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European Journal of Heart Failure 2000 2(1):7-11; doi:10.1016/S1388-9842(99)00061-6
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© 2000 European Society of Cardiology

Intravenous inotropic agents in the intensive therapy unit: do they really make a difference?

Cristina Opasicha,*, Alessandra Russob, Renato Mingronea, Mara Zambellia and Luigi Tavazzib

a S. Maugeri Foundation, Institute of Care and Scientific Research, Cardiology Division, Medical Center of Pavia 27100 Pavia, Italy
b Cardiology Division, Policlinico S. Matteo Institute of Care and Research 27100 Pavia, Italy

* Corresponding author. Tel.: +39-382-592-1; fax: +39-382-592-099. E-mail address: copasich{at}fsm.it


   Abstract
Top
 Abstract
1. Introduction
 2. β-Receptor agonists
 References
 
Part of the management of refractory heart failure is treatment aimed at preventing organ damage due to inadequate oxygen delivery, improving hemodynamics, and maximizing cardiac output while maintaining only mildly elevated ventricular filling pressures The aim of this paper is to review the most updated indications on intravenous inotropic agents, and to compare their cardiac and peripheral effects. Finally, clinical implications of their use (alone or in combination) are reviewed.

Key Words: Intravenous inotropics • Intensive therapy • Heart failure

Received February 12, 1999; Revised October 19, 1999; Accepted October 21, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. β-Receptor agonists
 References
 
Part of the management of refractory heart failure is treatment aimed at preventing organ damage due to inadequate oxygen delivery, improving hemodynamics, and maximizing cardiac output while maintaining only mildly elevated ventricular filling pressures.

Drugs that directly improve myocardial contractility have positive effects (increase in cardiac output, decrease in wall stress and in neurohormonal activation) but also negative effects (stressing myocytes already at their limits of contractile performance can lead to acceleration of myocyte death and progression of ventricular dysfunction). These negative aspects 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 i.v. dobutamine [1–3]. Recently, the FDA panel [4] recommended that labeling of intravenous positive inotropic agents should be revised because there is no experience from controlled trials on continuous infusions for periods >24–48 h nor is there any evidence that long-term intravenous use of these drugs does not carry risks similar to that of the same drugs given orally.

Thus, according to the FDA panel report, intravenous inotropic drugs are only indicated for patients who are hospitalized with an acute heart failure exacerbation which is refractory to standard therapy.

Short-term intravenous positive inotropic treatment is recommended by ACC/AHA [5] and European Society guidelines [6] during exacerbation for which hospitalization is necessary. This treatment may temporarily improve cardiac output and renal blood flow, ameliorate symptoms, and relieve salt and water retention in patients refractory to maximal oral therapy. Thus, patients for whom the addition of low-dose inotropic infusions is advisable include hospitalized patients not responding to diuretics alone or those patients in whom poor response is predicted by baseline renal dysfunction, very low serum sodium, or evidence of marked hypoperfusion.


   2. β-Receptor agonists
Top
 Abstract
 1. Introduction
 2. β-Receptor agonists
References
 
The most widely employed beta1-receptor agonists are dobutamine and dopamine.

2.1. Dobutamine
Dobutamine is a potent agonist at β1 and β1-adrenoceptors and a fair agonist at β2-adrenoceptors. The main hemodynamic effect of dobutamine are dose-dependent and are summarized in Table 1. The increase in left ventricular contractility is on average 15% and the decrease in total peripheral resistance is 25% on average. Pulmonary capillary wedge pressure, right atrial pressure and pulmonary artery pressure are also dose-dependently decreased (on average 29, 35 and 13%, respectively), and heart rate increases after a dose of 10 µg/kg/min. Pulmonary artery resistances do not decrease significantly [7–14].


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  		Table 1 Summary of the principal cardiac effects of dobutamine and phosphodiesterase inhibitors

 
Dobutamine represents a significant advance over the other inotropic agents such as epinephrine, norepinephrine and dopamine because of its favorable ‘vascular–ventricular coupling’ property [7,8]. Dobutamine at a dose ranging from 5 to 10–15 µg/kg/min has a vasodilating effect, which is lost at higher doses. Inasmuch as sympathetic tone and hence, arterial resistance are increased in CHF and dobutamine is a sympathomimetic drug, the peripheral dilation observed with the low doses results both from the improvement in cardiac function, which reflexively results in vascular smooth muscle relaxation, and probably from vascular β2-adrenoceptor stimulation. At higher doses muscular vascular relaxation is opposed by vasoconstriction probably resulting from β1-adrenoceptor stimulation [9]. Hence, 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 does not affect renal or hepatosplanchnic blood flow [9].

