REVIEW ARTICLE
Dopexamine Hydrochloride: Pharmacology and Use in Low Cardiac Output States Sunit Ghosh, FFARCS, Beverley Gray, FFARCS, Amo Oduro, FFARCS, and Raymond D. Latimer, FFARCS
T
HE TERM “INOTROPE” is broadly used to describe agents that enhance cardiac performance, although the mechanism by which some of these drugs improve myocardial function may be attributable less to their effect on myocardial contractility than to the other hemodynamic changes that are associated with their use. In the treatment of cardiac failure, agents with pharmacodynamic profiles that combine relatively mild direct effects on the myocardium with those resulting from a relatively greater effect on preload and afterload offer potential benefits from the standpoint of myocardial energy use. This is of prime concern in both the acutely or chronically ischemic heart and following cardiopulmonary bypass (CPB) when cardiac failure can, on occasion, be ascribed more to unavailability of energy reserves than to persisting ischemia. Dopexamine hydrochloride, a synthetic analog of dopamine, is characterized by just such a profile of action and may offer a favorable alternative to the more established therapeutic regimens of dopamine and dobutamine. The pharmacology of dopexamine and its use in the treatment of chronic or postoperative cardiac failure is reviewed here.
Thus, the chronotropic and inotropic effects of dopexamine (Fig 2) may be mediated through three separate mechanisms: indirect cardiac p,-receptor stimulation through the baroreceptor reflex response to a decrease in blood pressure,8 direct stimulation of cardiac 8,-adrenoreceptors,‘a2a5 and potentiation of neurally released norepinephrine at cardiac &-receptors by the inhibition of uptake 1.3.h-H The decrease in systemic vascular resistance (SVR) associated with the use of dopexamine appears predominantly to be mediated by &-adrenoreceptor stimulation and to a lesser degree by stimulation of vascular DA,- and DA2receptors.‘,* Studies of the peripheral vascular effects of dopexamine during CPB indicate that the drug has no influence on venous capacitance vessels and that its vasodilator effect is confined to the arterial side of the vascular bed.’ The relative contribution of each of the mechanisms described above to the overall hemodynamic effect is uncertain, but would probably vary in the clinical setting with the underlying pathophysiology and other therapeutic agents used. This may account for some of the conflicting results obtained in the studies outlined below.
PHARMACOLOGY
Dopexamine hydrochloride is a synthetic catecholamine designed to combine and enhance the desirable hemodynamic qualities of dopamine and dobutamine. Dopexamine, an N-substituted analog of dopamine, is structurally related to both of these drugs (Fig l), but differs from either in its pharmacological effects (Tables 1 and 2). Dopexamine is a potent &adrenoreceptor agonist’.’ with negligible direct B,-adrenergic activity,‘,3 no a-adrenergic effect,’ significant agonist activity at dopaminergic DA,-receptors,4.5 and minimal effect at DA,-receptors.’ In addition, dopexamine is a potent inhibitor of the reuptake of neurally released catecholamines into nerve terminals (uptake 1),3@sbut does not itself enter sympathetic nerve terminals by the uptake 1 process. Thus, dopexamine has no “tyramine-like” effect in displacing endogenous norepinephrine at these sites? and the indirect sympathomimetic effects of dopexamine result solely from inhibition of uptake 1.
From the Department of Anaesthesia, Papworth Hospital, Cambridge, England. Address reprint requests to Raymond D. Latimer, FFARCS, Department of Anaesthesia, Papworth Hospital, Papworth, Cambridge CB3 8RE, England. Copyright B 1991 by W.B. Saunders Company 1053-0770/91/0504-0016$03.00/0
382
Pharrnacokinetics
There are limited data available on the pharmacokinetic properties of dopexamine. Dopexamine is inactive orally and because of its short half-life is administered by intravenous (IV) infusion. In healthy volunteers, incremental increases in the rate of infusion result in proportionate increases in plasma concentration of the drug. On cessation of the infusion, plasma levels decline monoexponentially with a half-life of 6 to 7 minutes and a clearance rate of 36 mL/min/kg.‘” Clearance is by uptake into tissues, with dopexamine competing as a substrate for extraneuronal catecholamine uptake mechanisms (uptake 2) and in the liver where extensive metabolism occurs.” In patients with heart failure, clearance is marginally slower (28 mL/min/kg) and the half-life is prolonged to 11 minutes”; however, in postcardiac surgical patients clearance of dopexamine has been found to decrease to 17 mL/minikg, less than half the value quoted for healthy subjects, although the half-life remains unchanged.13 Such variations in clearance rate should not affect the establishment of an effective dosage regimen in clinical practice because the dose is titrated to effect. Metabolism of dopexamine is by methylation and sulphation of the catechol hydroxyl groups by the established pathways for catecholamine degradation.14 Excretion oc-
Journal of Cardiothoracic and Vascular Anesthesia, Vol5, No 4 (August), 1991: pp 382-389
DOPEXAMINE
HYDROCHLORIDE:
PHARMACOLOGY
383
AND USE
Table 1. Relative Potencies of Pharmacological Effects of Dopsxamine
CHZ-CH2-NH2
ReceptorAgonism
DOPAMINE
DA,
0.34
DA, a
0
0.17 0.16
PI
60
P2 Uptake 1 blockade
10 0
Tyramine-like effect
DOBUTAMINE
NOTE. Relative potency of dopamine = 1.
CH2-CH2-NH-(CH2)6-NH-CH2-CH2
In Chronic Cardiac Failure
DOPEXAMINE Fig 1.
Structures of dopamine, dobutamine, and dopexamine.
curs largely as metabolites in the urine and, to a much lesser extent, the feces.‘” The pharmacological activity of the metabolites, in particular the methoxy metabolite, has yet to be fully ascertained. HEMODYNAMIC
STUDIES
In the Nonfailing Heart
In healthy human volunteers, infusion of dopexamine at 1 to 8 &kg/min results in dose-related increases in heart rate (HR), cardiac output (CO), and pulse pressure, but with minimal change in mean arterial pressure (MAP).” In mildly to moderately hypertensive patients, similar increases in HR and CO occur in the absence of a significant change in SVR; thus, MAP increases.16 In contrast to these findings, dopexamine infusion (1 to 4 &kg/min) in anesthetized patients with ischemic heart disease increases CO, but there is a significant decrease in MAP and a dose-related tachycardia.” In the same study, dopamine (2.5 and 5 pg/kg/min) was noted to increase CO primarily by its effect on stroke volume, whereas the increase in CO produced by dopexamine appeared to be related to changes in HR and SVR as well as a nondose-related effect on stroke volume (Fig 3).” A study comparing the hemodynamic effects of dopexamine (2 &kg/min) with and without a controlled HR using atria1 pacing in patients undergoing diagnostic cardiac catheterization for suspected coronary artery disease concluded that dopexamine did produce HR-independent increases in cardiac index (CI) and in left ventricular (LV) contractility and relaxation, although improvement in LV function secondary to a decrease in SVR could not be excluded.”
Much of the information available about the hemodynamic effects of dopexamine comes from studies in patients with chronic cardiac failure.‘9-3” It should be emphasized that the pathophysiological changes accompanying this disease state (increased circulating catecholamine levels, down-regulation of cardiac PI-receptors:’ and attenuation of the baroreceptor reflex response32,33) are such that differences in response to dopexamine among healthy volunteers, patients with acute cardiac failure, and those with chronically failing hearts are only to be expected in view of the pharmacology of the drug. In vitro studies bear this out: dopexamine has a less pronounced inotropic effect on ventricular myocardial strips from patients in NYHA class III and IV heart failure than on that from nonfailing hearts and no effect on that from NYHA class IV patients.” In patients with moderate to severe chronic cardiac failure, dopexamine produces dose-related reductions in SVR and pulmonary vascular resistance (PVR) and rightand left-sided filling pressures. HR, CI, stroke volume index (SVI), and LV dP/dt max all increase in a dose-related manner. Minimal changes ( < 10%) in MAP occur at doses of 2 &kg/min or less; at 4 &kg/min decreases of up to 15% have been observed. Dopexamine has also been shown to increase hepatic and splanchnic blood flow in this group of patients without significant alteration in limb blood flo~,~~.‘~suggesting preferential redistribution of blood to visceral circulations. Data from several studies of the hemodynamic effects of dopexamine in NYHA class II, III, and IV cardiac failure patients are summarized in Table 3; these have been selected to demonstrate the range of results obtained. Comparative studies of dopexamine and dobutamine in chronic cardiac failure at doses producing similar increases in CO (dopexamine, 2 to 4 kg/kgimin, and dobutamine, 5 to 10 @g/kg/min) show that dopexamine reduces SVR and PVR more markedly than dobutamine, but has a lesser
Table 2. Pharmacological Effects of Dopexamine,
Dopamine, and Dobutamine
Receptor DA, Dopexamine Dopamine Dobutamine
DA,
Pl
+t
+
+++
++
(+I ++
0
0
++t
u
P2
Uptake 1 Inhibition
Tyramine-like Effect
+++
0
(+) +t
+++
++
tt
+t
+
0
NOTE. 0, inactive; (+), inactive in clinical dose range; t, mild; + +, moderate; t+-t,
powerful.
tti
0
384
GHOSH ET AL
beneficial systemic vasodilatation coupled with improvcment in myocardial function (Table 4). From the limited data available, dopexamine appears to have similar cffccts in acute and chronic cardiac failure except that cardiac filling pressures and pulmonary artery pressure are notably unaffected in the acute situation.
