International Journal of Cardiology, 30 (1991) 203-208 0 1991 Elsevier Science Publishers B.V. (Biomedical Division) ADONIS 016752739100059C
CARD10
203 0167-5273/91/$03.50
01190
Comparison of the haemodynamic effects of dopexamine and dobutamine in patients with severe congestive heart failure Lip-Bun Tan, William A. Littler and R. Gordon Murray Department
of Cardiology, (Received
Tan L-B, dobutamine
University of Birmingham, 20 March
1989; revision
East Birmingham Hospital, Birmingham, accepted
12 September
UK.
1990)
Littler WA, Murray RG. Comparison of the haemodynamic effects of dopexamine in patients with severe congestive heart failure. Int J Cardiol 1991;30:203-208.
and
Dopexamine hydrochloride is a novel compound with properties of DA, dopaminergic and &-adrenergic receptor agonism and neuronal noradrenaline uptake inhibition. It has been shown to produce beneficial renal and haemodynamic effects in patients with severe heart failure. We compared the haemodynamic effects of dopexamine (0.5 to 6 pg/kg/min) with those of dobutamine (5 to 25 pg/kg/min) in 9 patients with severe congestive heart failure. The two drugs were similar in their effects at peak infusion rates: heart rate increased (dopexamine 87 f 17 to 100 f 14; dobutamine 91 f 18 to 103 f 17 min- ‘), cardiac index increased (dopexamine 1.7 f 0.5 to 2.8 f 1.1; dobutamine 1.8 f 0.5 to 3.0 f 1.1 1 min-’ m-*) and systemic vascuhu resistance decreased (dopexamine 1553 f 221 to 1117 f 435 dobutamine 1721 f 347 to 1280 f 433 dyne s cm-‘). Neither drug affected pulmonary artery wedge pressure (dopexamine 24 f 6 to 22 f 6; dobutamine 25 f 9 to 24 f 10 mm Hg). Dopexamine had significantly lower peak effects on left ventricular stroke work index (dopexamine 20 f 9, dobutamine 27 f 15 g - m m-*, P < 0.05) and cardiac power output (dopexamine 0.71 f 0.36, dobutamine 0.93 f 0.46 W, P c 0.05). These haemodynamic effects, due largely to vasodilatation but with some contributory positive inotropy, indicate that dopexamine will be useful in the acute treatment of congestive heart failure. l
l
l
l
l
Key words:
Inotrope;
Vasodilator;
Heart
failure
Introduction Dopexamine is a dopaminergic drug producing renal vasodilatation via DA,-dopaminergic agonist activity and systemic vasodilatation via &-adren-
Correspondence to: Dr. L.B. Tan, Dept. of Cardiology, Killingbeck Hospital, Leeds LS14 6UH, U.K. This study was supported in part by a grant from the British Heart Foundation.
ergic agonism [1,2]. Unlike dopamine, it has no cY-adrenergic activity and it has less agonist activity at DA ,-dopaminergic (emesis-inducing) receptors [2]. Direct activity at the Pi-adrenoceptor is minimal but these receptors are stimulated indirectly via inhibition of uptake-l [3] and baroreflex activity [4]. We studied the central haemodynamic effects of dopexamine in patients with severe heart failure and compared its vasodilator, chronotropic and inotropic effects with those of dobutamine, a widely used positive inotropic agent.
204
Methods Patients
We studied 9 patients (7 males, 2 females; mean age 63.2 + 6.8 (SD) years). AU had severe cardiac failure due to ischaemic heart disease (post-myocardial infarction in 5 patients and exacerbation of chronic heart failure in the rest). Baseline cardiac index was 1.66 f 0.16 1. mm’ * m -2, with pulmonary wedge pressure of 23.6 f 2.1 mm Hg. All patients gave informed consent to participation in the study, which was approved by the Ethical Committee of East Birmingham Hospital.
study, nor fi-adrenoceptor of entry.
antagonists within 48 h
Data analysis
Cardiac index, left ventricular stroke work index and pulmonary and systemic vascular resistances were calculated according to standard formulae. We also calculated cardiac power output (W) as (mean arterial pressure-right atria1 pressure) x cardiac output x 2.217 x 10P3. Clinically equipotent doses of the two drugs were regarded as those producing the same increments of cardiac output. Statistical analysis was by Student’s paired t-test with Bonferroni adjustments. Differences were taken to be significant at P < 0.05. Results are expressed as means f SEM.
