Session II Acute Heart Failure in Intensive Care Cardiology 1990;77(suppl 3):34—41
©I990S. KargcrAG. Basel 0008-6312/90/0779-003452.75/0
Enoximone versus Dopamine in Patients Being Weaned from Cardiopulmonary Bypass D.E. Birnbaum, J.G. Preuner. R. Gieseke, D. Trenk, E. Jaehnchen Department of Cardiovascular Surgery, Rehabilitation Center, Bad Krozingen. FRG
Abstract. The efficacy of acute haemodynamic support with intravenous enoximone (2 X bolus 0.5 mg/kg; infusion 5.0 pg/kg/min) versus dopamine (3.0-4.0 pg/kg/min), over an 18hour period, was investigated in patients to be weaned from cardiopulmonary bypass (pla cebo-controlled trial). Under steady-state conditions, enoximone produced a substantial increase in cardiac index (20.6 ± 1.7%), but no change in heart rate. The improvement in cardiac index with time until constant values were reached (6 h) was not directly paralleled by the plasma concentration of enoximone. Pharmacodynamically relevant concentrations were already present after 1 h of infusion (480 ± 68 ng/ml) and comparable with the value determined after 6 h (442 ± 37 ng/ml). After 18 h of infusion, plasma concentration had reached 742 ± 47 ng/ml without a further improvement in cardiac function. The augmen tation of stroke volume index (23.3 ± 2.5%) occurred concomitantly with a decrease in systemic vascular resistance (-23.1 ± 0.6%), obviously due to a decrease in diastolic arterial pressure (-12.0 ±3.8%). The pulmonary capillary wedge pressure remained unaffected. There was only a slight decrease in pulmonary vascular resistance (-9.3 ± 3.2%). During both enoximone infusion and dopamine infusion, right atrial pressure increased (10.0 ± 3.1 and 9.0 ± 1.8%, respectively), in contrast to the untreated control group. This is contradic tory to the drugs’ described effect in patients suffering from congestive heart failure. At a concentration which would not normally cause cardiac acceleration, dopamine provided minor haemodynamic support in the period after cardiopulmonary bypass. A small increase in cardiac index (5.9 ± 2.2%) was accompanied by a slight decrease in systemic (-4.2 ± 3.2%) and pulmonary (- 11.4 ± 2.4%) vascular resistances. The results indicate that enoxi mone produced beneficial haemodynamic effects in the period following cardiopulmonary bypass. Both inotropic and vasodilatory effects appeared to be manageable.
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 12:40:11 PM
Key Words. Enoximone • Dopamine • Ventricular performance • Cardiac index • Systemic vascular resistance
Enoximone and Dopamine in Weaning from Cardiopulmonary Bypass
Materials and Methods A total of 20 patients was divided randomly into two groups and treated with either enoximone or dopamine while being weaned from cardiopulmonary bypass during the period thereafter. Details of these patients are given in table 1. Patients were compara ble in age, body surface area and in the type of surgery (number of coronary bypass grafts, duration of car diopulmonary bypass and aortic cross-clamp time). All patients had a left ventricular function which was impaired by infarction, but they were not in heart failure. The following haemodynamic parameters were measured at regular times: cardiac output, mean ar terial blood pressure, systolic and diastolic blood pressure, heart rate, right atrial pressure, pulmonary
Table 1. Characteristics of the patient groups
Age, years Sex, male/female Body surface area, m2 Weight, kg Height, cm Grafts, n Time on cardiopulmonary bypass, min Time on aortic crossclamp, min
Enoximone group ( n - 10)
Dopamine group (n - 10)
62 ±6 7/3 1.81 ±0.16 61 ±29 169 ±6 4.0±0.8
60 ±8 9/1 1.84 ±0.13 64 ±24 169 ±7 3.8± 1.0
105 ±39
97 ±24
47 ± 15
55 ±26
Values given are means ± SEM.
