independently of (3-receptor availability. PDE inhibitors increase cyclic adenosine monophosphate (cAMP) levels by inhibiting the PDE III isoenzyme present in cardiomyocytes and vascular smooth muscle cells. This increases intracellular calcium levels, causing positive inotropism and peripheral arteriolar relaxation. Peripheral vasodilatation by PDE inhibitors is generally considered more effective than that by dobutamine and it significantly decreases pulmonary vascular resistance.
Following a series of small inconclusive trials, a large randomized controlled double-blind trial, the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF), was conducted vs placebo in patients hospitalized with acute-on-chronic heart failure, in whom inotrope infusion was not considered mandatory. The 951 patients received a continuous infusion of milrinone or placebo for 48 hours to 72 hours in addition to their ongoing chronic heart failure therapy. The primary end point was the frequency of hospital readmission due to cardiovascular events in the 2 months following acute milrinone treatment. Secondary end points were safety and efficacy (parameters: acute clinical and symptomatic improvement, sustained benefit at follow-up, the ability to optimize medical therapy despite recent destabilization, and mortality). Results at 2 months did not differ in terms of symptoms and quality of life; mortality in hospital was 3.8% vs 2.3% on placebo, and 10.3% and 8.9%, respectively, at 2 months. These data confirmed lack of benefit, and a trend toward increased mortality on milrinone.
Calcium sensitization has been proposed as a novel therapy for enhancing cardiac performance. Interaction with the cardiac contractile proteins increases the contractile force generated for a given amount of cytoplasmic free calcium without predisposing to calcium-induced arrhythmias or increasing myocardial oxygen demand. Two agents have been tested in randomized controlled trials: pimobendan, which also has PDE
inhibitory activity and showed no benefit in the Pimobendan In COngestive Heart Failure (PICO) trial; and levosimendan, a non-PDE inhibitor at therapeutic doses whose maximal calcium-sensitizing effect coincides with peak intracellular calcium levels. Levosimendan is least active during cardiac relaxation, and thus does not impair diastolic function. It also induces vascular relaxation by opening the ATP-sensi-tive potassium (KATP) channels. In clinical studies, it has improved symptoms and hemodynamics in both ischemic and nonischemic decompensated heart failure. In comparative studies vs dobutamine, it was associated with significantly lower mortality. Calcium sensitization with levosimendan is thus emerging as a promising therapy for acute and acute-on-chronic heart failure.
Infusion of some (but not all) vasodilators is effective in severe heart failure refractory to conventional oral therapy or diuretics.
Nitroprusside significantiy improves left ventricular performance. In patients with low cardiac output and high filling pressures, it increases cardiac output at the same time as decreasing systemic and pulmonary vascular resistance, right atrial and left ventricular filling pressures, and mitral regurgitation. Long-term intermittent infusion is an effective acute unloading therapy in end-stage heart failure. It also forms an effective vasodila-tor/inotrope combination with dobutamine. However, long-term safety is limited by thiocyanate and cyanide accumulation. In transplantation candidates, nitroprusside infusion 0.76Â±0.99 fig/kg/min 12 hours daily for 22Â±38 days recendy proved safer and more effective than dobutamine in relieving symptoms, facilitating unloading management, and improving survival.
Other vasodilators have shown negative or unconvincing results: in the Prospective RandOmized Flosequinan Longevity Evaluation (PROFILE) studv, flosequinan improved symptoms and hemodynamics, but increased mortality.
The large-scale Flolan International Randomized Survival Trial (FIRST) of continuous epoprostenol infusion in refractory heart failure was terminated early due to excess mortality in the treated group. Exogenous prostacyclin is an effective treatment for primary pulmonary hypertension, and epoprostenol lowers pulmonary and systemic vascular resistance. But its neurohumoral activity remains uncertain.