Methods Results
The following haemodynamic variables were measured using thermodilution Swan-Ganz catheters, arterial cannulae and electrocardiogram: heart rate (mm’), right atria1 pressure (mm Hg), pulmonary arterial pressure (mm Hg), pulmonary artery wedge pressure (mm Hg), systemic mean arterial pressure (mm Hg) and cardiac output (1. mm’, measured in triplicate). Control haemodynamic data were obtained at least 20 min after insertion of the catheters and when two readings taken 15 min apart differed by less than 15%. The patients were randomly assigned to receive first either dopexamine (5 patients) or dobutamine (4 patients). Dobutamine was given via a central venous line, commencing at 5 pg/ kg/ min and increasing at 5-10 min intervals to a maximum of 25 pg/kg/min. Dopexamine was infused at rates of 0.5, 1.0, 2.0, 4.0 and 6.0 pg/kg/min, each dose being given for 20 min. Maximum doses in each patient were determined by the absence of a further rise in cardiac power output. The durations of infusion were adopted because in preliminary studies the haemodynamic responses in such patients reached a plateau within these times. Haemodynamics were allowed to return to baseline levels between the drug infusions. No food or drink (except sips of water) was given during the ) study. No diuretics, other vasodilators or inotropic agents were given within 4 h prior to entry to the
Since not all patients received the highest doses of the two drugs, haemodynamic responses up to 20 pg/kg/min of dobutamine and 4.0 pg/ kg/ min of dopexamine were analysed and are shown in Fig. 1. The figure is plotted to align equipotent doses of the two drugs so that dose-response curves can be compared. Both drugs produced significant, dose-related increases in cardiac index from almost identical mean baseline values of 1.7 + 0.5 and 1.8 + 0.5 1. mm’ . m-’ in the dopexamine and dobutamine groups, respectively. The responses to equipotent doses did not differ throughout the dose ranges tested. The increases in cardiac output were achieved through similar increases in heart rate and stroke volume with both treatments. The increases in stroke volume were partly due to the vasodilator effects of both drugs, as shown by the decreases in systemic and pulmonary vascular resistances. These changes occurred in the absence of any significant effect on right and left heart filling pressures. There was no significant difference between the responses to equipotent doses of the two drugs in any of the haemodynamic variables described in Fig. 1. Significant differences between the two drugs at higher infusion rates became apparent when we analysed the ability of the heart to perform work
205 0 Dobutamme A Dopexamme
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Fig. 1. Response to incremental doses of dopexamine and dobutamine of cardiac index, heart rate, stroke volume index (SVI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), left ventricular (PAW, pulmonary artery wedge) and right ventricular (RA, right atrial) filling pressures. * P < 0.05. * * P < 0.01for each dose relative to baseline.
per beat (left ventricular stroke work index) and work per unit time (cardiac power output) (Fig. 2). Both drugs produced significant, dose-related increases in each variable, but these cardiac work outputs reached significantly higher maximal values with dobutamine. These differences occurred despite the lack of differential chronotropic and vasodilator effects.
Discussion This study showed that in patients with severe congestive heart failure, dopexamine and dobutamine produced similar improvements in cardiac output via similar vasodilator and chronotropic effects, despite the fact that these drugs have different profiles of adrenergic and dopaminergic
206 350 Dobutamine A Dopexamine
“E
25-
** # **
Dobutamme (pg.kg ‘.min ”
Dopexamine (pg.kg ‘.mm ‘I
Fig. 2. Cardiac work output per beat (LVSWI, left ventricular stroke work index) and per second (cardiac power output) at incremental doses of dopexamine and dobutamine. *P < 0.05. * *P < 0.01 relative to baseline. # P < 0.05, # #P < 0.01 between dopexamine and dobutamine.
receptor activity. The relative potency of dobutamine and dopexamine in heart failure patients has so far not been determined. Our results showed that to produce similar haemodynamic responses (Fig. 1) the equipotent doses of dobutamine and dopexamine are in a ratio of approximately 5 : 1 in weight. It is worth noting that although the equipotency was based on cardiac output increments (vide supra), it was generally true for the other variables as well - heart rate, stroke volume and pulmonary and systemic vascular resistances (Fig. 1). Left ventricular filling pressure, representing preload, was unchanged by either drug, possibly owing to the severity of pump failure in these patients. Similar observations have been made previously in this class of patients [5,6].