Table 2. Plasma concentration of enoximone and its sulphoxide metabolite following cardiopulmonary bypass (2 X bolus 0.5 mg/kg, infusion 0.5 pg/kg/ min) Time after cardiopulmonary bypass
Enoximone concentration ng/ml (n = 10)
Enoximone sulphoxide concentration ng/ml (n - 10)
5 6 12 18
409 ±30 442 ±31 570±25 742 ±47
1,234 ± 1,317 ± 1,511 ± 1,578 ±
540± 106
1,410± 161
h h h h
Mean (5, 6, 12, 18 h)
144 135 136 159
Values are given as means ± SEM.
artery' pressure and pulmonary capillary wedge pres sure. From these measured values, further parameters were derived, such as cardiac index, stroke volume index, systemic vascular resistance, pulmonary vascu lar resistance and rate-pressure product. The plasma concentrations of enoximone and its main sulphoxide metabolite were determined by high-performance liq uid chromatography (table 2).
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 12:40:11 PM
Patients undergoing heart surgery often need the support of positive inotropic drugs, such as dopamine or dobutamine, during weaning from cardiopulmonary bypass. Re cently several selective phosphodiesteraseinhibiting, non-catecholamine agents have been studied, which are capable of improving cardiac haemodynamics acutely in patients with severe heart failure [1-4], The positive inotropic and vasodilating properties of one such agent, the selective phosphodiesterase IV inhibitor enoximone [5, 6], have been reported to produce a marked short-term and long-term improvement in patients with con gestive heart failure [7-12]. To the authors’ knowledge, a comparison of conventional catecholamines with enoxi mone in patients not suffering from heart failure has not yet been reported [13]. This study therefore investigated the benefits of enoximone in patients to be weaned from cardiopulmonary bypass after cardiac sur gery where no previous documented impair ment of ventricular function existed. This allowed the inclusion of a non-catecholamine-, nonglycoside-treated control group.
35
36
Birnbaum/Preuner/Gieseke/Trenk/Jaehnchen
Plasma concentration determination
sssss?
1 II I U I it
minium i
Enoximone/dopamine infusion dose
it
iitim
5.0 Mg/kg/miryÍ3-4 ^g/kg/mm Aortic cross-clamp CPB
Patient status
Anaesthesia II
Surgery
Intensive care
4---1----I----1----1--- 1------1---- 1---- 1---1----1----1----- 1-- 1----1—H Time (h) (min)
0 160
2
4
6
8
10
12
120
14
16 1080
18
20
22 24
26
28
30 1800
Fig. 1. Protocol for evaluation of patients after cardiopulmonary bypass. The first values were measured about 160-120 min before the end of cardiopulmonary bypass (CPB) at induction of anaesthesia. CPB time includes aortic cross-clamp time. Thereafter, the patients were observed in the intensive care unit. Arrows indicate points of evaluation, bolus doses and infusion of enoximone and dopamine, respectively.
determined simultaneously under identical condi tions (placebo control). The statistical analysis was performed using the Mann-Whitney U test.
Results All patients had an uneventful periopera tive course. None of the patients had an infarction or experienced difficulties during weaning from cardiopulmonary bypass so that no additional attempts to disconnect the cardiopulmonary bypass or apply circulatory assist methods were required. The most impressive effect of enoximone was an increase in cardiac index (fig. 2) and a corresponding decrease in systemic vascular
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 12:40:11 PM
Drugs were administered over a period of 18 h beginning with two bolus doses immediately after the pump flow was reduced for weaning from cardiopul monary bypass (fig. 1). A loading dose of enoximone. 2 X 0.5 mg/kg body weight, was added to the prime of the heart-lung machine, followed by continuous infu sion of 5 ng/kg/min. The two boluses were infused at 5-min intervals within a period of 10 min, to prevent an acute haemodynamic response. Dopamine was administered as a continuous infusion of 3-4 pg/kg/ min. The behaviour of the haemodynamic parame ters was monitored over an additional period of 12 h (fig. 1). In order to compare the haemodynamic effects of the two drugs, values were recorded as means ± SEM at 6, 10, 12, 14 and 18 h after pharmacodynamic equilibrium was reached. These values were ex pressed as percentage change compared to 10 control patients, who were not treated with any haemodynamically active drug. The corresponding values were
Enoximone and Dopamine in Weaning from Cardiopulmonary Bypass
37
Enoximone
Dopamine
30.0-1
Q. O -
o
20.0 -
c o o
E o
Fig. 2. Cardiac output (CO), cardiac index (Cl), stroke vol ume index (SVI) and heart rate (HR) for the two patient groups. Each value is the mean ± SEM of 5 separate determinations. * p < 0.05: significantly differ ent from the dopamine-treated group.