Nesiritide is a recombinant human brain (B-type) natriuretic peptide identical to the endogenous hormone produced by the ventricle in response to increased wall stress, hypertrophy, and volume overload. The Food and Drug Administration (FDA) has approved its use as an infusion therapy in decompensated heart failure. Nesiritide is a venous, arterial, and coronary vasodilator that reduces preload and afterload, and increases cardiac output, without direct inotropic effects. In addition, it is nonarrhyth-mogenic, increases the glomerular filtration rate and filtration fraction, and inhibits the renin-angiotensin-aldosterone axis. The Vasodilation in the Management of Acute CHF (VMAC) study in decompensated heart failure showed that, when added to conventional care in patients hospitalized with acute-on-chronic heart failure, intravenous nesiritide significandy improved hemodynamic function and some self-reported symptoms vs intravenous nitroglycerin or placebo. An efficacy study in decompensated heart failure showed a dose-related hemodynamic effect at 0.015 |ig/kg/min and 0.030 pg/kg/min. The Prospective Randomized Evaluation of Cardiac Ectopy with Dobuta-minE or Natrecor Therapy (PRECEDENT) study compared safety and proarrhythmogenicity between these same two dosages of nesiritide (0.015 pg/kg/min and 0.030 pg/kg/min) vs dobutamine (>5 pg/kg/min), each for at least 24 hours, in 255 patients with acutely decompensated heart failure: dobutamine was proar-rhythmogenic, while nesiritide (mainly at the lower dosage) induced significantly less ventricular tachycardia over 24 hours, fewer couplets, and fewer premature ventricular beats per hour. A comparative study of short-term outcome between nesiritide and dobutamine in patients with acutely decompensated heart failure showed that shorter infusion was required with nesiritide, with a trend toward fewer hospital readmissions; even 6-month mortality was lower on nesiritide. Several nesiritide studies are ongoing in heart failure. notropes are used to curtail severe heart failure episodes or as a bridge to heart transplantation in end-stage heart failure. However, their use is associated with complications and their relationship to prognosis is unclear. Repeated or prolonged oral inotrope therapy increases mortality.
Cardiac glycosides are used to treat heart failure in patients in sinus rhythm and to control the response of the ventricular rate to supraventricular arrhythmias, including atrial fibrillation.
The most potent drugs for increasing the contractility of the human heart are p-adrenergic receptor agonists. All P-agonists are given intravenously for short-term support in decompensated heart failure. All are arrhythmogenic to a degree, both directly and by increasing potassium deposition in skeletal muscle and decreasing serum magnesium. Administration should be carefully monitored, using the lowest possible effective dose. In addition, all P-agonists induce desensitization on continuous use, which is another reason for using low, short-term, or intermittent doses. All P-agonists have short half-lives (minutes), which is an advantage for powerful inotropes with potentially adverse effects.
Dobutamine is a useful inotrope in moderately decompensated heart failure. It is a potent Pr and P2-adrenoceptor agonist, a moderate a-adrenoceptor agonist, and has dose-dependent hemodynamic effects. Lower doses (<5 pg/kg/min) usually produce mild vasodilatation, reducing afterload and improving ven-tricular-vascular coupling by reducing aortic impedance. Dobutamine is preferable to dopamine for most patients with advanced decompensated heart failure responding inadequately to intravenous diuretics. Its favorable effect on left ventricular afterload also helps to decrease the functional mitral regurgitation often observed on infusion in patients with large dilated ventricles and high left ventricular end-diastolic pressure. Dobutamine also causes a mild decline in pulmonary vascular resistance that is present regardless of chronic background vasodilator therapy. Pulmonary capillary wedge pressure and right atrial pressure are also dose-dependently decreased, while pulmonary arterial resistances do not decrease significantly. Dobutamine does not affect renal or hepatosplanchnic blood flow. At higher doses dobutamine begins to have a!-adrenergic agonist effects, thereby preventing progressive vasodilatation and usually leading to only minimal changes in afterload and preload. The advantage of this a-adrenergic effect is that dobutamine can be administered without pulmonary artery catheter monitoring of left ventricular filling pressure, since preload and afterload do not change dramatically. Another advantage of the relative lack of vasodilatation coupled with the partial agonist action is that dobutamine 10 pg/kg/min or less does not appreciably increase the heart rate. Because of this vasoconstrictor effect, high doses are less favorable in terms of nutritional muscular peripheral blood flow, as well as in terms of myocardial oxygen consumption for the heart rate increase. Dobutamine infusion is initiated at 2 to 3 pg/kg/min and titrated to the hemodynamic response (usually not higher than 20 pg/kg/min). However, its use has been insufficiently documented in controlled trials and its effects on prognosis are unclear. The limitations are that dobutamine is a relatively weak P-agonist, only modestly lowers elevated pulmonary artery pressure, induces desensitization on chronic use, and cannot be effectively used in the presence of high levels of P- blockade. The first three of these limitations can be overcome by combination with a phosphodiesterase (PDE) inhibitor, which results in additive effects on myocardial performance, substantial reductions in pulmonary wedge and pulmonary artery pressures, and less desensitization as a result of using a lower dobutamine dose. Doubt over the impact of dobutamine on postintensive clinical outcome centers on the drug's potential adverse effects which include increased ventricular ectopy and the risk of antiarrhythmic death, an increased risk of myocardial ischemia, increased circulating catecholamines, and the risk of myocardial toxicity and apoptosis.
