Prolonged

Infusion

of Varied Doses of Dopexamine Hydrochloride Cardiac Output After Cardiac Surgery Frederik

W. Santman.

Circulatory failure after cardiac surgery often calls for active hemodynamic management with fluids, inotropes, and vasodilators. Dopexamine adrenergic inhibitor

hydrochloride

and DAT-dopaminergic of the uptake-l

is a new combined f32-

receptor

mechanism

agonist and an

of endogenous

cate-

cholamines. As a result, it exerts inotropic and vasodilator effects on the heart and systemic vasculature. The effects were

examined

over a mean

of 22 hours,

using 1 to 4

Pg/kg/min of dopexamine to treat low cardiac output states following coronary bypass and valvular/ventricular repair surgery. readily

In 8 out of 14 patients, reversed

by 1 Pg/kg/min

low cardiac

output

of dopexamine.

was

Six pa-

tients required higher doses (2 to 4 Pgl kg/min) to achieve a satisfactory cardiac index. Significant changes from control values were observed throughout

the infusion for heart rate

1

MMEDIATELY after cardiac surgery the circulation may be impaired by the negative influences of extracorporeal circulation, anesthesia, hypothermia, the surgical procedure itself, and preoperative medications such as @blockers. Postoperatively, drugs may be needed to support andior unload the ventricles. Inotropic drugs enhance cardiac contractility and improve blood flow. Some of the currently used inotropes, such as dopamine and dobutamine, combine this effect on contractility with varying effects on the peripheral vascular beds, specific redistribution of flow and organ perfusion, and an increase in heart rate.‘, Dopexamine hydrochloride is a newly developed B2adrenergic and DA,-dopaminergic receptor agonist, with an indirect effect at Bi-adrenoceptors through inhibition of the neuronal reuptake (uptake-1) of endogenous catecholamines. It is free of effects at a-adrenoceptors.3*4 This profile should have some advantages over drugs such as dopamine and dobutamine in terms of a greater reduction in afterload and a less potent positive inotropic effect. These clinical effects have been largely borne out in studies in patients with heart failure.“-7 Increases in renal and hepatic-splanchnic blood flow have also been reported with dopexamine: 5~8,9Previously, dopexamine has been successfully used in patients with congestive heart failure (CHF). However, its effects after cardiac surgery have only been reported during short-term, dose-titration studies.‘“-i3 In this open prospective trial, the effects of prolonged administration of dopexamine, given for up to 45 hours and titrated to restoration of normal hemodynamics, were studied in patients with low cardiac output states (LCOS) in the recovery phase after cardiac surgery.

From the Department of Intensive Care, University Hospita1 Nijmegen, Nijmegen, The Netherlands. NO reprints available. Copyright 0 1992 by W.B. Saunders Company 1053-0770/9210605-0008$03.00/0 568

for Low

MD

cardiac index (2.0 to 3.4 L/min/mZ), (67 to 102 beats/min), and systemic vascular resistance (1,945 to 914 dyne . s . cmeS). Pulmonary vascular resistance, pulmonary artery wedge pressure, and right atrial pressure were also significantly reduced during the infusion. Most of these changes reversed when dopexamine was discontinued, suggesting a drugspecific effect and a lack of tolerante. Nausea was a frequent complaint. but was no more frequent than in a random sample of similar patients. Titration of dopexamine, 1 to 4 pg/ kg/min, was efficacious in producing circulatory improvement in patients with a low cardiac output after cardiac surgery. Copyright o 7992 by W.B. Saunders Company KEY WORDS: low cardiac ride, open heart surgery