Despite the marked increase in cardiac output induced by dobutamine, Erleiner et al. [15] found only a slight increase in intrapulmonary shunting and no detrimental effects on PaO2. Thus, in contrast to vasodilatory therapy, dobutamine does not seem to cause potentially harmful pulmonary gas exchanges.

Despite its inotropic effect, dobutamine does not necessarily significantly alter myocardial oxygen consumption, partly because of the insignificant increase in the heart rate until high doses are used, but also because of the associated decrease in pre-load and left ventricular end-systolic wall stress. Moreover, an increase in coronary blood flow associated with an increase in coronary sinus oxygen content as a result of a direct coronary vasodilator effect in patients with idiopathic cardiomyopathy has been shown by Dubois-Randé et al. [10]. Such an effect on a resistance vessel could be predominantly mediated by activation of β2-adrenergic receptors contributing to decreased coronary resistance and increased coronary blood flow, as suggested by experimental studies [11,12]. The net change of coronary vascular tone after dobutamine infusion may be the result of the interplay between the β2 vasodilating action and the β-vasoconstricting activity, and of secondary changes caused by increased myocardial metabolic demand.

There are limits to the benefit of dobutamine. The major one is the rapid development of tolerance (within 48–72 h) with the need for increasing doses [13].Tolerance is due to a reduction in β-receptor density which already occurs by 24 h after starting dobutamine treatment [14]. Moreover, using non-invasive hemodynamic echocardiography Capomolla et al. [16] observed only erratic changes in mitral regurgitation and no systematic variations of left atrial pump function in patients being treated with dobutamine. In their study, the mean decreases in pulmonary wedge pressure and in end-diastolic volume induced by dobutamine infusion were similar (16% vs. 14%), implying a higher leftward than downward pressure–volume curve shift, with unchanged pre-A left ventricular diastolic fitness (left atrial afterload). The volume shift during atrial contraction was unchanged. The increase in atrial performance was used to develop pressure and probably to shift blood into the pulmonary veins, but not to improve the atrial contribution to left ventricular late diastolic filling and stroke volume generation. The potential detrimental effects of dobutamine, such as increased ventricular ectopy and risk of arrhythmic death, increased risk of myocardial ischemia, increased circulating catecholamines and risk of myocardial toxicity and apoptosis raise doubts about dobutamine’s effects on post-intensive clinical outcome.

2.2. Dopamine
Similarly to dobutamine, the effects of dopamine differ according to dosage. At low doses (0.5–2.5 µg/kg/min) (when there is little inotropic activity) dopamine acts via dopaminergic receptors (postsynaptic receptors D1 and presynaptic D2) and causes splanchnic (renal and mesenteric) vasodilation. Intermediate doses (2–5 µg/kg/min) favor β1 receptor stimulation and adrenergic effects. With higher doses (>5 µg/kg/min) the vasodilating effects are reversed by β receptor stimulation leading to potent vasoconstriction.

The mechanisms of the ‘renal effect’ of dopamine are complex: they are due in part to an increase in cardiac output (β1 effect) and global perfusion, in part to local vasodilation due to direct and selective simulation of the dopaminergic receptors in renal blood vessels, and in part to a direct effect on tubular function. Glomerular filtration increases as well as urinary output. Moreover, the ‘renal effect’ is consequent in part to increased delivery of diuretics to the distal tube, and in part to decreased serum aldosterone concentration. Low-dose or so called ‘renal dose’ dopamine is widely used in intensive care units for its presumed protective effect on renal function and it is often considered to be relatively free of serious adverse effects.