Intravenous dopamine is used for the short-term correction of severe hemodynamic episodes in worsening heart failure. At lower doses (<2.5 (ig/kg/min), it acts via dopaminergic receptors to cause relatively selective vasodilatation of splanchnic and renal arterial beds. This can promote renal blood flow and maintain glomerular filtration in selected patients who become refractory to diuretics, especially if due to borderline renal perfusion. Dopamine also has direct renal tubular effects that promote natriuresis. Low-dose (âœrenal-doseâ) dopamine is widely used in intensive care units for its presumed protective effect on renal function and is often considered to be relatively free of serious adverse effects. Tolerance to the vasodilator effects develops within 2 to 3 days.
Low-dose dopamine inhibits chemoreceptor drive and thus may depress ventilatory response to hypoxemia and hypercapnia. It may also reduce arterial oxygen saturation by impairing regional ventilation/perfusion matching in the lung, and depressing local vasoconstriction in response to alveolar hypoxia. Ventilatory inhibition may impair outcome in heart failure with associated significant hypoxia.
At intermediate infusion rates (2 to 5 |ig/kg/min), dopamine, by virtue of its tyramine and neuronal uptake-inhibiting properties, enhances norepinephrine release from vascular and myocardial adrenergic neurons, thereby resulting in increased cardiac (3-adreno-ceptor activation and increased peripheral vascular resistance. In advanced heart failure, however, when intracardiac norepinephrine stores are frequently depleted, dopamine becomes less effective as a positive inotrope than direct-acting alternatives.
At higher infusion rates (5 to 20 ^g/kg/min), peripheral vasoconstriction occurs as a result of direct a-adrenoceptor stimulation. Increases in systemic vascular resistance are common even at intermediate infusion rates. On initial administration, tachycardia and arrhythmia tend to be more pronounced than with dobutamine and are related to cardiac norepinephrine release.
In advanced, decompensated heart failure, dopamine should not be used as a positive inotrope, but rather in low doses for renal perfusion and in intermediate to high doses to increase peripheral resistance.
The use of dopamine has not been evaluated in prospective controlled trials and its effects on prognosis are unclear. Currently, insufficient data are available to recommend oral dopamine analogues for heart failure treatment. The dopaminergic agent ibopamine, which also has sympathomimetic properties, is not recommended for the treatment of chronic heart failure due to systolic left ventricular dysfunction.
The use of epinephrine, isoproterenol, norepinephrine and phenylephrine should be restricted to denervated transplanted hearts or to cases that need peripheral vascular resistance support (sepsis, iatrogenic overvasodilatation, brain injury).
Specific type III PDE inhibitors, particularly at low doses, have a relatively selective effect on phospholam-ban phosphorylation and sarcoplasmic reticulum (SR) function. The SR-selective effect is probably the reason why highly type Ill-specific PDE increase contractile function without greatly increasing the heart rate. Type III PDE inhibitors are also potent vasodilators, particularly on venous capacitance and pulmonary vascular beds. In fact, they are among the best agents for lowering pulmonary artery pressure and pulmonary vascular resistance, which is why they have assumed an important role in postoperative cardiac surgical regimens, including cardiac transplantation.