The fact that the filling pressures were virtually identical at the higher doses, and that both drugs produced similar reductions in systemic vascular resistance, allow us to infer that the higher left ventricular stroke work index produced by dobutamine was the result of the stronger positive inotropic stimulation by this agent. Whether this generalization can be extended to individual patients requires closer scrutiny, since the mean results do not represent the response of every patient. Four patients, three of whom had acute heart failure following myocardial infarction, followed the pattern of mean responses. Four other patients, one of whom had failure following acute myocardial infarction, showed less of a clear positive inotropic response to higher doses of dobutamine. The remaining patient, who had heart failure secondary to acute myocardial infarction, showed a greater positive inotropic response to dopexamine. These observations could not be attributed to the order in which the drugs were given. The extent of vasodilator and chronotropic effects observed in this study is consistent with the known mechanisms of action of these drugs. Dopexamine caused vasodilatation by stimulating vascular &-adrenergic and DA,-dopaminergic receptors [1,2], whereas dobutamine affects vessel tone via the combined agonistic action on vascular &- and a-adrenoceptors [7]. The chronotropic effects of dopexamine are exerted via direct &adrenergic stimulation and reflex tachycardia secondary to the vasodilatation induced, whereas that of dobutamine is via &, &- and a-adrenergic stimulation. &-Adrenergic stimulation as a mechanism of positive inotropism is an attractive theory to account for dopexamine’s positive inotropic effect [8] given the well-known &-adrenoceptor downregulation in heart failure [9]. In vitro work on isolated human cardiac muscle tissue has shown, however, that the contractile response to &adrenergic stimulation by dopexamine is lessened in proportion to the severity of heart failure [lo] presumably due to &adrenoceptor uncoupling [ll], so it appears that uptake-l inhibition may assume increasing importance in patients such as those in our study. Further in vitro work has
207
suggested that the contractile response to dopexamine is reduced by 60% or more in tissue from transplanted hearts, which are denervated and in which uptake-l inhibition would have no effect [12]. Thus, the &-adrenergic agonist activity of dopexamine may be enhanced, especially in the light of increased neuronal noradrenaline reuptake in heart failure patients [13]. Notwithstanding the variable myocardial noradrenaline concentrations in heart failure patients [14] the cardiac noradrenaline spillover rate at rest is still significant and markedly higher in heart failure patients than in normals [15]. There are several possible reasons for the limited positive inotropic effect at higher doses of dopexamine. The study was performed at rest, in which state the rate of neuronal noradrenaline release is much lower than during stress [16]. At higher doses of dopexamine the increased DA,dopaminergic stimulation of presynaptic receptors may inhibit noradrenaline release from nerve terminals [17,18]. Increased noradrenaline levels arising from uptake-l inhibition would act on the inhibitory, presynaptic a,-adrenoceptors, thus further limiting noradrenaline release [19]. The difference in duration of infusions is unlikely to have been a factor, since tolerance would not be expected to develop within the 2 hours of dopexamine infusions [20,2]. The two drugs produced similar increments in cardiac output despite the difference in inotropic effect. The clinical relevance of these different drug properties depends on the therapeutic goal. Pure vasodilators redistribute blood flow such that preferential vasodilatation of the skeletal muscular and cutaneous vasculature tends to compromise blood pressure and perfusion to the more vital organs, e.g. the kidney. Thus, increasing cardiac output at the expense of perfusion pressure is not therapeutically beneficial. There are two ways of circumventing this problem. First, if the agent has positive inotropic activity in addition to vasodilatation, hypotension and hypoperfusion can be prevented. However, the use of potent inotropes (e.g. dobutamine) as first-line therapy should be tempered by the likely increased risk of arrhythmia, higher metabolic cost to the failing heart, and potential cardiotoxic effects of such agents [22-251.