output,

dopexamine

hydrochío-

METHODS Patients who had undergone coronary artery bypass surgery (CABG), and/or valvulariventricular repair surgery, were selected following admission to the cardiothoracic intensive care unit. Entry criteria included (1) a cardiac index (CI) of less than 2.5 L/min/m”. 15 and 5 minutes prior to the start of the study; and (2) a pulmonary capillary wedge pressure (PCWP) of 10 mmHg or higher, thus defining a study population with mild left ventricular (LV) impairment, but who were not hypovolemic. NO inotropes other than digoxin were allowed; vasodilators were permitted if a stable dose was maintained during the period of dopexamine titration. Exclusion criteria included (1) pregnancy; (2) current myocardial ischemia (ST segment elevation or depression); (3) a serious arrhythmia other than atria1 fibrillation; or (4) a systolic blood pressure less than 85 mmHg. Pulmonary artery catheters were inserted preoperatively for recording of right atria1 and pulmonary artery (PA) pressures, PCWP, and cardiac output (CO). Transducers were calibrated before the start of the study and thereafter every 8 hours; al1 pressures were zero-referenced to a point 5 cm below the second sternal Costa1 junction. Cardiac output was measured by thermodilution using 10 mL aliquots of cold normal saline injected at end-expiration. Measurements were repeated until there was less than 10% variation among three subsequent values. Blood pressure was continuously recorded from a radial artery cannula. Pulmonary (PVR) and systemic vascular resistances (SVR) were calculated by standard formulae. Patients were continuously monitored by an electrocardiogram. Any unusual symptoms, including arryhthmias, were recorded together with details of any action taken and an opinion as to whether the event could be attributed to the test infusion. Blood samples for monitoring myocardial enzyme changes were taken immediately prior to the infusion, at 24 hours. and after the end of the infusion. Routine laboratory values were measured preoperatively and 24 hours after completion of the infusion. Upon confirmation of a low CI at two separate times at least 10 minutes apart. dopexamine was given at the starting dose of I pgikgimin. Thirty minutes later, hemodynamic measurements were repeated to assess the effects of the drug. Further increments of 2. 4, and 6 ugikgimin could be administered depending on the patient’s clinical response. Endpoints were a CI over 2.5 L/min/m2 without a clinically undesirable increase in heart rate (HR). Once a satisfactory hemodynamic condition had been reached, dopexamine was continued at that dose for the duration of the patient’s

Journalof Cardiothoracic and VascularAnesthesia, Vol 6, NO 5 (October), 1992: pp 568-572

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570

Table 2. Hemodynamic Responses (mean 2 SD) Dwing Long-Term Dopexamine Hydrochloride Infusion LeE,t

Time

Control HR Cl SVR

66.7 + 6.7 1.99 + 0.36 1545 + ia9

Slgniflcant

Infusloli

Differente

17-35 min

4-6 h

83.9 -t i i .5*

93.2 + 12.8~

2.69 + 0.76*

3.12 ? 0.59*

3.37 f 0.51*

3.21 t 0.51*

3.09 + 0.56*

2.51 + 0.36*1

1181 + 233*

919 + 152*

914 + 168X

966 * 211*

973 2 184*

1304 i 220*t

PCWP

12.8 -t 2.9

ll.5

SVI

29.9 f 5.5

35.1 i 8.7s

r 4.2

6.6 t 4.2* 33.1 + 4.6

8-10 h

100.4 * 9.Y

12.14 h

100.9 * 15.5*

8.9 * 3.8’ 33.8 2 6.1

9.2 + 4.2* 32.4 + 6.5

16-18 h

Post

lol.8 f

i9.i*

9.7 r 3.7s 31.7 ? 7.5

98.1 i i2.a*

11.6?

0.33

4.4

2.2

26.6 -t 3.6t

4.4

ia3 2 59

166 + 58

138 2 45*

120 5 35*

128 t 3a*

113 + 44*

143 ? 54*t

84.3 2 9.6

87.7 2 10

76.7 + 9.5*

75.8 k 9.3*

79.0 5 ll.2

80.2 tr 10.9

87.7 i 12.1

RAP

6.6 & 2.5

6.9 2 3.8

5.4 2 2.7*

4.2 ? 2.3*

5.1 t 3.1*

6.4 + 3.3*

7.9 2 3.8

2.0

21.4 Of-5.6

22.4 ? 4.9

17.7 + 4.8*

20.0 2 5.8

2.7

6.0

18.4 ? 5.6*

ia.8 f 6.3

Effect

154

PVR

18.8 2

Treatment

9.3

MBP MPAP

Signlflcance of

30 7.5

NOTE. Analysis of variance test of treatment effect for all timepoints. N = 10 for all variables except HR, SVR, SVI, RAP, where n = 9. Abbreviations: HR. heart rate (beats/min);