The effects of low-dose dopamine on renal function are, however, variable and modest. This selective effect may be absent or greatly muted [17]. Only small studies have documented a renal protective effect [18]. The first published randomized, controlled trial of low-dose dopamine in critically ill patients [19] did not show renal sparing and indeed the authors hinted at a serious toxic potential. Recently, the results of a randomized study comparing the use of i.v. diuretics alone or in association with low-dose dopamine in 20 CHF patients with mild to moderate renal insufficiency were published [20]. This study supports the beneficial role of low-dose dopamine in preserving and even improving renal function, but the results should be confirmed in a larger, randomized, controlled study. There is a great overlap in dopamine dose-related effects, and also significant individual variation. Even at low doses dopamine may increase contractility and systemic vascular resistances. No dose is clearly only a ‘renal-dose’ [18]. Patients with decompensated heart failure generally have systemic effects of vasodilation and increased cardiac output with the low dose of dopamine that is similar to the effects seen with low-dose dobutamine, making their association useless.

In theory low-dose, long-term therapy with dopamine would not lead to the development of tolerance (no involvement of β receptors). In practice tolerance to the vasodilatory effects develops within 2–3 days [21].

Because of dopamine-induced inhibition of chemoreceptor drive (by stimulation of the dopaminergic receptors in the carotid bodies which have an inhibitory influence on chemoreceptor afferent activity), low-dose dopamine may depress ventilatory response to hypoxemia and hypercapnia, as van de Borne et al. recently showed [22]. Dopamine 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 adversely influence the outcome of HF patients who are also significantly hypoxic.

2.3. Phosphodiesterase inhibitors
Phosphodiesterase inhibitors mediate their pharmacologic activity by inhibiting intracellular enzymes responsible for the breakdown of cyclic adenosine monophosphate (cAMP), which acts as a second messenger and promotes an influx of calcium into the sarcolemma leading to increased contractile force [23].

These agents have potent positive inotropic and vasodilatory effects, leading to an enhanced pump function associated with optimal low ventricular wall stress and low myocardial oxygen consumption. These combined inotropic/vasodilator actions increase myocardial contractility and simultaneously unload the failing heart by means of a vasodilating effect on both resistance and capacitance vessels [24–26].

Dose-dependent hemodynamic effects of phosphodiesterase inhibitors are summarized in Table 1, and indicate that vasodilation and inotropic stimulation but not tachycardia account for the improvement in cardiac function.

Long duration of action and excretion by kidneys complicate dosage adjustment. Plasma drug concentration at the equilibrium state for obtaining significant inotropic/vasodilating hemodynamic effects in patients receiving continuous infusion therapy should range from 170 to 200 ng/ml [25,26].

Thrombocytopenia (mainly for amrinone) and hypotension may be collateral effects.

Comparisons between phosphodiesterase inhibitors and dobutamine [9,27,28] have shown that the former induce a greater [27] or equivalent [9] or smaller [28] decrease in pulmonary capillary wedge and right atrial pressures, an equivalent increase in cardiac output and stroke volume, an equivalent decrease in total peripheral resistance, but, differently from dobutamine, no significant change in heart rate and a lower myocardial energy cost. Neither dobutamine nor phosphodiesterase inhibitors affect renal or hepatosplanchnic blood flow. However, in the muscle bed, brachial blood flow and brachial artery diameter increase dose-dependently after enoximone use, but increase only with low doses of dobutamine [9]. Consequently, because of the major role played by peripheral vasodilation in the phosphodiesterase inhibitors-induced modification of systemic hemodynamics, the inotropic stimulation is less marked with phosphodiesterase inhibitors than with dobutamine. These differences tend to make phosphodiesterase inhibitors preferred for patients with severe ischemic heart disease and easily provoked angina.

2.3.1. Combination between dobutamine and a phosphodiesterase inhibitor
Because the hemodynamic profile and sites of action of these two drugs are different, their combination could be useful in patients with very low cardiac output.

Total peripheral and forearm vascular resistances, as well as right and left ventricular filling pressures, are not further improved by the combination and the tachycardia is similar to that occurring after the highest doses of dobutamine. However, the increase in cardiac index and the brachial artery flow and diameter are greater than after the administration of either drug alone, indicating that the combination of a phosphodiesterase inhibitor with a low dose of dobutamine may indeed be useful in the management of acute severe heart failure [9]. However, consistent information on the safety of this association are lasting yet.

2.4. Clinical implications
Short-term intravenous inotropes used to treat acutely decompensated, congestive, refractory patients produce an improvement in hemodynamics and symptoms. The achievement of dry weight improves clinical status and allows clinical stabilization. Even in this context, few data exist on the efficacy of such treatment on end-points other than hemodynamic.