The alternative is to use a vasodilator which does not compromise the perfusion pressure and which increases the proportion of blood flow into the renal vasculature. Stimulation of dopaminergic receptors to dilate the preglomerular vessels [26] would appear to be a preferable mode of treating renal hypoperfusion. Dopamine has been widely used in patients with oliguria unresponsive to potent diuretics. However, it tends to produce marked vasoconstriction at higher doses and it must be infused via a central vein to avoid painful thrombophlebitis. Dopexamine, on the other hand, can be infused via a large peripheral vein and, with its demonstrable ability to increase regional blood flow to the liver and kidneys and to expedite fluid and sodium excretion [27,30] it may be the more suitable drug for treating such patients. Its mild positive inotropic effect acts as a safeguard against the likely falls in perfusion pressure secondary to the vasodilatation. Potent positive inotropic agents such as dobutamine could be added when dopexamine alone appears to be ineffective. The concurrent use of dopexamine and dobutamine should be undertaken with careful monitoring of systemic arterial pressure. Whether the chronotropic, inotropic and vasodilator effects of these two agents are additive needs to be elucidated. In conclusion, this study has demonstrated that in patients with severe congestive heart failure dopexamine exerts similar chronotropic and vasodilator effects in equipotent doses as dobutamine. In general, it has less positive inotropic effect than dobutamine but, in about half of these patients, its positive inotropic effect was comparable with that of dobutamine. It would appear that dopexamine is a useful addition to the agents used in the acute treatment of patients with severe congestive heart failure, especially in those ‘with severe vasoconstriction. Acknowledgements We are grateful to Mrs. Elsie Gale and her team of technicians for their expert assistance, and to Mr. Barry Read and Dr. Richard Foulds of Fisons plc for supplying the dopexamine.
208
References 1 Brown 2
3
4
5
6
RA,. Dixon J, Farmer JB, et al. Dopexamine: a novel agonist at peripheral dopamine receptors and & adrenoceptors. Br J Pharmac 1985;85:599-608. Brown RA, Farmer JB, Hall JC, Humphries RG, O’Connor SE, Smith GW. The effects of dopexamine on the cardiovascular system of the dog. Br J Pharmac 1985;85:609-619. Bass AS, Kohli JD, Lubbers N, Goldberg LI. Mechanisms mediating the positive inotropic and chronotropic effects induced by dopexamine in the anesthetized dog. J Pharmacol Exp Ther 1987;242:940-944. Smith GW, Hall JC, Farmer JB, Simpson WT. The cardiovascu& actions of dopexamine hydrochloride, an agonist at dopamine receptors and &-adrenoceptors in the dog. J Pharm Pharmacol1987;39:636-641. Francis GS, Sharma B, Hodges M. Comparative effects of dopamine and dobutamine in patients with acute cardiogenie circulatory collapse. Am Heart J 1982;103:995-1000. Richard C, Ricome JL, Rimailho A, Bottineau G, Auzepy P. Combined hemodynamic effects of dopamine and dobutamine in cardiogenic shock. Circulation 1983;67:
620-626. 7 Leier ‘CV, Uhverferth DV. Dobutamine. Diagnosis and treatment. Drugs five years later. Ann Intern Med 1983;99:490-496. 8 Lang AM, Borow KM, Neumann A, et al. Role of the beta, adrenoceptor in mediating positive inotropic activity in the failing heart and its relation to the hemodynamic actions of ‘dopexamine hydrochloride. Am J Cardiol 1988;62:46C-52C. 9 Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR. Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation 1986;74:1290-1302. 10 Behm M, Pieske B, Schnabel P, et al. Reduced effects of dopexamine on force of contraction in the failing human heart despite preserved &-adrenoceptor population. J Cardiovasc Pharmacol 1989;14:549-559. MR, Hershberger RE, Port JD, Minobe W, 11 Bristow Rasmussen R. &- and &-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol 1989;35: 295-303. 13 Port JD, Gilbert EM, Larrabee P, et al. Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart. Circulation 1990;81:929-938. 13 Clemson B, Davis D, Baily R, DeiIing S, Strzelecka D, Zelis R. Norepinephrine ‘Clearance in heart failure is low despite abnormal neuronal uptake. Circulation 1988;78(suppl II):106. 14Xerpont GL, Francis GS, DeMaster EG, et al. Heterogeneous myocardial catecholamine concentrations in patients with congestive heart failure. Am J Cardiol 1987;60:316321.