Cl, cardiac index (L/min/m*);

SVR, systemic vascular resistance (dyn

capillary wedge pressure (mmHg); SVI, stroke volume index (mL/mZ); PVR, pulmonary vascular resistance (dyn

s. cm-5); s. cm-5);

PACWP, pulmonary MBP, mean blood

pressure (mmHg); RAP, right atrial pressure (mmHg); MPAP, mean pulmonary artery pressure (mmHg). “Significantly different from control (P < 0.05). tsignificantly different from value at 16 to 18 h timepoint (P < 0.05) using method of least significant differente (LSD), where means that differ by more than the LSD are significantly different at P < 0.05. *P i 0.01. OP < 0.001.

Adverse events occurred in 8 patients. One patient developed sinus tachycardia after about 38 hours of the dopexamine infusion. Because of simultaneously occurring ventricular extrasystoles, dopexamine was discontinued, but without a reduction of the ventricular extrasystoles. Lidocaine treatment was successful and it was possible to restart dopexamine without a recurrence of the extra systoles and with a return to sinus rhythm. NO new ischemic changes on the ECG were observed during the infusion of dopexamine, or enzymatic evidente of myocardial damage (a CK-MB fraction over 5% of total). Nausea and vomiting occurred in 7 patients during infusion of dopexamine. Routine laboratory analysis of blood samples showed no clinically untoward effects. DISCUSSION

Dopexamine effectively reversed the LCOS in patients after cardiac surgery. With properties similar to a combination of dopamine and dobutamine, dopexamine is a new intravenous agent for circulatory support in this setting. In this series of patients, mostly with preoperatively decreased cardiac performance due to longstanding ischemia and previous infarctions, a beneficial hemodynamic response was seen after low to moderate doses of dopexamine. It produced significant changes in CI, stroke volume/index, and SVR. The finding of a statistically significant reversal of the hemodynamic variables after discontinuation of the drug points to a lack of tolerante and suggests a continuing need for treatment despite the effects of natura1 recovery. The hemodynamic analysis excluded three patients, who did not complete the infusion because of adverse events, and another patient in whom data were missing because the actual times of measurement fel1 outside the chosen time periods. In a further 2 patients, one paced, certain data were omitted or were unavailable. Although there are statistical methods for dealing with missing data sets, these methods depend on the missing data being random in

occurrence so that missing values can be estimated. Most of the excluded data in this study were accounted for by the three patients in whom the infusion was prematurely terminated, al1 because of adverse events, so that the missing data occurred in the later stages of the infusion; the conditions necessary for conducting an analysis that included missing data were, therefore, not met. However, it is interesting to know whether the excluded data would have affected the conclusions, and an informal analysis of al1 available data for the principal variables of HR, CI, SVR, and MBP showed that mean results were within 5% of those presented in Table 2. Occasional larger differences were inconsistent and did not affect the overall hemodynamic trends. In hemodynamic terms, the results and conclusions were unaffected by the excluded data. In safety terms, the reasons for exclusion are more important: hypertension in one patient and nausea in two, together with nausea in a further 5 of the 14 patients. As a DA,-agonist, dopexamine could be associated with this apparently high incidence of nausea; however, it was not different from that usually seen in this ICU. Nausea and vomiting are common postsurgical events and are multifactorial in origin. At the start of the dopexamine infusion, HR increased to an average of 84 beatsimin from a low prestudy value of 67 beats/min. The pre-drug low HR was probably due to the preoperative adrenergic blockade (preinduction heart rate was 62 * 6.2) or the use of opioid anesthesia.14 Because these effects attenuated with time, a return to the low initial HR was not seen when the drug was stopped at the end of the study. The effects of dopexamine on HR stem from several sources: stimulation of myocardial Bz-receptors, indirectly via uptake-l inhibition at P,-receptors, and baroreflex activation secondary to a decrease in blood pressure? The chronotropic effect of dopexamine was especially evident in these patients because of the low initial HR, and was, therefore, not of concern since dopexamine normal-