The OPTIME CHF trial (Outcome of a Prospective Trial of Intravenous Milrinone for Exacerbation of Chronic Heart Failure) is an on-going multicenter randomized placebo-controlled trial of a treatment strategy using early intravenous administration of milrinone for acute exacerbations of coronary heart failure. The primary end-point is a reduction in the total number of days of hospitalization for cardiovascular events in the 60 days following therapy. Secondary end-points are the proportion of patients achieving target dosing of ACE-inhibitors at discharge, reduction in treatment failures at 48 h, improved subjective outcome and reduction in all hospital days, death and adverse events at 60 days. Enrolment of 1000 patients began in July 1997 in 80 US centers and should be completed within 2 years [29].

When congestion is absent and symptoms of low cardiac output are predominant, the benefit of brief use of intravenous inotropic agents does not usually extend beyond the short-term support. Long-term low-dose inotropes, intermittently or continuously administered to improve subjective status in end-stage heart failure patients no bridged to transplant, to preserve hepatorenal function in heart transplant candidates or to facilitate β–blockers in end-stage patients are still under debate.

As regards as the last point, the addition of a β–blocker to a phosphodiesterase inhibitor would eliminate or attenuate the negative inotropic side effects of the former and the long-term negative adverse effects of the latter. Such a combination was well tolerated and induced beneficial hemodynamic changes in refractory heart failure patients in Shakar’s [30] experience. This was a retrospective, not controlled study on a small number of patients, but its favorable results call for a prospective, randomized trial [31].

In conclusion, from this review it derives that the treatment of refractory heart failure patients by short-term intravenous inotropes is really effective.