15 Hasking GJ, Esler MD, Jennings GL, Dewar E, Lambert G. Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects. Circulation 1988;78:516-521. 16 Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Komer PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986;73:615-621. 17 Goldberg LI, Rajfer SI. Dopamine receptors: applications in clinical cardiology. Circulation 1985;72:245-248. 18 Mercuro G, Gessa G, Rivano CA, Lai L, Cherchi A. Evidence for a dopaminergic control of sympathoadrenal catecholamine release. Am J Cardiol 1988;62:827-828. 19 Langer SZ, Presynaptic regulation of the release of catecholamines. Pharmacol Rev 1981;32:133-151. 20 Gollub SB, Emmot WW, Johnson DE, et al. Hemodynamic effects of dopexamine hydrochloride infusions of 48 to 72 hours’ duration for severe congestive heart failure. Am J Cardiol 1988;62:83C-88C. 21 Murphy JJ, Hampton JR. Failure of dopexamine to maintain haemodynamic improvement in patients with chronic heart failure. Br Heart J 1988;60:45-49. 22 Grose R, Strain J, Greenberg M, LeJemtel TH. Systemic and coronary effects of intravenous milrinone and dobutamine in congestive heart failure. J Am Co11 Cardiol 1986;7:1107-1113. 23 Packer M, Leier CV. Survival in congestive heart failure during treatment in drugs with positive inotropic actions. Circulation 1987;75(suppl IV):55-63. 24 Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol 1985;17:291-306. 25 Gavras H, Kremer D, Brown JJ, et al. Angiotensinand norepinephrine-induced myocardial lesions: experimental and clinical studies in rabbits and man. Am Heart J 1975;89:321-332. LI. Comparative systemic and re26 Robie NW, Goldberg gional hemodynamic effects of dopamine and dobutamine. Am Heart J 1975$X):340-345. 27 Baumann G, Felix SB, Filcek SAL. Usefulness of dopexamine hydrochloride versus dobutamine in chronic congestive heart failure and effects on hemodynamics and urine output. Am J Cardiol 1990;65:748-754. J, Randolph PH, Un28 Leier CV, Binkley PF, Carpenter verferth DV. Cardiovascular pharmacology of dopexamine in low output congestive heart failure. Am J Cardiol 1988;62:94-99. 29 Magrini F, Foulds R, Roberts N, Mac&i G, Mondadori C, Zanchetti A. Human renovascular effects of dopexamine hydrochloride. A novel agonist of peripheral dopamine and beta,-adrenoreceptors. Eur J Clin Pharmacol 1987;32:1-4. 30 Tan LB. Smith SA, Murray RG, Littler WA. Renal response to dopexamine infusion in low output heart failure. Br Heart J 1987;57:81.
CARD10
203 0167-5273/91/$03.50
01190
Comparison of the haemodynamic effects of dopexamine and dobutamine in patients with severe congestive heart failure Lip-Bun Tan, William A. Littler and R. Gordon Murray Department
of Cardiology, (Received
Tan L-B, dobutamine
University of Birmingham, 20 March
1989; revision
East Birmingham Hospital, Birmingham, accepted
12 September
UK.
1990)
Littler WA, Murray RG. Comparison of the haemodynamic effects of dopexamine in patients with severe congestive heart failure. Int J Cardiol 1991;30:203-208.