“”
HR
SVR
SV
dP,‘dT’P
LONG-TERM
-60
L
134.3
13 43 1.34.3
13 43 1.34.3
13 43 1.342
dopexamine
13 43 I.343
13 43 1.342
13 43
Ikg/kg/minl
Fig 2. Hemodynsmic effects of dopexamine in anesthetized dogs (mean % change from baseline ‘_ standard error of mean). (Adapted with permission.‘)
positive effect on LV dP/dt max. Other than this, the two drugs appear to have similar hemodynamic effects.z”.z”.‘” In patients with moderate to severe cardiac failure, dopamine (2.5 to 10 &kg/min) and dopexamine (0.5 to 2.0 p&kg/min) produce similar changes in CO; dopexamine does so primarily by dose-related increases in HR and peripheral vasodilatation with mild inotropic effects, whereas dopamine reduces afterload at doses of 2.5 to 5 f@kg/min, increases HR only at higher doses, produces vasoconstriction only at the highest dose, and has a more marked inotropic effect at all doses.*‘~” Dopexamine and sodium nitroprusside have comparable effects on preload at a dose of each agent producing a 30% increase in CO in patients with chronic cardiac failure. However, nitroprusside produces a greater decrease in afterload, a markedly greater decrease in MAP, with a concomitantly greater tachycardia and less pronounced effect on stroke volume.27 In Acute Cardiac Failure
Studies in patients with acute exacerbations of chronic severe heart failure,” and in acute cardiac failure following myocardial infarction,” indicate that dopexamine produces
A
150 HR
PVR
MAP
Cl
SVR
*
SVI
AND TOLERANCE
Dysrhythmic Effects
As with dopamine and dobutamine, the use of dopexamine is associated with the development of tachycardia. In the majority of cases the increase is not of clinical significance, although myocardial ischemia in association with dopexamine infusion has been reported.““’ There is little evidence to suggest that the drug has a propensity to cause dysrhythmias. Dopexamine, unlike dopamine and other catecholamines, produces no atria1 or ventricular dysrhythmias in halothane-sensitized ratq4” and furthermore is associated with a significantly lower incidence of ventricular dysrhythmias following coronary artery ligation in animal models of myocardial ischemia than either dopamine or
B
100
_______-._.
150 HR
PVR
MAP
SVR
-
. SW
Cl
100 -
%
I
% 50
50 -
;
+*
+*
;
a
a
0
n 9 e
INFUSION
Most studies of prolonged dopexamine infusion, of up to 72 hours’ duration, in patients with stable chronic cardiac failure, have shown a progressive attenuation of the hemodynamic efficacy of the drug.“.‘7.2VAlthough in one study” the hemodynamic responses to dopexamine were maintained after 48 hours of infusion, this may have resulted from an improvement in baseline hemodynamic characteristics masking any drop-off in responsiveness. In patients with acute cardiac failure, a multicenter comparison of dopexamine and dobutamine noted a decline in the hemodynamic response to both drugs at a similar rate over a 24-hour infusion period.‘” However, tolerance was not observed to develop in a smaller, singlecenter study of 24-hour infusion of dopexamine at a much lower mean dose.” There appears to be wide intersubject variability in the degree of hemodynamic tolerance to prolonged dopexamine infusion, but the use of high-dose regimens is a determining factor in the rapidity and extent of the development of tolerance.
n
9 e
-50
-100
I ” 124
I
124
I L /
124
1I
dopexamine
I L
124
/ / I I ’ 124
(pg/kg/minl
124
/ I
I \ dL;;;Id
-50
-loo
2.5
+
+
5
dopamine
(pg/kg/min)
Fig 3. (A) Hemodynamic effects of dopexamine in anesthetized patients prior to CAB0 (mean % change from baseline). P < 0.05 at all doses compared with baseline; ?? P < 0.05 compered with 2 pglkglmin. (B) Hemodynamic effects of dopamine in anesthetized patients prior to CABG 2.5 pg/kg/min. (Adapted with parmission.‘7) (mean % change from baseline). P < 0.05 compared with + baseline, ??
DOPEXAMINE
HYDROCHLORIDE:
PHARMACOLOGY
385
AND USE
Table 3. Hemodynamic Effects of Dopexamine
in Chronic Cardiac Failure Mean % ChangeFrom Baseline
Dose
Reference 20
24
25 26
27
28
No. of Patients IO (NYHA Ill)
9 (NYHA Ill-IV)
9 (NYHA Ill-IV) 8 (NYHA Ill-IV)
9 (NYHA Ill-IV)
8 (NYHA Ill-IV)
(Fglkgiminl
30
23
12 (NYHA ll-lll)
12 (NYHA ll-lll)
33 (NYHA Ill-IV)
0
1.0 f20
6.0
+33 0
1.0
+13
2.0
+20
4.0
+23
PCWP
PAP
RAP
Cl
SVR
PVR
SVI
0
0
-17
t45
-30
-15
t40
0
0
-33
+70
-42
-10
+50
0
0
~25
+120
-49
-25
+60
0
0
0
0
t26
-14
t13
0
0
t39
-27
+21
0
+56
-39
-8
0
0
0
0
0
2.0
0
0
0
0
0
0
0
0
1.0
+32 0
0 +32
-19
0
0
0
0
1.0
+11
0
t29
~16
2.0
+12
0
+49
-25
4.0
+14
0
t110
-50
1.0
t7
0
0
0
t14
-11
0
2.0
t9
0
0
0
t28
-15
0
4.0
+14
0
0
0
+44
-28
-20
+26
6.0
+18
0
0
0
+56
-34
-32
+32
0
0
0
+I8
-15
t15
0
0
0
t32
-27
+22
0
0.5 1.0
29
HR
3.0 0.5
MAP
t7 0
0.5 1.0
t5
2.0
+9
0.5
0
1.0
t13
2.0
t24
0
+a2
0
+5
t8
-6
0
+7
-7
-13
-12
+14
-7
0
t8
-14
-20
0
-15
+25
-12
0
-17
+12
-9
0
-19
t24
-21
-17
t37
-29
-3
-12
-17
-20
t30
-24
0 0
1.0
0
0 t32 0 0
0 t13 0 t9 t6
-19
t27
2.0
t6
-7
-21
-29
-36
t65
-41
-34
+52
3.0
+a
-9
-28
-40
-48
i87
-48
-39
t68
-9
-35
-48
-55
t95
-50
-43
t65
4.0
t15
NOTE. 0 = No significant change, P < 0.05. Abbreviations: HR, heart rate; MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; Cl, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; SVI, stroke volume index; NYHA, New York Heart Association class.
The lower dysrhythmogenic potential of dobutamine.a’ dopexamine may result from its relative lack of activity at &-receptors, which have been implicated in dysrhythmias induced by other catecholamines.42 It is also interesting to note that infusion of either dopexamine or dopamine prior to and during the period of coronary occlusion appears to suppress the development of ventricular dysrhythmias to a level below that observed in untreated controls. Dopexamine achieves this apparent stabilization of the ischemic myocardium to a greater extent than dopamine, and there is evidence from studies of isolated cardiac conducting tissue
to suggest that, under ischemic conditions, dopexamine has a class l-like antiarrhythmic effect.” Effects on Myocardial Metabolism
The data available on the effects of dopexamine on myocardial metabolism come mainly from measurements in patients with chronic cardiac failure. Infusion of dopexamine (1 to 6 &kdmin) for up to 1 hour in NYHA class III cardiac failure patients produced no significant alteration in myocardial oxygen consumption or coronary sinus blood
Table 4. Hemodynamic Effects of Dopexamine in Patients With Acute Cardiac Failure Mean % Change
DOW
Reference 21
No. of Patients
(pg/kg/min)
12 (post-MI)
0.5 1.0
38
IO (acute or chronic failure/post-Ml)
HR
0 t9
0.5
0
MAP
PAP
PCWP
From
Baseline
RAP
Cl
SVR
0
0
0
0
+15
-13
0
0
0
0
t32
-25
PVR 0
t12 t23
t4
0
0
0
0
t20
0
0
t55
-20
+23
0
0
t70
-30
t35
1.0
t5
t9
2.0
t15
t9
4.0
+17
0
+9
-18
SVI
0 0
0 t12
NOTE. 0 = No significant change from baseline, P < 0.05. Abbreviations: HR. heart rate: MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; Cl, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; SVI. stroke volume index; Ml, myocardial infarction.