In the absence of elevated right-sided venous pressure in a patient with biventricular failure, it is best to confirm, via pulmonary artery catheter, that the pulmonary wedge mean pressure exceeds 15 mm Hg before administering a PDE inhibitor intravenously. Otherwise, a precipitous drop in blood pressure may accompany drug administration.
Type III PDE inhibitors dilate epicardial coronary arteries and bypass grafts, and inhibit platelet aggregation. They also inhibit proinflammatory cytokine formation, the effects of endotoxin, and neointimal formation after vascular injury.
The increase in cardiac output from PDE inhibitors is preferentially distributed to skeletal muscle, thus increasing the maximal exercise response. In addition, in the dilated failing heart, PDE inhibitors have a positive energy effect, improving both diastolic and systolic function.
In summary, PDE inhibitors are potent positive inotropes and vasodilators. They enhance pump function while inducing optimal decreases in ventricular wall stress and myocardial oxygen consumption. As a result, they increase myocardial contractility while simultaneously unloading the failing heart by dilating both resistance and capacitance vessels.
Renal elimination and a prolonged duration of action complicate dosage adjustment. Plasma drug levels at the steady state required for significant inotropism and vasodilation during continuous infusion therapy should range from 170 to 200 ng/mL. Hypotension is the main side effect. Because of the major role played by peripheral vasodilatation in their impact on systemic hemodynamics, PDE inhibitors have a less marked inotropic effect than dobutamine. This may make them preferable for patients with severe ischemic heart disease and easily provoked angina. Yet, precisely because the two drug classes differ in hemodynamic profile and site of action, their combined use could be advantageous in patients with very low cardiac output. However, consistent information on the safety of this combination is not yet available.
In placebo-controlled trials, selective type III PDE inhibitors have increased mortality when given in doses that produce large hemodynamic effects. The cause is an increase in sudden death, presumably due to arrhythmia. Despite these discouraging results, PDE inhibitors continue to be developed for heart failure therapy via two new approaches. One is a low-dose approach that takes advantage of the fact that doses one sixth to one third those used in earlier clinical trials retain hemodynamic activity, increase exercise tolerance, do not increase heart rate, are nonarrhythmo-genic, and apparently do not increase mortality. The second approach to safe long-term use is to combine a PDE inhibitor with a (3-blocker. This combination is possible because the site of action of PDE inhibitors lies beyond the |3-adrenoceptor. The combination actually enhances the hemodynamic effects of PDE inhibitors. A practical consequence is that decompensation to the point of needing positive inotropic support in patients on long-term |3-blockade is an indication for a PDE inhibitor rather than dobutamine.
Amrinone causes thrombocytopenia and may be associated with a rapid subsensitivity in advanced heart failure. Thus, it is no longer widely used to treat decompensated heart failure.
Milrinone does not commonly cause thrombocytopenia. Although it is a highly selective type III PDE inhibitor, other actions capable of producing an inotropic effect have been described, including stimulation of the calcium release channel, calcium channel blockade, and effects on sarcolemmal calcium ATPase. Development of oral milrinone was abandoned following the increased mortality in the Prospective RandOm-ized Milrinone Survival Evaluation (PROMISE) trial, which used doses at least four times higher than the minimum effective hemodynamic dose. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) trial found no differences in clinical and mortality endpoints between patients randomized within 48 hours of admission for acute exacerbation of chronic heart failure to infusion for 48 hours with milrinone vs placebo.
Such evidence indicates lack of benefit in either stable severe heart failure or acute exacerbations. It must also be doubted whether milrinone even has a role in the management of hemodynamic crises requiring inotropic therapy.
Enoximone is approved for intravenous use in Europe and is in development in the United States for oral use as both low-dose monotherapy and in combination with prselective blockade. It is a highly selective type
III PDE inhibitor that rarely causes thrombocytopenia. The intravenous loading dose is 0.25 to 0.75 mg/kg; the continuous infusion rate is 1.25 to 7.5 pg/kg/min. Enoximone is extensively metabolized by the liver to suffixed derivatives, including at least one active metabolite. Sulfoxide metabolites are eliminated by the kidney, and dose reductions in renal failure are the same as with milrinone. Doses should also be reduced in hepatic failure.