o 05 c (0 JZ
100-
a> 05 iS
c o o
©I990S. KargcrAG. Basel 0008-6312/90/0779-003452.75/0
Enoximone versus Dopamine in Patients Being Weaned from Cardiopulmonary Bypass D.E. Birnbaum, J.G. Preuner. R. Gieseke, D. Trenk, E. Jaehnchen Department of Cardiovascular Surgery, Rehabilitation Center, Bad Krozingen. FRG
Abstract. The efficacy of acute haemodynamic support with intravenous enoximone (2 X bolus 0.5 mg/kg; infusion 5.0 pg/kg/min) versus dopamine (3.0-4.0 pg/kg/min), over an 18hour period, was investigated in patients to be weaned from cardiopulmonary bypass (pla cebo-controlled trial). Under steady-state conditions, enoximone produced a substantial increase in cardiac index (20.6 ± 1.7%), but no change in heart rate. The improvement in cardiac index with time until constant values were reached (6 h) was not directly paralleled by the plasma concentration of enoximone. Pharmacodynamically relevant concentrations were already present after 1 h of infusion (480 ± 68 ng/ml) and comparable with the value determined after 6 h (442 ± 37 ng/ml). After 18 h of infusion, plasma concentration had reached 742 ± 47 ng/ml without a further improvement in cardiac function. The augmen tation of stroke volume index (23.3 ± 2.5%) occurred concomitantly with a decrease in systemic vascular resistance (-23.1 ± 0.6%), obviously due to a decrease in diastolic arterial pressure (-12.0 ±3.8%). The pulmonary capillary wedge pressure remained unaffected. There was only a slight decrease in pulmonary vascular resistance (-9.3 ± 3.2%). During both enoximone infusion and dopamine infusion, right atrial pressure increased (10.0 ± 3.1 and 9.0 ± 1.8%, respectively), in contrast to the untreated control group. This is contradic tory to the drugs’ described effect in patients suffering from congestive heart failure. At a concentration which would not normally cause cardiac acceleration, dopamine provided minor haemodynamic support in the period after cardiopulmonary bypass. A small increase in cardiac index (5.9 ± 2.2%) was accompanied by a slight decrease in systemic (-4.2 ± 3.2%) and pulmonary (- 11.4 ± 2.4%) vascular resistances. The results indicate that enoxi mone produced beneficial haemodynamic effects in the period following cardiopulmonary bypass. Both inotropic and vasodilatory effects appeared to be manageable.
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 12:40:11 PM
Key Words. Enoximone • Dopamine • Ventricular performance • Cardiac index • Systemic vascular resistance
Enoximone and Dopamine in Weaning from Cardiopulmonary Bypass
Materials and Methods A total of 20 patients was divided randomly into two groups and treated with either enoximone or dopamine while being weaned from cardiopulmonary bypass during the period thereafter. Details of these patients are given in table 1. Patients were compara ble in age, body surface area and in the type of surgery (number of coronary bypass grafts, duration of car diopulmonary bypass and aortic cross-clamp time). All patients had a left ventricular function which was impaired by infarction, but they were not in heart failure. The following haemodynamic parameters were measured at regular times: cardiac output, mean ar terial blood pressure, systolic and diastolic blood pressure, heart rate, right atrial pressure, pulmonary
Table 1. Characteristics of the patient groups
Age, years Sex, male/female Body surface area, m2 Weight, kg Height, cm Grafts, n Time on cardiopulmonary bypass, min Time on aortic crossclamp, min
Enoximone group ( n - 10)
Dopamine group (n - 10)
62 ±6 7/3 1.81 ±0.16 61 ±29 169 ±6 4.0±0.8
60 ±8 9/1 1.84 ±0.13 64 ±24 169 ±7 3.8± 1.0
105 ±39
97 ±24
47 ± 15
55 ±26
Values given are means ± SEM.
Table 2. Plasma concentration of enoximone and its sulphoxide metabolite following cardiopulmonary bypass (2 X bolus 0.5 mg/kg, infusion 0.5 pg/kg/ min) Time after cardiopulmonary bypass
Enoximone concentration ng/ml (n = 10)
Enoximone sulphoxide concentration ng/ml (n - 10)
5 6 12 18
409 ±30 442 ±31 570±25 742 ±47
1,234 ± 1,317 ± 1,511 ± 1,578 ±
540± 106
1,410± 161
h h h h
Mean (5, 6, 12, 18 h)
144 135 136 159
Values are given as means ± SEM.
artery' pressure and pulmonary capillary wedge pres sure. From these measured values, further parameters were derived, such as cardiac index, stroke volume index, systemic vascular resistance, pulmonary vascu lar resistance and rate-pressure product. The plasma concentrations of enoximone and its main sulphoxide metabolite were determined by high-performance liq uid chromatography (table 2).