386
flow despite a marked increase in LV work.“’ Dopexamine infusion (2 to 6 kg/kg/min) of 1 hour’s duration in NYHA class III and IV patients resulted in no significant alteration in transmyocardial lactate extraction despite increases in rate-pressure product and in arterial and coronary sinus lactate levels.“” The beneficial effects of dopexamine in reducing the preload and afterload presented to the failing heart may offset the metabolic demands imposed by its positive inotropic and chronotropic effects and, thus, may improve myocardial efficiency in patients with cardiac failure. In a randomized study comparing the effects of dopexamine and dobutamine on myocardial oxygen consumption, patients with normal LV function undergoing coronary angiography for disabling angina pectoris received dopexamine (1 and 2 &kg/min) or dobutamine (5 and 10 &kg/min).4” At these doses, CO and LV contractility were comparably increased, but myocardial oxygen consumption increased significantly by 25% in patients receiving dobutamine and by only 8% in the dopexamine group. Further investigations are required to provide an adequate explanation for this finding, which may be related to differences in the effect of the two agents on myocardial relaxation rate and, hence, on LV wall stress and coronary blood flo~.~~ Renal Effects
The renal effects of dopexamine are complex. Systemic or direct intrarenal arterial injection of dopexamine in dogs produces renal vasodilatation and reduction in renal vascular resistance (RVR); this is mediated by agonism at DA,-receptors, with a potency one third that of dopamine, and, in contrast to dopamine, also by stimulation of &-receptors. These changes appear to be selective in that the increases in renal blood flow (RBF) occur despite a decrease in blood pressure and an unchanged CO, implying that the decrease in RVR exceeds that in SVR. Further studies have shown that urinary water and electrolyte excretion are unaltered by 2 p@kg/min of dopexamine in anesthetized dogs despite an increase in glomerular filtration rate. It appears that at the tubular level dopexamine enhances water and electrolyte excretion by stimulation of DA,-receptors, but that these effects may be partially opposed by the agonistic effects of the drug at tubular 8,-receptors.47 Two studies in healthy volunteers have shown that dopexamine (1 to 4 kg/kg/min) reduces RVR and increases effective renal plasma flow (RPF) in a dose-related manner.“,“” Significant changes in effective RPF were produced by 2 to 4 pg/kglmin of dopexamine, whereas dopamine (2.5, 5, 10 &kg/min) produced a 3 times greater increase at all doses, and dobutamine (2.5, 5, 10 &kg/min) had no effect.4” These observations are in accordance with the relative pharmacological effects of the three agents at the DA,-receptor, although in the absence of CI and SVR measurements conclusions about the selectivity of this renal effect cannot be drawn. Conflicting results have been obtained in two investigations of the renovascular effects of dopexamine in which CI and RVR were concomitantly measured. In a group of
GHOSH ET AL
hypertensive patients undergoing diagnostic renal vein catheterization, infusion of 3 kgikgimin of dopexaminc increased RBF by a greater proportion than the associated increase in CI (20% v 13%); RVR decreased significantly whereas SVR remained unchanged,lh suggesting a selective renal effect. In contrast, in patients with ischemic heart disease anesthetized prior to cardiac surgery, infusion of dopexamine (1 to 4 &kg/min) produced greater increases in CI than in RBF (117% v 66% at 4 @kg/min); SVR decreased more than RVR at all doses studied,” implying that the renal effects of dopexamine may result purely from an increase in CI and generalized vasodilatation in response to &-receptor stimulation and not by selective stimulation of renal DA,-receptors. It should be kept in mind when comparing the results of these two studies that the patient populations are at different ends of the physiological spectrum with regard to underlying autonomic tone and reflex hemodynamic responses. Studies on the effects of short-term (2 to 3 hours) infusion of dopexamine on renal function in patients with moderate to severe chronic cardiac failure have not shown any significant effect of the drug on RVR, RBF, glomerular filtration rate, or diuresis except at doses below 1 &kg/ mitt, at which RVR is reduced and RBF does increase, but without alteration in the RBF-to-CO ratio.25.‘5 However, long-term infusion of 48 hours’ duration at a mean dose of 1.9 &kg/min in patients with severe chronic cardiac failure has been shown to result in significant diuresis with marked increase in creatinine clearance. Moreover, these changes were greater than those produced by dobutamine at a dose producing similar changes in CI.” Similarly, in 5 of 10 patients studied with acute cardiac failure, 4 &kgimin of dopexamine produced significant increases in diuresis, natriuresis, and creatinine clearance.“’ Work in progress in canine models of acute renal failure indicates that dopexamine may be of value in restoring renal function to control levels following hypovolemic or ischemic insult. The use of dopexamine as a renal protective agent in patients at risk of renal impairment has been evaluated in a comparative trial of dopexamine (1 to 3 t&kg/min) and dopamine (2 &kg/min) infused during orthotopic liver transplantation and continued for 48 hours postoperatively.‘” The two drugs had similar effects on postoperative urine output, but the incidences of renal impairment (defined as oliguria CO.5 ml/kg/h despite adequate preload) and renal failure (defined as need for extracorporeal renal support) were greater in the dopamine group. DOPEXAMINE
AND POSTOPERATIVE
LOW CO
A low CO state following cardiac surgery commonly occurs in association with a high SVR and a progressive metabolic acidosis resulting from poor tissue perfusion and the “oxygen debt” acquired during CPB. Myocardial excitability is enhanced with a tendency to dysrbythmias and there may be residual myocardial ischemia, as a result of inadequate revascularization, coronary vasospasm, or intracoronary embolism. In addition, metabolic “paralysis” at the myocardial cellular level from residual effects of the
DOPEXAMINE
HYDROCHLORIDE:
PHARMACOLOGY
387
AND USE
cardioplegia solution may further impair cardiac function. In the management of this situation, the ideal agent would offer positive inotropism, minimal increase in myocardial energy use, pulmonary and systemic vasodilatation of a magnitude offset by an increase in CO, (thus, without compromise of tissue perfusion), and selective increases in blood flow to those organs most susceptible to ischemic damage. Furthermore, enhancement of renal function would augment its effect on vascular resistance in optimizing preload and afterload. The pharmacological profile of dopexamine suggests that the drug should match some of these ideal characteristics. The currently available information on the use of dopexamine in the treatment of the low CO state following cardiac surgery is outlined subsequently. Hemodynamic Effects
Comparable hemodynamic changes have been observed in most studies of the effects of dopexamine following cardiac surgery and the results of three of these studies are summarized in Table 5. Short-term ( < 2 hours) infusion of dopexamine (1 to 10 &kg/min) following coronary artery bypass grafting (CABG) in patients with unimpaired LV function preoperatively and a mean CO of 3.5 L/min postoperatively has been shown to produce dose-related increases in CI, HR, systolic blood pressure, MAP, mean pulmonary artery pressure, and pulmonary capillary wedge pressure, decreases in SVR and PVR, and no change in right atria1 pressure.5’ Of a total of 20 patients, 3 failed to complete this study because of adverse effects (hypertension in 1 and atria1 fibrillation in 2). In a study of 14 patients (12 CABG and 2 valve replacement procedures) who preoperatively were predicted to require postoperative inotropic support, lo-minute infusions of dopexamine at each of four doses in the 1 to 6 Fg/kg/min range produced similar results to the previously mentioned study, except that there were less marked decreases in SVR and no significant changes in pulmonary arterial or wedge presTable 5. Hsmodynamic Effects
sure.” Adverse effects were noted in 3 patients (atria1 fibrillation in 1, tachycardia > 120 beats/min in 1, and hypotension in 1). In a study of 16 patients with a mean CI of 1.8 L/min/m2 following CABG, dopexamine was infused at 1 and 2 kg/kg/min for lo-minute periods in 9 patients and at 1, 2, and 4 p&kg/min in the other 7 patients postoperatively.“3 Significant increases in HR, CI, and in right ventricular ejection fraction were observed at doses of 2 ygikgimin or greater, PVR and SVR decreased, and mean systemic and pulmonary arterial pressures were unaffected. The improvement in right ventricular ejection fraction demonstrates the potential value of dopexamine in treating right ventricular failure after CABG. Dose titration of dopexamine in the range of 0.5 to 3 &kg/min in 7 patients following aortic valve replacement and 5 following mitral valve replacement with a mean CI of 2.58 L/min/m’ resulted in significant increase in CI and decrease in SVR.‘” HR increased in a dose-related fashion and there were no significant changes in systemic blood pressure or cardiac filling pressures. PVR increased significantly in patients who had mitral valve replacement, but decreased in those who had aortic valve replacement. Transient ventricular ectopic beats were observed in three patients during dopexamine infusion. Three trials of longer term infusion of dopexamine following CABG or valvular surgery have noted beneficial hemodynamic effects, which were sustained during the 18-, 36-, and 48-hour investigation periods of the three studies, respectively.54-56However, the changes in baseline hemodynamics that occur in the natural course of postoperative recovery may have influenced the outcome of these studies to some extent. Effects on Tissue @gen
of Dopexamine in Patients With Low Postoperative Cardiac Output Mean % ChangeFrom Baseline
Dose Reference 13
51
No. of Patients
bglkglmin)
HR
0.5
+5
12 (post-AVR, MVR)
17 (post-CABG)
16 (post-CABG)
MAP
PAP
0
PCWP
0
0
RAP
Cl
0
+15
SW
PVR
-8
SW
0
RVEF
+10
1.0
t27
0
0
0
t24
-14
0
0
2.0
t34
0
0
0
0
-24
0
0
3.0 1.0
+30
0
0
0
0
+31 t41
-27
0
0
f4 +20
0 0
0 +6
+14
-8
-16
+44
-24
-23
+a
+54
-32
-26
+I8
+57
-32
-22
+15
2.0
53
Delivery and Extraction
In a randomized study of 16 patients with unimpaired ventricular function undergoing elective CABG, infusion of 2 &kg/min of dopexamine commenced in the pre-CPB period. continued for 24 hours, and was associated with
4.0
+29
6.0
+3a
0 t6
t11
t17
0 +20
8.0
+45
+7
+16
+67
-34
-30
+16
10.0 1.0
+52
+10
+15
i-80
-36
-34
+18
t10
0
0
0
0
t22
-18
2.0
+18
0
0
0
0
+2a
-24
-10
0
+16
4.0
+13
0
0
0
0
t55
-32
-18
0
+17
0
0
+16
NOTE. 0 = No significant change, P < 0.05. Abbreviations: HR, heart rate; MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; Cl, cardiac index; SVR. systemic vascular resistance; PVR, pulmonary vascular resistance; SVI, stroke volume index; RvEF, ventricular ejection fraction; AVR, aortic valve replacement; MVR, mitral valve replacement; CABG, coronan/ artery bypass grafting.