and
Dopexamine hydrochloride is a novel compound with properties of DA, dopaminergic and &-adrenergic receptor agonism and neuronal noradrenaline uptake inhibition. It has been shown to produce beneficial renal and haemodynamic effects in patients with severe heart failure. We compared the haemodynamic effects of dopexamine (0.5 to 6 pg/kg/min) with those of dobutamine (5 to 25 pg/kg/min) in 9 patients with severe congestive heart failure. The two drugs were similar in their effects at peak infusion rates: heart rate increased (dopexamine 87 f 17 to 100 f 14; dobutamine 91 f 18 to 103 f 17 min- ‘), cardiac index increased (dopexamine 1.7 f 0.5 to 2.8 f 1.1; dobutamine 1.8 f 0.5 to 3.0 f 1.1 1 min-’ m-*) and systemic vascuhu resistance decreased (dopexamine 1553 f 221 to 1117 f 435 dobutamine 1721 f 347 to 1280 f 433 dyne s cm-‘). Neither drug affected pulmonary artery wedge pressure (dopexamine 24 f 6 to 22 f 6; dobutamine 25 f 9 to 24 f 10 mm Hg). Dopexamine had significantly lower peak effects on left ventricular stroke work index (dopexamine 20 f 9, dobutamine 27 f 15 g - m m-*, P < 0.05) and cardiac power output (dopexamine 0.71 f 0.36, dobutamine 0.93 f 0.46 W, P c 0.05). These haemodynamic effects, due largely to vasodilatation but with some contributory positive inotropy, indicate that dopexamine will be useful in the acute treatment of congestive heart failure. l
l
l
l
l
Key words:
Inotrope;
Vasodilator;
Heart
failure
Introduction Dopexamine is a dopaminergic drug producing renal vasodilatation via DA,-dopaminergic agonist activity and systemic vasodilatation via &-adren-
Correspondence to: Dr. L.B. Tan, Dept. of Cardiology, Killingbeck Hospital, Leeds LS14 6UH, U.K. This study was supported in part by a grant from the British Heart Foundation.
ergic agonism [1,2]. Unlike dopamine, it has no cY-adrenergic activity and it has less agonist activity at DA ,-dopaminergic (emesis-inducing) receptors [2]. Direct activity at the Pi-adrenoceptor is minimal but these receptors are stimulated indirectly via inhibition of uptake-l [3] and baroreflex activity [4]. We studied the central haemodynamic effects of dopexamine in patients with severe heart failure and compared its vasodilator, chronotropic and inotropic effects with those of dobutamine, a widely used positive inotropic agent.
204
Methods Patients
We studied 9 patients (7 males, 2 females; mean age 63.2 + 6.8 (SD) years). AU had severe cardiac failure due to ischaemic heart disease (post-myocardial infarction in 5 patients and exacerbation of chronic heart failure in the rest). Baseline cardiac index was 1.66 f 0.16 1. mm’ * m -2, with pulmonary wedge pressure of 23.6 f 2.1 mm Hg. All patients gave informed consent to participation in the study, which was approved by the Ethical Committee of East Birmingham Hospital.
study, nor fi-adrenoceptor of entry.
antagonists within 48 h
Data analysis
Cardiac index, left ventricular stroke work index and pulmonary and systemic vascular resistances were calculated according to standard formulae. We also calculated cardiac power output (W) as (mean arterial pressure-right atria1 pressure) x cardiac output x 2.217 x 10P3. Clinically equipotent doses of the two drugs were regarded as those producing the same increments of cardiac output. Statistical analysis was by Student’s paired t-test with Bonferroni adjustments. Differences were taken to be significant at P < 0.05. Results are expressed as means f SEM.
Methods Results
The following haemodynamic variables were measured using thermodilution Swan-Ganz catheters, arterial cannulae and electrocardiogram: heart rate (mm’), right atria1 pressure (mm Hg), pulmonary arterial pressure (mm Hg), pulmonary artery wedge pressure (mm Hg), systemic mean arterial pressure (mm Hg) and cardiac output (1. mm’, measured in triplicate). Control haemodynamic data were obtained at least 20 min after insertion of the catheters and when two readings taken 15 min apart differed by less than 15%. The patients were randomly assigned to receive first either dopexamine (5 patients) or dobutamine (4 patients). Dobutamine was given via a central venous line, commencing at 5 pg/ kg/ min and increasing at 5-10 min intervals to a maximum of 25 pg/kg/min. Dopexamine was infused at rates of 0.5, 1.0, 2.0, 4.0 and 6.0 pg/kg/min, each dose being given for 20 min. Maximum doses in each patient were determined by the absence of a further rise in cardiac power output. The durations of infusion were adopted because in preliminary studies the haemodynamic responses in such patients reached a plateau within these times. Haemodynamics were allowed to return to baseline levels between the drug infusions. No food or drink (except sips of water) was given during the ) study. No diuretics, other vasodilators or inotropic agents were given within 4 h prior to entry to the