Vesnarinone is approved for the treatment of heart failure in Japan. In human myocardium, therapeutic concentrations produce PDE inhibition and potassium channel antagonism. This confers a hemodynamic profile similar to that of enoximone or milrinone, but coupled with type III antiarrhythmic properties. Vesnarinone inhibits cytokine production by stimulated blood cells in healthy subjects and patients with heart failure. The VEsnarinone Survival Trial (VEST) showed that vesnarinone induced small, but dose-related, increases in mortality.
Phosphodiesterase inhibitors with calcium sensitizer activity
These positive inotropes act in part by increasing the sensitivity of troponin C or some other part of the myofibrillar calcium-binding apparatus to ionized calcium. On its own, this property would prolong the contraction time and decrease diastolic function; however, these agents are also PDE inhibitors, a property that cancels out the increased contraction time and enhances diastolic function. The fact that calcium sensitizers increase neither intracellular calcium nor the heart rate also confers a theoretical energy advantage. In acute exacerbations, short-term levosimendan appears safer than dobutamine. In acute heart failure after myocardial infarction, levosimendan improved symptoms, halved mortality in the first 72 hours, and maintained the difference in mortality over the next 6 months. However, this effect on mortality requires confirmation from formal trials.
Levosimendan induces rapid, dose-dependent hemodynamic improvement in decompensated heart failure with minimal side effects. There are theoretical reasons for thinking that it may not have the adverse mortality effect seen with other positive inotropes, but this remains to be proved.
Despite improving exercise tolerance and quality of life, pimobendan, a calcium-sensitizing PDE inhibitor, was also found to increase mortality. Flosequinan, a vasodilator inotrope, also improved functional capacity and was widely prescribed after its release until increased mortality forced its withdrawal.
Drugs that directly improve myocardial contractility have effects that are both positive and negative: increased cardiac output and decreased wall stress and neurohumoral activation, on the one hand, and accelerated myocyte death and ventricular dysfunction caused by stressing myocytes already at their limit of contractile performance, on the other. These negative effects limit chronic inotropic therapy, the safety of which has also been challenged by the increased mortality and morbidity shown in some trials of oral inotropes and in the only randomized trial of intravenous dobutamine. Recent recommendations restrict intravenous inotropes to patiehts hospitalized with acute on chronic heart failure refractory to conventional therapy. Candidates for adjuvant low-dose inotrope infusion include hospitalized nonresponders to diuretic monotherapy, or those in whom poor response can be predicted by baseline renal dysfunction, very low serum sodium, or evidence of marked hypoperfusion.
What are the indications for ambulatory therapy with intravenous positive inotropes in heart failure?
Short-term and mid-term therapy with positive inotropes, such as ^-adrenergic agonists (dobutamine) and phosphodiesterase III inhibitors (milrinone), improves cardiac performance not only by enhancing cardiac contractility, due to the increase in myocardial cyclic adenosine monophosphate levels, but also via peripheral vasodilatation. However, long-term oral therapy fails to maintain these hemodynamic benefits and is associated with significantly increased mortality, particularly in advanced heart failure. An alternative approach has been intravenous positive inotrope therapy on a regular intermittent or continuous basis in a supervised ambulatory setting.
Nearly all available results using this approach derive from inconclusive, short-term, uncontrolled, open-label studies in small patient populations. Only two studies were place-bo-controlled. They used intermittent administration to overcome the significant clinical problem of tachyphylaxis due to p-receptor downregulation or uncoupling. In the first study, Leier et al reported improved clinical parameters and exercise time with dobutamine infusion, 7.4 |ig/kg/min to 8.6 |ig/kg/min, in 26 patients over a mean follow-up of 24 weeks. Dies et al administered dobutamine
drug; positive inotrope; ambulatory therapy; intermittent infusion therapy; side effect; beneftt-risk ratio