right
388
GHOSH ET AL
significant increases in CI and oxygen delivery compared to a saline-treated control group. Tissue oxygen consumption increased significantly 4 hours postbypass in the dopexamine-treated group, and this increase occurred 14 hours earlier than in the control group. Serum lactate level increased significantly from baseline in both groups following CPB, but the earlier elevation in oxygen consumption in the dopexamine group was associated with a more rapid reduction in serum lactate.” Such improvements in tissue oxygen delivery and metabolism may be of benefit in higher risk patients.”
Renal Effects Two studies in patients with a low CO following cardiac surgery have failed to demonstrate that dopexamine has any effect on diuresis,‘“,‘” glomerular filtration rate, or the RBF-to-CO ratio.“’ CONCLUSION
Dopexamine is a “designer” agent with a pharmacological profile that has been tailored to meet many of the requirements for the optimal short-term treatment of cardiac failure. The drug exerts its effects by diverse mechanisms, but the pathophysiology of cardiac failure alters sympathetic tone, adrenergic receptor activity, and density and autonomic reflexes. These adjustments in the
“milieu intericur,” coupled with those imposed by the myriad other drugs and, in some circumstances, ancsthcsia that may have been concurrently used, result in modification of the overall effects of dopcxamine in distinct ways in acute, chronic, and postcardiotomy cardiac failure. The studies that are available indicate that the drug is a useful agent in improving ventricular performance in the acutely failing heart without clinically unacceptable increases in HR and myocardial work. The drug produces dose-related hemodynamic changes of rapid onset and reversibility and appears to have a low incidence of side effects. Moreover, it is free of the vasoconstrictive effects of dopamine, whereas its vasodilator effects are well balanced by its inotropic activity in maintaining tissue and organ perfusion. Quantitative data on the effects of dopexamine on myocardial oxygen balance and energy utilization in postcardiac surgical patients and on the distribution of myocardial blood flow, particularly in relation to coronary steal, are not yet available. Dopexamine, dopamine, and dobutamine are pharmacologically related, but the inodilator effects of dopexamine bear close resemblance to those of the phosphodiesterase inhibitors. Comparative studies are needed to determine whether the drug offers any benefit over the more cstablished therapeutic regimens, as well as over other novel agents in the treatment of postcardiotomy cardiac failure.
REFERENCES 1. Brown RA, Dixon J, Farmer JB, et al: Dopexamine: A novel
agonist at peripheral dopamine receptors and p,-adrenoreceptors. Br J Pharmacol85:599-608,1985 2. Smith GW, Hall JC: The cardiovascular pharmacology of dopexamine hydrochloride, in Beart PM, Woodruff GN, Jackson DM, (eds): Pharmacological and Functional Regulation of Dopaminergic Neurones. New York, NY, Macmillan, 1988, pp 312-314 3. Mitchell PD, Smith GW, Wells E, West PA: Inhibition of uptake-l by dopexamine hydrochloride (in vitro). Br J Pharmacol 92:265-270,1987 4. Brown RA, Farmer JB, Hall JC, et al: The effects of dopexamine on the cardiovascular system of the dog. Br J Pharmacol85:609-619, 1985 5. Smith GW, Hall JC, Farmer JB, Simpson WT: The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and B,-adrenoreceptors in the dog. J Pharm Pharmacol 39:636-641, 1987 6. Smith GW, Naya I: Inhibition of uptake 1 in the dog by dopexamine hydrochloride. Br J Pharmacol92:265-207,1987 7. Nedergard OA: Inhibition of tritiated noradrenaline accumulation by dopexamine hydrochloride in the isolated aorta of the rabbit. Naunyn Schmiedebergs Arch Pharmacol340:270-273, 1989 8. Bass AS, Kholi JD, Lubbers N, Goldberg LI: Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetised dog. J Pharmacol Exp Ther 242:940-944, 1987 9. Siemons AW, Van der Starre PJ: Peripheral vascular effects of dopexamine hydrochloride during cardiopulmonary bypass. J Cardiothorac Anesth 3:14, 1989 (suppl 1) 10. Neale MG, Baker P, Brown K et al: Pharmacokinetics and metabolism of dopexamine in man. Acta Pharmacol Toxic01 59:69, 1986 Il. Gray PA, Bodenham AR, Park GR: The pharmacokinetics of dopexamine hydrochloride in patients undergoing orthotopic liver transplantation. Intens Care Med 16:A143,1990
12. Fisons PLC: Dopacard product monograph, Loughborough, Leicestershire, England, 1990, p 41 13. Hakim M, Foulds R, Latimer RD, English TAH: Dopexamine hydrochloride, a B,-adrenergic and dopaminergic agonist; haemodynamic effects following cardiac surgery. Eur Heart J 9:853-858, 1988 14. Crossland J: Lewis’s Pharmacology (ed 5). New York, NY, Churchill-Livingstone, 1980, pp 258286 15. Foulds RA: Clinical development of dopexamine hydrochloride and an overview of its hemodynamic effects. Am J Cardiol 62:41C45C, 1988 16. Magrini F, Foulds RA, Roberts N, et al: Renal hemodynamic effects of dopexamine hydrochloride. Am J Cardiol62:53C56C, 1988 17. Stephan H, Sontag H, Henning H, et al: Cardiovascular and renal haemodynamic effects of dopexamine: Comparison with dopamine. Br J Anaesth 65:380-387,199O 18. Jaski BE, Wijns W, Foulds RA, et al: The hemodynamic and myocardial effects of dopexamine: A new &adrenoreceptor and dopaminergic agonist. Br J Clin Pharmacol21:393-400, 1986 19. Dunselman PH, Tijssen JP, Hugenholtz PG: Dopexamine and dobutamine in cardiac failure: A randomized, double-blind comparison in 110 patients. Circulation 80:176, 1989 (suppl2) 20. Dawson JR, Thompson DS, Signy M, et al: Acute haemodynamic and metabolic effects of dopexamine, a new dopaminergic receptor agonist, in patients with chronic heart failure. Br Heart J 54:313-320, 1985 21. Svenson G, Strandberg L-E, Lindvall B, Erhardt L: Haemodynamic response to dopexamine hydrochloride in postinfarction heart failure: Lack of tolerance after continuous infusion. Br Heart J 60:489-496,1988 22. Bohm M, Pieske B, Schnabel P, et al: Reduced effects of dopexamine on force of contraction in the failing human heart despite preserved beta-2 adrenoreceptor subpopulation. J Cardiovast Pharmacol 14:549-559. 1989
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23. Baumann G, Felix SB, Filcek SAL: Usefulness of dopexamine hydrochloride versus dobutamine in chronic congestive heart failure and the effects on hemodynamics and urine output. Am J Cardiol65:748-754, 1990 24. Colardyn FA, Vandenbogaerde JF: Use of dopexamine hydrochloride in intensive care patients with low output left ventricular heart failure. Am J Cardiol62:68C-72C, 1988 25. Jamison M, Widerhorn J, Weber L, et al: Central and hemodynamic effects of a new agonist at peripheral dopamine and P,-adrenoreceptors in patients with heart failure. Am Heart J 117:607-614, 1989 26. Lang RM, Borow KM. Neumann A, et al: Role of the P,-adrenoreceptor in mediating positive inotropic activity in the failing heart and its relation to the hemodynamic effects of dopexamine hydrochloride. Am J Cardiol62:46C-52C, 1988 27. Murphy JJ, Hampton JR: Failure of dopexamine to maintain hemodynamic improvement in patients with chronic heart failure. Br Heart J 60:45-49, 1988 28. Svenson G, Sjogren A, Erhardt L: Short term hemodynamic effects of dopexamine in patients with chronic congestive heart failure. Eur Heart J 7:697-703, 1986 29. Bonnier JJ. Read BH: Dopexamine hydrochloride and dobutamine: A comparison of the hemodynamic effects in patients with chronic cardiac failure. Tijdsschr Ther Geneesmiddel Onderzoek 13:237-240,1988 30. Jackson NC, Taylor SH, Frais MA: Hemodynamic comparison of dopexamine hydrochloride and dopamine in ischemic left ventricular dysfunction. Am J Cardiol62:73C-77C, 1988 31. Bristow MR, Ginsburg R, Umans V, et al: p, and &-receptor subpopulations in nonfailing and failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective &-receptor down regulation in heart failure. Circ Res 59:297-309, 1986 32. Cohn JN, Franciosa JA: Vasodilator therapy of cardiac failure. N Engl J Med 297:254-258, 1987 33. Goldstein RE, Beijer GD, Stampfer M, et al: Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 36:571-578,1975 34. Leier CV, Binkley PF, Carpenter J, et al: Cardiovascular pharmacology of dopexamine in low output congestive heart failure. Am J Cardiol62:94-99, 1988 35. Leier CV: Regional blood flow responses to vasodilators and inotropes in congestive heart failure. Am J Cardiol 62:86E-93E, 1988 36. Jaski BE, Peters C: Inotropic, vascular and neuroendocrine effects of dopexamine hydrochloride and comparison with dobutamine. Am J Cardiol62:63C-67C, 1988 37. Baumann G, Gutting M, Pfafferot C, et al: Comparison of acute hemodynamic effects of dopexamine hydrochloride, dobutamine and sodium nitroprusside in chronic heart failure. Eur Heart J 9:503-512,1988 38. Tan LB, Littler WA, Murray RG: Beneficial hemodynamic effects of dopexamine in patients with low output heart failure. J Cardiovasc Pharmacol 10:280-286, 1987 39. 