   References
Top
 Abstract
 1. Introduction
 2. β-Receptor agonists
 References
 

  1. Packer M., Carver J., Rodeheffer R., Ivanhoe R., et al. Effect of oral milrinone on mortality in severe congestive heart failure. N Engl J Med (1991) 325:1468–1475.[Abstract]
  2. Uretsky B., Jesupp M., Konstam M., Dec G., et al. Multicenter trail of oral enoximone in patients with moderate to severe congestive heart failure. Lack of benefit when compared with placebo. Circulation (1990) 82:774–780.[Abstract/Free Full Text]
  3. Dies F., Krell M., Whitlow P. Intermittent dobutamine in ambulatory out patients with chronic cardiac failure. Circulation (1986) 74(Suppl_II):II–39.
  4. Thadani U., Roden D.M. FDA panel report: January 1998. Circulation (1998) 97:2295–2296.[Free Full Text]
  5. ACC/AHA Task Force Report. Guidelines for the evaluation and management of heart failure. J Am Coll Cardiol (1995) 26:1376–1398.[Web of Science][Medline]
  6. The Task Force of the Working Group of Heart Failure of the European Society of Cardiology. The treatment of heart failure. Eur Heart J (1997) 18:736–753.[Free Full Text]
  7. Binkley P.F., Van Fossen D.B., Nunziata E., Unverferth D.V., et al. Influence of positive inotropic therapy on pulsatile hydraulic load and ventricular–vascular coupling in congestive heart failure. J Am Coll Cardiol (1990) 15:1127–1135.[Abstract]
  8. Ruffolo R.R. Jr. Review: the pharmacology of dobutamine. Am J Med Sci (1987) 294:244–248.[Web of Science][Medline]
  9. Thuillez C., Richard C., Teboul J.L., et al. Arterial hemodynamics and cardiac effects of enoximone, dobutamine, and their combination in severe heart failure. Am Heart J (1993) 125:799–808.[CrossRef][Web of Science][Medline]
  10. Dubois-Randé J.L., Merlet P., Duval-Moulin A.M., et al. Coronary vasodilating action of dobutamine in patients with idiopathic dilated cardiomyopathy. Am Heart J (1993) 125:1329–1336.[CrossRef][Web of Science][Medline]
  11. Vatner S.F., MecRitchie R.J., Braunwald E. Effects of dobutamine on left ventricular performance, coronary dynamics and distribution of cardiac output in conscious dogs. J Clin Invest (1974) 53:1265–1273.[Web of Science][Medline]
  12. Main J.S., Forster C., Armstrong P.W. Inhibitory role of the coronary arterial endothelium to alpha-adrenergic stimulation in experimental heart failure. Circ Res (1991) 68:940–951.[Abstract/Free Full Text]
  13. Unverferth D.V., Blanford M., Kates R.E., et al. Tolerance to dobutamine after a 72 hour continuous infusion. Am J Med (1980) 69:262–266.[CrossRef][Web of Science][Medline]
  14. Teng J.K., Kwan C.M., Lin L.J., et al. Down-regulation of beta adrenergic receptors on mononuclear leukocytes induced by dobutamine treatment in patients with congestive heart failure. Eur Heart J (1993) 14:1349–1353.[Abstract/Free Full Text]
  15. Erlemeier H.H., Kupper W., Bleifeld B. Effect of dobutamine on pulmonary gas exchange in patients with heart failure. Eur Heart J (1992) 13:1545–1548.[Abstract/Free Full Text]
  16. Capomolla S., Pozzoli M., Opasich C., Febo O., et al. Dobutamine and nitroprusside infusion in patients with severe congestive heart failure: hemodynamic improvement by discordant effects on mitral regurgitation, left atrial function, and ventricular function. Am Heart J (1997) 134:1089–1098.[CrossRef][Web of Science][Medline]
  17. Thompson B.T., Cockrill B.A. Renal-dose dopamine: a Siren song? Lancet (1994) 344:7–8.[CrossRef][Web of Science][Medline]
  18. Johnson R.L. Low-dose dopamine and oxygen transport by the lung. Circulation (1998) 98:97–99.[Free Full Text]
  19. Baldwin M., Henderson A., Ichman P. Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery. Ann Intern Med (1994) 120:744–747.[Abstract/Free Full Text]
  20. Varriale P., Mossavi A. The benefit of low-dose dopamine during vigorous diuresis for congestive heart failure associated with renal insufficiency: does it protect renal? Clin Cardiol (1997) 20:627–630.[Web of Science][Medline]
  21. Orme M., Brechenridge A., Dollery C. The effect of long term administration of dopamine on renal function in hypertensive patients. J Clin Pharmacol (1973) 6:150–154.[CrossRef]
  22. Van de Borne P., Oren R., Somers V. Dopamine depresses minute ventilation in patients with heart failure. Circulation (1998) 98:126–131.[Abstract/Free Full Text]
  23. Shipley J.B., Hess M.L. Inotropic therapy for the failing myocardium. Clin Cardiol (1995) 18:615–619.[Web of Science][Medline]
  24. Seino J., Takano T., Hayakawa H., et al. Hemodynamic effects and pharmacokinetics of oral milrinone for short term support in acute heart failure. Cardiology (1995) 86:34–40.[CrossRef][Web of Science][Medline]
  25. Anderson J.L. For the United States Milrinone Multicenter Investigators: hemodynamic and clinical benefits with intravenous milrinone in severe chronic heart failure: results of a multicenter study in the United States. Am Heart J (1991) 121:1956–1964.[CrossRef][Web of Science][Medline]
  26. Seino J., Momomura S., Takano T., Hayakawa H., Kazuzou K. Multicenter, double-blind study of intravenous milrinone for patients with acute heart failure in Japan. Crit Care Med (1996) 24(9):1490–1497.[CrossRef][Web of Science][Medline]
  27. Monrad E.S., Baim D.S., Smith H.S., et al. Effects of milrinone on coronary hemodynamics and myocardial energetics in patients with congestive heart failure. Circulation (1985) 7:1107–1113.
  28. Rich M.W., Woods W.L., Davila-Roman V.G., et al. A randomized comparison of intravenous amrinone versus dobutamine in older patients with decompensated congestive heart failure. J Am Geriatr Soc (1995) 43:271–274.[Web of Science][Medline]
  29. Gheorghiade M., Cody R.J., Francis G.S., et al. Current medical therapy for advanced heart failure. Am Heart J (1998) 135:S231–S248.[CrossRef][Web of Science][Medline]
  30. Shakar S.F., Abraham W.T., Gilbert E.M., Robertson A., et al. Combined positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol (1998) 31:1336–1340.[Abstract/Free Full Text]
  31. De Marco T., Chatterjee K. Phosphodiesterase inhibitors in refractory heart failure: bridge to beta-blockade? J Am Coll Cardiol (1998) 31:1341–1343.[Free Full Text]

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