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 12:40:11 PM
Patients undergoing heart surgery often need the support of positive inotropic drugs, such as dopamine or dobutamine, during weaning from cardiopulmonary bypass. Re cently several selective phosphodiesteraseinhibiting, non-catecholamine agents have been studied, which are capable of improving cardiac haemodynamics acutely in patients with severe heart failure [1-4], The positive inotropic and vasodilating properties of one such agent, the selective phosphodiesterase IV inhibitor enoximone [5, 6], have been reported to produce a marked short-term and long-term improvement in patients with con gestive heart failure [7-12]. To the authors’ knowledge, a comparison of conventional catecholamines with enoxi mone in patients not suffering from heart failure has not yet been reported [13]. This study therefore investigated the benefits of enoximone in patients to be weaned from cardiopulmonary bypass after cardiac sur gery where no previous documented impair ment of ventricular function existed. This allowed the inclusion of a non-catecholamine-, nonglycoside-treated control group.
35
36
Birnbaum/Preuner/Gieseke/Trenk/Jaehnchen
Plasma concentration determination
sssss?
1 II I U I it
minium i
Enoximone/dopamine infusion dose
it
iitim
5.0 Mg/kg/miryÍ3-4 ^g/kg/mm Aortic cross-clamp CPB
Patient status
Anaesthesia II
Surgery
Intensive care
4---1----I----1----1--- 1------1---- 1---- 1---1----1----1----- 1-- 1----1—H Time (h) (min)
0 160
2
4
6
8
10
12
120
14
16 1080
18
20
22 24
26
28
30 1800
Fig. 1. Protocol for evaluation of patients after cardiopulmonary bypass. The first values were measured about 160-120 min before the end of cardiopulmonary bypass (CPB) at induction of anaesthesia. CPB time includes aortic cross-clamp time. Thereafter, the patients were observed in the intensive care unit. Arrows indicate points of evaluation, bolus doses and infusion of enoximone and dopamine, respectively.
determined simultaneously under identical condi tions (placebo control). The statistical analysis was performed using the Mann-Whitney U test.
Results All patients had an uneventful periopera tive course. None of the patients had an infarction or experienced difficulties during weaning from cardiopulmonary bypass so that no additional attempts to disconnect the cardiopulmonary bypass or apply circulatory assist methods were required. The most impressive effect of enoximone was an increase in cardiac index (fig. 2) and a corresponding decrease in systemic vascular
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 12:40:11 PM
Drugs were administered over a period of 18 h beginning with two bolus doses immediately after the pump flow was reduced for weaning from cardiopul monary bypass (fig. 1). A loading dose of enoximone. 2 X 0.5 mg/kg body weight, was added to the prime of the heart-lung machine, followed by continuous infu sion of 5 ng/kg/min. The two boluses were infused at 5-min intervals within a period of 10 min, to prevent an acute haemodynamic response. Dopamine was administered as a continuous infusion of 3-4 pg/kg/ min. The behaviour of the haemodynamic parame ters was monitored over an additional period of 12 h (fig. 1). In order to compare the haemodynamic effects of the two drugs, values were recorded as means ± SEM at 6, 10, 12, 14 and 18 h after pharmacodynamic equilibrium was reached. These values were ex pressed as percentage change compared to 10 control patients, who were not treated with any haemodynamically active drug. The corresponding values were
Enoximone and Dopamine in Weaning from Cardiopulmonary Bypass
37
Enoximone
Dopamine
30.0-1
Q. O -
o
20.0 -
c o o
E o
Fig. 2. Cardiac output (CO), cardiac index (Cl), stroke vol ume index (SVI) and heart rate (HR) for the two patient groups. Each value is the mean ± SEM of 5 separate determinations. * p < 0.05: significantly differ ent from the dopamine-treated group.
o 05 c (0 JZ
100-
a> 05 iS
c o o