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 62:83C88C, 1988 40. Smith GW, O’Connor SE: An introduction to the pharmacologic properties of dopexamine hydrochloride. Am J Cardiol 62:9C-17C, 1988 41. Parrat JR, Wainwright CL, Fagbemi 0: Effect of dopex-
amine in the early stages of experimental myocardial infarction and comparison with dopamine and dobutamine. Am J Cardiol62:18C23C, 1988 42. Katz RL, Lord CO, Eakins KE: Anaesthetic-dopamine cardiac arrhythmias and their prevention by P-adrenergic blockade. J Pharmacol Exp Therap 158:40-45,1967 43. Boachie-Ansa G, Kane KA, Parrat JR: The cardiac electrophysiologic effects of dopexamine under normal and simulated ischaemic conditions. J Mol Cell Cardiol21:S23,1989 (suppl II) 44. De Marco T, Kwasman M, Lau D, et al: Dopexamine hydrochloride in chronic congestive heart failure with improved cardiac performance without increased metabolic cost. Am J Cardiol62:57C-62C, 1988 45. Koolen JJ, van Wezel HB, Visser CA: Myocardial oxygen consumption of dopexamine in comparison to dobutamine. J Cardiothorac Anesth 4:56,1990 (suppl3) 46. Demeyere R, Flameng W, Lunkenheimer P: Haemodynamic effects of dopexamine hydrochloride administered by an intracoronary infusion technique. J Cardiothorac Anesth 3:15, 1989 (suppl 1) 47. Bass AS: Contrasting effects of dopexamine hydrochloride on electrolyte excretion in canine kidney. J Pharmacol Exp Ther 253:798-802, 1990 48. Mousdale S, Clyburn PA, Mackie AM, et al: Comparison of the effects of dopamine, dobutamine and dopexamine upon renal blood flow: A study in normal healthy volunteers. Br J Clin Pharmacol25:555-560,1988 49. Tan LB, Smith SA, Littler WA, et al: Haemodynamic and renal effects of dopexamine in low output heart failure. Br Heart J 57:81, 1987 50. Gray PA, Bodenham AR, Park GR: A comparison of low dose dopexamine and dopamine infusions in prevention of renal impairment in patients undergoing orthotopic liver transplantation. Intens Care Med 16:A149,1990 51. Van Der Starre PJA, Rosseel PMJ: Dopexamine hydrochloride after coronary artery bypass grafting. Am J Cardiol 62:78C92C, 1988 52. Hunter DN, Gray H, Moudaliar Y, et al: The effects of dopexamine hydrochloride on cardiopulmonary haemodynamics following cardiac surgery. Int J Cardiol23:365-371, 1989 53. Poelaert JI. Mungroop HE, Koolen JJ, et al: Hemodynamic effects of dopexamine in patients following coronary artery bypass surgery. J Cardiothorac Anesth 3:441-443, 1989 54. Santman FW, Thomas SM, Hoskins RD: Prolonged infusion of varied doses of dopexamine hydrochloride for circulatory failure after cardiac surgery. J Cardiothorac Anesth 3:13, 1989 (suppl 1) 55. Friedel N, Matheis H, Kuppe H, et al: Long term effects of dopexamine hydrochloride in low cardiac output states following cardiac surgery. J Cardiothorac Anesth 4:80, 1990 (suppl3) 56. Du Gres B, Flamens C, Gruner MC: The use of dopexamine hydrochloride in patients with low cardiac output after cardiac surgery. J Cardiothorac Anesth 3:16,1989 (suppl I) 57. McDonagh PD, White M, Phelan D, et al: The effect of perioperative dopexamine on tissue perfusion in patients undergoing cardiac surgery. J Cardiothorac Anesth 4:98, 1990 (suppl3) 58. Shoemaker WC, Appel PL, Kram HB, et al: Prospective trial of supranormal values of survivors as therapeutic goals in high risk surgical patients. Chest 94:1176-l 186, 1988 59. Lauwers JB, Luiten TH, Luiten CG, et al: Renal effects of dopamine, dobutamine and dopexamine hydrochloride. J Cardiothorac Anesth 4:82, 1990 (suppl3)
Dopexamine Hydrochloride: Pharmacology and Use in Low Cardiac Output States Sunit Ghosh, FFARCS, Beverley Gray, FFARCS, Amo Oduro, FFARCS, and Raymond D. Latimer, FFARCS
T
HE TERM “INOTROPE” is broadly used to describe agents that enhance cardiac performance, although the mechanism by which some of these drugs improve myocardial function may be attributable less to their effect on myocardial contractility than to the other hemodynamic changes that are associated with their use. In the treatment of cardiac failure, agents with pharmacodynamic profiles that combine relatively mild direct effects on the myocardium with those resulting from a relatively greater effect on preload and afterload offer potential benefits from the standpoint of myocardial energy use. This is of prime concern in both the acutely or chronically ischemic heart and following cardiopulmonary bypass (CPB) when cardiac failure can, on occasion, be ascribed more to unavailability of energy reserves than to persisting ischemia. Dopexamine hydrochloride, a synthetic analog of dopamine, is characterized by just such a profile of action and may offer a favorable alternative to the more established therapeutic regimens of dopamine and dobutamine. The pharmacology of dopexamine and its use in the treatment of chronic or postoperative cardiac failure is reviewed here.
Thus, the chronotropic and inotropic effects of dopexamine (Fig 2) may be mediated through three separate mechanisms: indirect cardiac p,-receptor stimulation through the baroreceptor reflex response to a decrease in blood pressure,8 direct stimulation of cardiac 8,-adrenoreceptors,‘a2a5 and potentiation of neurally released norepinephrine at cardiac &-receptors by the inhibition of uptake 1.3.h-H The decrease in systemic vascular resistance (SVR) associated with the use of dopexamine appears predominantly to be mediated by &-adrenoreceptor stimulation and to a lesser degree by stimulation of vascular DA,- and DA2receptors.‘,* Studies of the peripheral vascular effects of dopexamine during CPB indicate that the drug has no influence on venous capacitance vessels and that its vasodilator effect is confined to the arterial side of the vascular bed.’ The relative contribution of each of the mechanisms described above to the overall hemodynamic effect is uncertain, but would probably vary in the clinical setting with the underlying pathophysiology and other therapeutic agents used. This may account for some of the conflicting results obtained in the studies outlined below.
PHARMACOLOGY
Dopexamine hydrochloride is a synthetic catecholamine designed to combine and enhance the desirable hemodynamic qualities of dopamine and dobutamine. Dopexamine, an N-substituted analog of dopamine, is structurally related to both of these drugs (Fig l), but differs from either in its pharmacological effects (Tables 1 and 2). Dopexamine is a potent &adrenoreceptor agonist’.’ with negligible direct B,-adrenergic activity,‘,3 no a-adrenergic effect,’ significant agonist activity at dopaminergic DA,-receptors,4.5 and minimal effect at DA,-receptors.’ In addition, dopexamine is a potent inhibitor of the reuptake of neurally released catecholamines into nerve terminals (uptake 1),3@sbut does not itself enter sympathetic nerve terminals by the uptake 1 process. Thus, dopexamine has no “tyramine-like” effect in displacing endogenous norepinephrine at these sites? and the indirect sympathomimetic effects of dopexamine result solely from inhibition of uptake 1.