DOPEXAMINE

AFTER CARDIAC SURGERY

,,~

HR

bestslmln

1

,,,PVR

“1

PACWP

IAP

Fig 1. Dopexamine effects dwing prolonged infusion indicated by double horizontal arrow. For abbreviations and statistical significances see legend Table 2.

dynealeoolom-6

rnlnli~

*,

mnlig

MPAP

1

mmHp

” ,

. INFUSION

ized HR. However, tachycardia unfavorably alters the myocardial oxygen supply: demand ratio and increases the risk of arrhythmias. During the dopexamine infusion, no ischemic electrocardiogram changes or enzyme changes were noted in this group operated on for progressive ischemia. In studies in patients with CHF, improved cardiac performance by dopexamine was not associated with increased metabolic cost,15J6 and it has been shown that dopexamine may be more favorable in this respect than dobutamine.’ Animal studies have shown that dopexamine has a very low arrhythmogenic potential.” Nevertheless, careful monitoring and cautious titration of dose are essential, because tachycardia is undesirable in postoperative CABG patients who may stil1 have a degree of residual myocardial ischemia. Although the effects of dopexamine on regional organ systems were not evaluated, its pharmacologic profile should

.

HOUrS

INFUSION

produce vasodilation of the renal and splanchnic vasculatures. There have been recent reports of improved renal blood flow and function in patients with myocardial impairment,QJs and of a protective effect, claimed to be equivalent to that afforded by dopamine, against renal dysfunction in patients who have undergone major surgery.19 Furthermore, the increased hepatic-splanchnic blood flow reported in CHF patients8 may have future applications in the treatment of splanchnic ischemia, which can occur during cardiopulmonary bypass,20 and which is currently arousing great interest in view of its role as an index of tissue oxygenation in the critically i11.21 The performance of the LV is determined by HR, filling status or preload, and contraction in relation to afterload. In order to assure adequate filling of the heart and systemic vascular bed (in view of the B2- and DA,-vasodilator effect of dopexamine), a PCWP of at least 10 mmHg was chosen

572

FREDERIK W. SANTMAk

as an entry criterion. The significant decrease in PCWP is also compatible with the usual postoperative pattern in this type of patient, owing to factors such as rewarming vasodilatation22 and loss of fluids to the interstitium.z3 The decrease in PCWP may also have resulted partly from a reduction in ventricular volume and Ming pressures secondary to an increase in HR.24 Both upon starting and discontinuing the drug infusion, SVI changed by approximately lg%, as evidente of an improvement in contractility andior a reduction in afterload. A majority (8 out of 14) of the patients displayed a sufficiently adequate hemodynamic response to the first dose of dopexamine (1 kg/kg/min) so, in accordance with the protocol, a further dose increase was not pursued. When the higher doses of 2 and 4 ~gikgimin were given, the remaining patients were satisfactorily stabilized with a CI above 2.5 L/min/m2. This was a preliminary trial conceived at a time when dopexamine had been previously evaluated only in dose-

titration studies in patients wtth near-normai LV functron The study was. therefore, designed to investigate long-term effects in patients whose LV impairment. though rmid, warranted active treatment. In conclusion, titration of I to 4 pg/kg/min of dopexamine hydrochloride to a subset of patients with a LUX following cardiac surgery, proved an effective way to stabilize the circulation in the immediate postoperative period. Thus, dopexamine extends the choice of drugs available for hemodynamic support after cardiac surgery. ACKNOWLEDGMENT 1 am most thankful for the advice and comments of Dr lan Thomson and Sarah Filcek in reviewing this manuscript. 1 wish to acknowledge Sue Thomas for her part in the data processing, Rachel Blackshaw for her statistical analysis, my colleagues and the H-30 nursing staff for their assistance in carrying out this study, and Fisons pharmaceuticals for the drug supplies.

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