Since not all patients received the highest doses of the two drugs, haemodynamic responses up to 20 pg/kg/min of dobutamine and 4.0 pg/ kg/ min of dopexamine were analysed and are shown in Fig. 1. The figure is plotted to align equipotent doses of the two drugs so that dose-response curves can be compared. Both drugs produced significant, dose-related increases in cardiac index from almost identical mean baseline values of 1.7 + 0.5 and 1.8 + 0.5 1. mm’ . m-’ in the dopexamine and dobutamine groups, respectively. The responses to equipotent doses did not differ throughout the dose ranges tested. The increases in cardiac output were achieved through similar increases in heart rate and stroke volume with both treatments. The increases in stroke volume were partly due to the vasodilator effects of both drugs, as shown by the decreases in systemic and pulmonary vascular resistances. These changes occurred in the absence of any significant effect on right and left heart filling pressures. There was no significant difference between the responses to equipotent doses of the two drugs in any of the haemodynamic variables described in Fig. 1. Significant differences between the two drugs at higher infusion rates became apparent when we analysed the ability of the heart to perform work
205 0 Dobutamme A Dopexamme
P
P
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Fig. 1. Response to incremental doses of dopexamine and dobutamine of cardiac index, heart rate, stroke volume index (SVI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), left ventricular (PAW, pulmonary artery wedge) and right ventricular (RA, right atrial) filling pressures. * P < 0.05. * * P < 0.01for each dose relative to baseline.
per beat (left ventricular stroke work index) and work per unit time (cardiac power output) (Fig. 2). Both drugs produced significant, dose-related increases in each variable, but these cardiac work outputs reached significantly higher maximal values with dobutamine. These differences occurred despite the lack of differential chronotropic and vasodilator effects.
Discussion This study showed that in patients with severe congestive heart failure, dopexamine and dobutamine produced similar improvements in cardiac output via similar vasodilator and chronotropic effects, despite the fact that these drugs have different profiles of adrenergic and dopaminergic
206 350 Dobutamine A Dopexamine
“E
25-
** # **
Dobutamme (pg.kg ‘.min ”
Dopexamine (pg.kg ‘.mm ‘I
Fig. 2. Cardiac work output per beat (LVSWI, left ventricular stroke work index) and per second (cardiac power output) at incremental doses of dopexamine and dobutamine. *P < 0.05. * *P < 0.01 relative to baseline. # P < 0.05, # #P < 0.01 between dopexamine and dobutamine.
receptor activity. The relative potency of dobutamine and dopexamine in heart failure patients has so far not been determined. Our results showed that to produce similar haemodynamic responses (Fig. 1) the equipotent doses of dobutamine and dopexamine are in a ratio of approximately 5 : 1 in weight. It is worth noting that although the equipotency was based on cardiac output increments (vide supra), it was generally true for the other variables as well - heart rate, stroke volume and pulmonary and systemic vascular resistances (Fig. 1). Left ventricular filling pressure, representing preload, was unchanged by either drug, possibly owing to the severity of pump failure in these patients. Similar observations have been made previously in this class of patients [5,6].
The fact that the filling pressures were virtually identical at the higher doses, and that both drugs produced similar reductions in systemic vascular resistance, allow us to infer that the higher left ventricular stroke work index produced by dobutamine was the result of the stronger positive inotropic stimulation by this agent. Whether this generalization can be extended to individual patients requires closer scrutiny, since the mean results do not represent the response of every patient. Four patients, three of whom had acute heart failure following myocardial infarction, followed the pattern of mean responses. Four other patients, one of whom had failure following acute myocardial infarction, showed less of a clear positive inotropic response to higher doses of dobutamine. The remaining patient, who had heart failure secondary to acute myocardial infarction, showed a greater positive inotropic response to dopexamine. These observations could not be attributed to the order in which the drugs were given. The extent of vasodilator and chronotropic effects observed in this study is consistent with the known mechanisms of action of these drugs. Dopexamine caused vasodilatation by stimulating vascular &-adrenergic and DA,-dopaminergic receptors [1,2], whereas dobutamine affects vessel tone via the combined agonistic action on vascular &- and a-adrenoceptors [7]. The chronotropic effects of dopexamine are exerted via direct &adrenergic stimulation and reflex tachycardia secondary to the vasodilatation induced, whereas that of dobutamine is via &, &- and a-adrenergic stimulation. &-Adrenergic stimulation as a mechanism of positive inotropism is an attractive theory to account for dopexamine’s positive inotropic effect [8] given the well-known &-adrenoceptor downregulation in heart failure [9]. In vitro work on isolated human cardiac muscle tissue has shown, however, that the contractile response to &adrenergic stimulation by dopexamine is lessened in proportion to the severity of heart failure [lo] presumably due to &adrenoceptor uncoupling [ll], so it appears that uptake-l inhibition may assume increasing importance in patients such as those in our study. Further in vitro work has