From the Department of Anaesthesia, Papworth Hospital, Cambridge, England. Address reprint requests to Raymond D. Latimer, FFARCS, Department of Anaesthesia, Papworth Hospital, Papworth, Cambridge CB3 8RE, England. Copyright B 1991 by W.B. Saunders Company 1053-0770/91/0504-0016$03.00/0
382
Pharrnacokinetics
There are limited data available on the pharmacokinetic properties of dopexamine. Dopexamine is inactive orally and because of its short half-life is administered by intravenous (IV) infusion. In healthy volunteers, incremental increases in the rate of infusion result in proportionate increases in plasma concentration of the drug. On cessation of the infusion, plasma levels decline monoexponentially with a half-life of 6 to 7 minutes and a clearance rate of 36 mL/min/kg.‘” Clearance is by uptake into tissues, with dopexamine competing as a substrate for extraneuronal catecholamine uptake mechanisms (uptake 2) and in the liver where extensive metabolism occurs.” In patients with heart failure, clearance is marginally slower (28 mL/min/kg) and the half-life is prolonged to 11 minutes”; however, in postcardiac surgical patients clearance of dopexamine has been found to decrease to 17 mL/minikg, less than half the value quoted for healthy subjects, although the half-life remains unchanged.13 Such variations in clearance rate should not affect the establishment of an effective dosage regimen in clinical practice because the dose is titrated to effect. Metabolism of dopexamine is by methylation and sulphation of the catechol hydroxyl groups by the established pathways for catecholamine degradation.14 Excretion oc-
Journal of Cardiothoracic and Vascular Anesthesia, Vol5, No 4 (August), 1991: pp 382-389
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Table 1. Relative Potencies of Pharmacological Effects of Dopsxamine
CHZ-CH2-NH2
ReceptorAgonism
DOPAMINE
DA,
0.34
DA, a
0
0.17 0.16
PI
60
P2 Uptake 1 blockade
10 0
Tyramine-like effect
DOBUTAMINE
NOTE. Relative potency of dopamine = 1.
CH2-CH2-NH-(CH2)6-NH-CH2-CH2
In Chronic Cardiac Failure
DOPEXAMINE Fig 1.
Structures of dopamine, dobutamine, and dopexamine.
curs largely as metabolites in the urine and, to a much lesser extent, the feces.‘” The pharmacological activity of the metabolites, in particular the methoxy metabolite, has yet to be fully ascertained. HEMODYNAMIC
STUDIES
In the Nonfailing Heart
In healthy human volunteers, infusion of dopexamine at 1 to 8 &kg/min results in dose-related increases in heart rate (HR), cardiac output (CO), and pulse pressure, but with minimal change in mean arterial pressure (MAP).” In mildly to moderately hypertensive patients, similar increases in HR and CO occur in the absence of a significant change in SVR; thus, MAP increases.16 In contrast to these findings, dopexamine infusion (1 to 4 &kg/min) in anesthetized patients with ischemic heart disease increases CO, but there is a significant decrease in MAP and a dose-related tachycardia.” In the same study, dopamine (2.5 and 5 pg/kg/min) was noted to increase CO primarily by its effect on stroke volume, whereas the increase in CO produced by dopexamine appeared to be related to changes in HR and SVR as well as a nondose-related effect on stroke volume (Fig 3).” A study comparing the hemodynamic effects of dopexamine (2 &kg/min) with and without a controlled HR using atria1 pacing in patients undergoing diagnostic cardiac catheterization for suspected coronary artery disease concluded that dopexamine did produce HR-independent increases in cardiac index (CI) and in left ventricular (LV) contractility and relaxation, although improvement in LV function secondary to a decrease in SVR could not be excluded.”
Much of the information available about the hemodynamic effects of dopexamine comes from studies in patients with chronic cardiac failure.‘9-3” It should be emphasized that the pathophysiological changes accompanying this disease state (increased circulating catecholamine levels, down-regulation of cardiac PI-receptors:’ and attenuation of the baroreceptor reflex response32,33) are such that differences in response to dopexamine among healthy volunteers, patients with acute cardiac failure, and those with chronically failing hearts are only to be expected in view of the pharmacology of the drug. In vitro studies bear this out: dopexamine has a less pronounced inotropic effect on ventricular myocardial strips from patients in NYHA class III and IV heart failure than on that from nonfailing hearts and no effect on that from NYHA class IV patients.” In patients with moderate to severe chronic cardiac failure, dopexamine produces dose-related reductions in SVR and pulmonary vascular resistance (PVR) and rightand left-sided filling pressures. HR, CI, stroke volume index (SVI), and LV dP/dt max all increase in a dose-related manner. Minimal changes ( < 10%) in MAP occur at doses of 2 &kg/min or less; at 4 &kg/min decreases of up to 15% have been observed. Dopexamine has also been shown to increase hepatic and splanchnic blood flow in this group of patients without significant alteration in limb blood flo~,~~.‘~suggesting preferential redistribution of blood to visceral circulations. Data from several studies of the hemodynamic effects of dopexamine in NYHA class II, III, and IV cardiac failure patients are summarized in Table 3; these have been selected to demonstrate the range of results obtained. Comparative studies of dopexamine and dobutamine in chronic cardiac failure at doses producing similar increases in CO (dopexamine, 2 to 4 kg/kgimin, and dobutamine, 5 to 10 @g/kg/min) show that dopexamine reduces SVR and PVR more markedly than dobutamine, but has a lesser
Table 2. Pharmacological Effects of Dopexamine,
Dopamine, and Dobutamine
Receptor DA, Dopexamine Dopamine Dobutamine
DA,
Pl
+t
+
+++
++
(+I ++
0
0
++t
u
P2
Uptake 1 Inhibition
Tyramine-like Effect
+++
0
(+) +t
+++
++
tt
+t
+
0
NOTE. 0, inactive; (+), inactive in clinical dose range; t, mild; + +, moderate; t+-t,
powerful.
tti
0
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GHOSH ET AL
beneficial systemic vasodilatation coupled with improvcment in myocardial function (Table 4). From the limited data available, dopexamine appears to have similar cffccts in acute and chronic cardiac failure except that cardiac filling pressures and pulmonary artery pressure are notably unaffected in the acute situation.
“”
HR
SVR
SV
dP,‘dT’P
LONG-TERM
-60
L
134.3
13 43 1.34.3
13 43 1.34.3
13 43 1.342
dopexamine
13 43 I.343
13 43 1.342
13 43
Ikg/kg/minl
Fig 2. Hemodynsmic effects of dopexamine in anesthetized dogs (mean % change from baseline ‘_ standard error of mean). (Adapted with permission.‘)
positive effect on LV dP/dt max. Other than this, the two drugs appear to have similar hemodynamic effects.z”.z”.‘” In patients with moderate to severe cardiac failure, dopamine (2.5 to 10 &kg/min) and dopexamine (0.5 to 2.0 p&kg/min) produce similar changes in CO; dopexamine does so primarily by dose-related increases in HR and peripheral vasodilatation with mild inotropic effects, whereas dopamine reduces afterload at doses of 2.5 to 5 f@kg/min, increases HR only at higher doses, produces vasoconstriction only at the highest dose, and has a more marked inotropic effect at all doses.*‘~” Dopexamine and sodium nitroprusside have comparable effects on preload at a dose of each agent producing a 30% increase in CO in patients with chronic cardiac failure. However, nitroprusside produces a greater decrease in afterload, a markedly greater decrease in MAP, with a concomitantly greater tachycardia and less pronounced effect on stroke volume.27 In Acute Cardiac Failure
Studies in patients with acute exacerbations of chronic severe heart failure,” and in acute cardiac failure following myocardial infarction,” indicate that dopexamine produces
A
150 HR
PVR
MAP
Cl
SVR
*
SVI
AND TOLERANCE
Dysrhythmic Effects
As with dopamine and dobutamine, the use of dopexamine is associated with the development of tachycardia. In the majority of cases the increase is not of clinical significance, although myocardial ischemia in association with dopexamine infusion has been reported.““’ There is little evidence to suggest that the drug has a propensity to cause dysrhythmias. Dopexamine, unlike dopamine and other catecholamines, produces no atria1 or ventricular dysrhythmias in halothane-sensitized ratq4” and furthermore is associated with a significantly lower incidence of ventricular dysrhythmias following coronary artery ligation in animal models of myocardial ischemia than either dopamine or
B
100
_______-._.
150 HR
PVR
MAP
SVR
-
. SW
Cl
100 -
%
I
% 50
50 -
;
+*
+*
;
a
a
0
n 9 e
INFUSION
Most studies of prolonged dopexamine infusion, of up to 72 hours’ duration, in patients with stable chronic cardiac failure, have shown a progressive attenuation of the hemodynamic efficacy of the drug.“.‘7.2VAlthough in one study” the hemodynamic responses to dopexamine were maintained after 48 hours of infusion, this may have resulted from an improvement in baseline hemodynamic characteristics masking any drop-off in responsiveness. In patients with acute cardiac failure, a multicenter comparison of dopexamine and dobutamine noted a decline in the hemodynamic response to both drugs at a similar rate over a 24-hour infusion period.‘” However, tolerance was not observed to develop in a smaller, singlecenter study of 24-hour infusion of dopexamine at a much lower mean dose.” There appears to be wide intersubject variability in the degree of hemodynamic tolerance to prolonged dopexamine infusion, but the use of high-dose regimens is a determining factor in the rapidity and extent of the development of tolerance.
n
9 e
-50
-100
I ” 124
I
124
I L /
124
1I
dopexamine
I L
124
/ / I I ’ 124
(pg/kg/minl
124
/ I
I \ dL;;;Id
-50
-loo
2.5
+
+
5
dopamine
(pg/kg/min)
Fig 3. (A) Hemodynamic effects of dopexamine in anesthetized patients prior to CAB0 (mean % change from baseline). P < 0.05 at all doses compared with baseline; ?? P < 0.05 compered with 2 pglkglmin. (B) Hemodynamic effects of dopamine in anesthetized patients prior to CABG 2.5 pg/kg/min. (Adapted with parmission.‘7) (mean % change from baseline). P < 0.05 compared with + baseline, ??
DOPEXAMINE
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Table 3. Hemodynamic Effects of Dopexamine
in Chronic Cardiac Failure Mean % ChangeFrom Baseline
Dose
Reference 20
24
25 26
27
28
No. of Patients IO (NYHA Ill)
9 (NYHA Ill-IV)
9 (NYHA Ill-IV) 8 (NYHA Ill-IV)
9 (NYHA Ill-IV)
8 (NYHA Ill-IV)
(Fglkgiminl
30
23
12 (NYHA ll-lll)
12 (NYHA ll-lll)
33 (NYHA Ill-IV)
0
1.0 f20
6.0
+33 0
1.0
+13
2.0
+20
4.0
+23
PCWP
PAP
RAP
Cl
SVR
PVR
SVI
0
0
-17
t45
-30
-15
t40
0
0
-33
+70
-42
-10
+50
0
0
~25
+120
-49
-25
+60
0
0
0
0
t26
-14
t13
0
0
t39
-27
+21
0
+56
-39
-8
0
0
0
0
0
2.0
0
0
0
0
0
0
0
0
1.0
+32 0
0 +32
-19
0
0
0
0
1.0
+11
0
t29
~16
2.0
+12
0
+49
-25
4.0
+14
0
t110
-50
1.0
t7
0
0
0
t14
-11
0
2.0
t9
0
0
0
t28
-15
0
4.0
+14
0
0
0
+44
-28
-20
+26
6.0
+18
0
0
0
+56
-34
-32
+32
0
0
0
+I8
-15
t15
0
0
0
t32
-27
+22
0
0.5 1.0
29
HR
3.0 0.5
MAP
t7 0
0.5 1.0
t5
2.0
+9
0.5
0
1.0
t13
2.0
t24
0
+a2
0
+5
t8
-6
0
+7
-7
-13
-12
+14
-7
0
t8
-14
-20
0
-15
+25
-12
0
-17
+12
-9
0
-19
t24
-21
-17
t37
-29
-3
-12
-17
-20
t30
-24
0 0
1.0
0
0 t32 0 0
0 t13 0 t9 t6
-19
t27
2.0
t6
-7
-21
-29
-36
t65
-41
-34
+52
3.0
+a
-9
-28
-40
-48
i87
-48
-39
t68
-9
-35
-48
-55
t95
-50
-43
t65
4.0
t15
NOTE. 0 = No significant change, P < 0.05. Abbreviations: HR, heart rate; MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; Cl, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; SVI, stroke volume index; NYHA, New York Heart Association class.
The lower dysrhythmogenic potential of dobutamine.a’ dopexamine may result from its relative lack of activity at &-receptors, which have been implicated in dysrhythmias induced by other catecholamines.42 It is also interesting to note that infusion of either dopexamine or dopamine prior to and during the period of coronary occlusion appears to suppress the development of ventricular dysrhythmias to a level below that observed in untreated controls. Dopexamine achieves this apparent stabilization of the ischemic myocardium to a greater extent than dopamine, and there is evidence from studies of isolated cardiac conducting tissue
to suggest that, under ischemic conditions, dopexamine has a class l-like antiarrhythmic effect.” Effects on Myocardial Metabolism
The data available on the effects of dopexamine on myocardial metabolism come mainly from measurements in patients with chronic cardiac failure. Infusion of dopexamine (1 to 6 &kdmin) for up to 1 hour in NYHA class III cardiac failure patients produced no significant alteration in myocardial oxygen consumption or coronary sinus blood
Table 4. Hemodynamic Effects of Dopexamine in Patients With Acute Cardiac Failure Mean % Change
DOW
Reference 21
No. of Patients
(pg/kg/min)
12 (post-MI)
0.5 1.0
38
IO (acute or chronic failure/post-Ml)
HR
0 t9
0.5
0
MAP
PAP
PCWP
From
Baseline
RAP
Cl
SVR
0
0
0
0
+15
-13
0
0
0
0
t32
-25
PVR 0
t12 t23
t4
0
0
0
0
t20
0
0
t55
-20
+23
0
0
t70
-30
t35
1.0
t5
t9
2.0
t15
t9
4.0
+17
0
+9
-18
SVI
0 0
0 t12
NOTE. 0 = No significant change from baseline, P < 0.05. Abbreviations: HR. heart rate: MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; Cl, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; SVI. stroke volume index; Ml, myocardial infarction.
386
flow despite a marked increase in LV work.“’ Dopexamine infusion (2 to 6 kg/kg/min) of 1 hour’s duration in NYHA class III and IV patients resulted in no significant alteration in transmyocardial lactate extraction despite increases in rate-pressure product and in arterial and coronary sinus lactate levels.“” The beneficial effects of dopexamine in reducing the preload and afterload presented to the failing heart may offset the metabolic demands imposed by its positive inotropic and chronotropic effects and, thus, may improve myocardial efficiency in patients with cardiac failure. In a randomized study comparing the effects of dopexamine and dobutamine on myocardial oxygen consumption, patients with normal LV function undergoing coronary angiography for disabling angina pectoris received dopexamine (1 and 2 &kg/min) or dobutamine (5 and 10 &kg/min).4” At these doses, CO and LV contractility were comparably increased, but myocardial oxygen consumption increased significantly by 25% in patients receiving dobutamine and by only 8% in the dopexamine group. Further investigations are required to provide an adequate explanation for this finding, which may be related to differences in the effect of the two agents on myocardial relaxation rate and, hence, on LV wall stress and coronary blood flo~.~~ Renal Effects
The renal effects of dopexamine are complex. Systemic or direct intrarenal arterial injection of dopexamine in dogs produces renal vasodilatation and reduction in renal vascular resistance (RVR); this is mediated by agonism at DA,-receptors, with a potency one third that of dopamine, and, in contrast to dopamine, also by stimulation of &-receptors. These changes appear to be selective in that the increases in renal blood flow (RBF) occur despite a decrease in blood pressure and an unchanged CO, implying that the decrease in RVR exceeds that in SVR. Further studies have shown that urinary water and electrolyte excretion are unaltered by 2 p@kg/min of dopexamine in anesthetized dogs despite an increase in glomerular filtration rate. It appears that at the tubular level dopexamine enhances water and electrolyte excretion by stimulation of DA,-receptors, but that these effects may be partially opposed by the agonistic effects of the drug at tubular 8,-receptors.47 Two studies in healthy volunteers have shown that dopexamine (1 to 4 kg/kg/min) reduces RVR and increases effective renal plasma flow (RPF) in a dose-related manner.“,“” Significant changes in effective RPF were produced by 2 to 4 pg/kglmin of dopexamine, whereas dopamine (2.5, 5, 10 &kg/min) produced a 3 times greater increase at all doses, and dobutamine (2.5, 5, 10 &kg/min) had no effect.4” These observations are in accordance with the relative pharmacological effects of the three agents at the DA,-receptor, although in the absence of CI and SVR measurements conclusions about the selectivity of this renal effect cannot be drawn. Conflicting results have been obtained in two investigations of the renovascular effects of dopexamine in which CI and RVR were concomitantly measured. In a group of
GHOSH ET AL
hypertensive patients undergoing diagnostic renal vein catheterization, infusion of 3 kgikgimin of dopexaminc increased RBF by a greater proportion than the associated increase in CI (20% v 13%); RVR decreased significantly whereas SVR remained unchanged,lh suggesting a selective renal effect. In contrast, in patients with ischemic heart disease anesthetized prior to cardiac surgery, infusion of dopexamine (1 to 4 &kg/min) produced greater increases in CI than in RBF (117% v 66% at 4 @kg/min); SVR decreased more than RVR at all doses studied,” implying that the renal effects of dopexamine may result purely from an increase in CI and generalized vasodilatation in response to &-receptor stimulation and not by selective stimulation of renal DA,-receptors. It should be kept in mind when comparing the results of these two studies that the patient populations are at different ends of the physiological spectrum with regard to underlying autonomic tone and reflex hemodynamic responses. Studies on the effects of short-term (2 to 3 hours) infusion of dopexamine on renal function in patients with moderate to severe chronic cardiac failure have not shown any significant effect of the drug on RVR, RBF, glomerular filtration rate, or diuresis except at doses below 1 &kg/ mitt, at which RVR is reduced and RBF does increase, but without alteration in the RBF-to-CO ratio.25.‘5 However, long-term infusion of 48 hours’ duration at a mean dose of 1.9 &kg/min in patients with severe chronic cardiac failure has been shown to result in significant diuresis with marked increase in creatinine clearance. Moreover, these changes were greater than those produced by dobutamine at a dose producing similar changes in CI.” Similarly, in 5 of 10 patients studied with acute cardiac failure, 4 &kgimin of dopexamine produced significant increases in diuresis, natriuresis, and creatinine clearance.“’ Work in progress in canine models of acute renal failure indicates that dopexamine may be of value in restoring renal function to control levels following hypovolemic or ischemic insult. The use of dopexamine as a renal protective agent in patients at risk of renal impairment has been evaluated in a comparative trial of dopexamine (1 to 3 t&kg/min) and dopamine (2 &kg/min) infused during orthotopic liver transplantation and continued for 48 hours postoperatively.‘” The two drugs had similar effects on postoperative urine output, but the incidences of renal impairment (defined as oliguria CO.5 ml/kg/h despite adequate preload) and renal failure (defined as need for extracorporeal renal support) were greater in the dopamine group. DOPEXAMINE