207
suggested that the contractile response to dopexamine is reduced by 60% or more in tissue from transplanted hearts, which are denervated and in which uptake-l inhibition would have no effect [12]. Thus, the &-adrenergic agonist activity of dopexamine may be enhanced, especially in the light of increased neuronal noradrenaline reuptake in heart failure patients [13]. Notwithstanding the variable myocardial noradrenaline concentrations in heart failure patients [14] the cardiac noradrenaline spillover rate at rest is still significant and markedly higher in heart failure patients than in normals [15]. There are several possible reasons for the limited positive inotropic effect at higher doses of dopexamine. The study was performed at rest, in which state the rate of neuronal noradrenaline release is much lower than during stress [16]. At higher doses of dopexamine the increased DA,dopaminergic stimulation of presynaptic receptors may inhibit noradrenaline release from nerve terminals [17,18]. Increased noradrenaline levels arising from uptake-l inhibition would act on the inhibitory, presynaptic a,-adrenoceptors, thus further limiting noradrenaline release [19]. The difference in duration of infusions is unlikely to have been a factor, since tolerance would not be expected to develop within the 2 hours of dopexamine infusions [20,2]. The two drugs produced similar increments in cardiac output despite the difference in inotropic effect. The clinical relevance of these different drug properties depends on the therapeutic goal. Pure vasodilators redistribute blood flow such that preferential vasodilatation of the skeletal muscular and cutaneous vasculature tends to compromise blood pressure and perfusion to the more vital organs, e.g. the kidney. Thus, increasing cardiac output at the expense of perfusion pressure is not therapeutically beneficial. There are two ways of circumventing this problem. First, if the agent has positive inotropic activity in addition to vasodilatation, hypotension and hypoperfusion can be prevented. However, the use of potent inotropes (e.g. dobutamine) as first-line therapy should be tempered by the likely increased risk of arrhythmia, higher metabolic cost to the failing heart, and potential cardiotoxic effects of such agents [22-251.
The alternative is to use a vasodilator which does not compromise the perfusion pressure and which increases the proportion of blood flow into the renal vasculature. Stimulation of dopaminergic receptors to dilate the preglomerular vessels [26] would appear to be a preferable mode of treating renal hypoperfusion. Dopamine has been widely used in patients with oliguria unresponsive to potent diuretics. However, it tends to produce marked vasoconstriction at higher doses and it must be infused via a central vein to avoid painful thrombophlebitis. Dopexamine, on the other hand, can be infused via a large peripheral vein and, with its demonstrable ability to increase regional blood flow to the liver and kidneys and to expedite fluid and sodium excretion [27,30] it may be the more suitable drug for treating such patients. Its mild positive inotropic effect acts as a safeguard against the likely falls in perfusion pressure secondary to the vasodilatation. Potent positive inotropic agents such as dobutamine could be added when dopexamine alone appears to be ineffective. The concurrent use of dopexamine and dobutamine should be undertaken with careful monitoring of systemic arterial pressure. Whether the chronotropic, inotropic and vasodilator effects of these two agents are additive needs to be elucidated. In conclusion, this study has demonstrated that in patients with severe congestive heart failure dopexamine exerts similar chronotropic and vasodilator effects in equipotent doses as dobutamine. In general, it has less positive inotropic effect than dobutamine but, in about half of these patients, its positive inotropic effect was comparable with that of dobutamine. It would appear that dopexamine is a useful addition to the agents used in the acute treatment of patients with severe congestive heart failure, especially in those ‘with severe vasoconstriction. Acknowledgements We are grateful to Mrs. Elsie Gale and her team of technicians for their expert assistance, and to Mr. Barry Read and Dr. Richard Foulds of Fisons plc for supplying the dopexamine.
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