AND POSTOPERATIVE
LOW CO
A low CO state following cardiac surgery commonly occurs in association with a high SVR and a progressive metabolic acidosis resulting from poor tissue perfusion and the “oxygen debt” acquired during CPB. Myocardial excitability is enhanced with a tendency to dysrbythmias and there may be residual myocardial ischemia, as a result of inadequate revascularization, coronary vasospasm, or intracoronary embolism. In addition, metabolic “paralysis” at the myocardial cellular level from residual effects of the
DOPEXAMINE
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AND USE
cardioplegia solution may further impair cardiac function. In the management of this situation, the ideal agent would offer positive inotropism, minimal increase in myocardial energy use, pulmonary and systemic vasodilatation of a magnitude offset by an increase in CO, (thus, without compromise of tissue perfusion), and selective increases in blood flow to those organs most susceptible to ischemic damage. Furthermore, enhancement of renal function would augment its effect on vascular resistance in optimizing preload and afterload. The pharmacological profile of dopexamine suggests that the drug should match some of these ideal characteristics. The currently available information on the use of dopexamine in the treatment of the low CO state following cardiac surgery is outlined subsequently. Hemodynamic Effects
Comparable hemodynamic changes have been observed in most studies of the effects of dopexamine following cardiac surgery and the results of three of these studies are summarized in Table 5. Short-term ( < 2 hours) infusion of dopexamine (1 to 10 &kg/min) following coronary artery bypass grafting (CABG) in patients with unimpaired LV function preoperatively and a mean CO of 3.5 L/min postoperatively has been shown to produce dose-related increases in CI, HR, systolic blood pressure, MAP, mean pulmonary artery pressure, and pulmonary capillary wedge pressure, decreases in SVR and PVR, and no change in right atria1 pressure.5’ Of a total of 20 patients, 3 failed to complete this study because of adverse effects (hypertension in 1 and atria1 fibrillation in 2). In a study of 14 patients (12 CABG and 2 valve replacement procedures) who preoperatively were predicted to require postoperative inotropic support, lo-minute infusions of dopexamine at each of four doses in the 1 to 6 Fg/kg/min range produced similar results to the previously mentioned study, except that there were less marked decreases in SVR and no significant changes in pulmonary arterial or wedge presTable 5. Hsmodynamic Effects
sure.” Adverse effects were noted in 3 patients (atria1 fibrillation in 1, tachycardia > 120 beats/min in 1, and hypotension in 1). In a study of 16 patients with a mean CI of 1.8 L/min/m2 following CABG, dopexamine was infused at 1 and 2 kg/kg/min for lo-minute periods in 9 patients and at 1, 2, and 4 p&kg/min in the other 7 patients postoperatively.“3 Significant increases in HR, CI, and in right ventricular ejection fraction were observed at doses of 2 ygikgimin or greater, PVR and SVR decreased, and mean systemic and pulmonary arterial pressures were unaffected. The improvement in right ventricular ejection fraction demonstrates the potential value of dopexamine in treating right ventricular failure after CABG. Dose titration of dopexamine in the range of 0.5 to 3 &kg/min in 7 patients following aortic valve replacement and 5 following mitral valve replacement with a mean CI of 2.58 L/min/m’ resulted in significant increase in CI and decrease in SVR.‘” HR increased in a dose-related fashion and there were no significant changes in systemic blood pressure or cardiac filling pressures. PVR increased significantly in patients who had mitral valve replacement, but decreased in those who had aortic valve replacement. Transient ventricular ectopic beats were observed in three patients during dopexamine infusion. Three trials of longer term infusion of dopexamine following CABG or valvular surgery have noted beneficial hemodynamic effects, which were sustained during the 18-, 36-, and 48-hour investigation periods of the three studies, respectively.54-56However, the changes in baseline hemodynamics that occur in the natural course of postoperative recovery may have influenced the outcome of these studies to some extent. Effects on Tissue @gen
of Dopexamine in Patients With Low Postoperative Cardiac Output Mean % ChangeFrom Baseline
Dose Reference 13
51
No. of Patients
bglkglmin)
HR
0.5
+5
12 (post-AVR, MVR)
17 (post-CABG)
16 (post-CABG)
MAP
PAP
0
PCWP
0
0
RAP
Cl
0
+15
SW
PVR
-8
SW
0
RVEF
+10
1.0
t27
0
0
0
t24
-14
0
0
2.0
t34
0
0
0
0
-24
0
0
3.0 1.0
+30
0
0
0
0
+31 t41
-27
0
0
f4 +20
0 0
0 +6
+14
-8
-16
+44
-24
-23
+a
+54
-32
-26
+I8
+57
-32
-22
+15
2.0
53
Delivery and Extraction
In a randomized study of 16 patients with unimpaired ventricular function undergoing elective CABG, infusion of 2 &kg/min of dopexamine commenced in the pre-CPB period. continued for 24 hours, and was associated with
4.0
+29
6.0
+3a
0 t6
t11
t17
0 +20
8.0
+45
+7
+16
+67
-34
-30
+16
10.0 1.0
+52
+10
+15
i-80
-36
-34
+18
t10
0
0
0
0
t22
-18
2.0
+18
0
0
0
0
+2a
-24
-10
0
+16
4.0
+13
0
0
0
0
t55
-32
-18
0
+17
0
0
+16
NOTE. 0 = No significant change, P < 0.05. Abbreviations: HR, heart rate; MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; Cl, cardiac index; SVR. systemic vascular resistance; PVR, pulmonary vascular resistance; SVI, stroke volume index; RvEF, ventricular ejection fraction; AVR, aortic valve replacement; MVR, mitral valve replacement; CABG, coronan/ artery bypass grafting.
right
388
GHOSH ET AL
significant increases in CI and oxygen delivery compared to a saline-treated control group. Tissue oxygen consumption increased significantly 4 hours postbypass in the dopexamine-treated group, and this increase occurred 14 hours earlier than in the control group. Serum lactate level increased significantly from baseline in both groups following CPB, but the earlier elevation in oxygen consumption in the dopexamine group was associated with a more rapid reduction in serum lactate.” Such improvements in tissue oxygen delivery and metabolism may be of benefit in higher risk patients.”
Renal Effects Two studies in patients with a low CO following cardiac surgery have failed to demonstrate that dopexamine has any effect on diuresis,‘“,‘” glomerular filtration rate, or the RBF-to-CO ratio.“’ CONCLUSION
Dopexamine is a “designer” agent with a pharmacological profile that has been tailored to meet many of the requirements for the optimal short-term treatment of cardiac failure. The drug exerts its effects by diverse mechanisms, but the pathophysiology of cardiac failure alters sympathetic tone, adrenergic receptor activity, and density and autonomic reflexes. These adjustments in the
“milieu intericur,” coupled with those imposed by the myriad other drugs and, in some circumstances, ancsthcsia that may have been concurrently used, result in modification of the overall effects of dopcxamine in distinct ways in acute, chronic, and postcardiotomy cardiac failure. The studies that are available indicate that the drug is a useful agent in improving ventricular performance in the acutely failing heart without clinically unacceptable increases in HR and myocardial work. The drug produces dose-related hemodynamic changes of rapid onset and reversibility and appears to have a low incidence of side effects. Moreover, it is free of the vasoconstrictive effects of dopamine, whereas its vasodilator effects are well balanced by its inotropic activity in maintaining tissue and organ perfusion. Quantitative data on the effects of dopexamine on myocardial oxygen balance and energy utilization in postcardiac surgical patients and on the distribution of myocardial blood flow, particularly in relation to coronary steal, are not yet available. Dopexamine, dopamine, and dobutamine are pharmacologically related, but the inodilator effects of dopexamine bear close resemblance to those of the phosphodiesterase inhibitors. Comparative studies are needed to determine whether the drug offers any benefit over the more cstablished therapeutic regimens, as well as over other novel agents in the treatment of postcardiotomy cardiac failure.
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