Eur J Cardio-thorac
Surg (1992) 6:311-317
0 Springer-Verlag
1992
Enoximone in newborns with refractory postoperative low-output states (LOS) G. Hausdorf I, N. Friedel I, E Berdjis ‘, H. A. Dieterich 2, J. J. Fell 2, H. T. DreDler 2, A. Werneyer ‘, R. Hetzer I, and P. E. Lange ’ 1 German Heart Center, Berlin, FRG * Mere11 Dow Research Institute, Riisselsheim,
FRG
Abstract. Enoximone was administered to 16 newborns with postoperative, catecholamine-refractory cardiac low-output states in addition to high-dose catecholamlne treatment. Haemodynamic changes were assessed at baseline and during treatment. Haemodynamic parameters were improved in 12 newborns (“responders”), 9 of these survived. Three responders died; one from cardiac low+utput and 2 from uncorrectable congenital heart disease verified by autopsy. Four newborns did not respond to enoximone therapy (“non-responders”) and died. The haemodynamic effects of enoximone were characterized by an increase in cardiac index (+ 160%, P < 0.0008), and a fall in right (- 26%, P < 0.0004) and left (- 34%, P < 0.003) atria1 pressures. It is concluded that enoximone can be an effective agent in the treatment of cardiac low-output states refractory to high-dose catecholamines in neonates up to 7 months old. [Eur J Cardio-thorac Surg (1992) 6:311-3171 Key words: Congenital Neonates
heart disease - Postoperative
cardiac low-output
Surgical repair and palliative surgery in neonates with congenital heart disease carries the risk of postoperative cardiac low-output syndrome caused by inadequate adaptation to postoperative loading conditions. However, adaptation occurs within days by means of growth and hypertrophy of cardiac muscle. Thus, pharmacological “bridging” until the heart has adapted to the changes in load is of increasing importance for postoperative intensive care medicine in this age group. Enoximone is a new imidazolone derivative which selectively inhibits phosphodiesterase (PDE) III [9,21,22]. It increases the concentration of intracellular CAMP and leads to increased myocardial contractility by increasing intracellular free calcium ion concentration by influx through slow calcium channels. The major advantage of enoximone compared to catecholamines is that the principal mechanism of action of the PDE inhibitor is independent of adrenergic cardiac receptors. However, its effectiveness depends on intracellular CAMP and therefore stimulation of cardiac /3-receptors increases its effectiveness. Despite this, p-receptor down-regulation [5] does not occur due to PDE inhibitors. Furthermore, enoxi-
Received for publication: Accepted for publication:
August 19, 1991 January 6, 1992
state - Catecholamines
- Enoximone
-
mone does not lead to an increase in heart rate, while the increase of myocardial oxygen consumption is controversial [12, 14, 161. In addition, it is a vasodilator [I]. The mechanism of vasodilatation is thought to be inhibition of myosinkinase by CAMP. Enoximone has been shown to be effective in the treatment of sustained cardiac pump failure where traditional treatment with catecholamines was ineffective [7,8, 10,171. Its use in adult pretransplant patients has also shown promising results [3,4,6, 19,221. Duffet et al. [l 11 successfully used enoximone for cardiac recompensation in a 16-month-old girl with congenital cardiomyopathy refractory to treatment with catecholamines and digitalis. Cardiac function increased and clinical symptoms improved i.e. dyspnoea decreased so that successful cardiac transplantation could be performed after 3 days of therapy [Ill. Experience with enoximone in neonatal cardiac surgery is limited. Schranz et al. showed that intravenous enoximone led to acute haemodynamic improvement in 6 children suffering from postoperative heart failure. Twenty-five children between the ages of 3 days and 14 years who underwent cardiac surgery were included in a pilot study by Jayais [15]. They were treated with enoximone or a combination of enoximone and dopamine postoperatively. Enoximone was well tolerated by all children and haemodynamic parameters improved significantly.
312
The purpose of the present study was to determine whether enoximone could be helpful in the management of newborns with postoperative low-output states refractory to conventional treatment with catecholamines. Material and methods Sixteen neonates were included in this study. The criteria of the study protocol were: low cardiac output syndrome despite high dose catecholamine therapy (Table I), optimal preload, cardiac index below 2.0 l/min per m’, central venous oxygen saturation below 45%. Individual patient demographic and surgical data are summarized in Tables 2 and 3. The mortality in all patients was clinically judged to be higher than 80% but this judgement was based on clinical experience only. A positive response to enoximone treatment was defined as an increase in cardiac index by more than 20%. Enoximone was administered intravenously in addition to high dose catecholamine therapy (Table 1) with a loading dose of 1.0 mg/ kg over IO min, followed by an infusion of 10 ug/kg per min, 30 min after the bolus dose. Haemodynamic parameters were assessed at baseline, before enoximone was administered, 30 min after administration of the loading dose (i.e. before the infusion was started) and 30-60 min after onset of the infusion. The following parameters were measured: CI = cardiac index; MAP = mean arterial pressure in the femoral artery; RAPm = mean right atria1 pressure; LAPm = mean left atria1 pressure; AVDO, = arterio-venous oxygen difference; HR = heart rate. The AVDO, was calculated as follows: AVDO, = (arterial O,content) - (venous O,-content) were comprised of O,-content = O,saturation. 1.34. Hb+0.0031 . PO,. Cardiac index was calculated using PW Doppler echocardiography of the aorta, as previously described [13]. Blood flow in the pulmonary artery was measured only in patient 15 due to turbulent flow in the ascending aorta. In all other patients, Doppler flow was measured in the ascending aorta, just beyond the aortic valve. The angle between the ultrasound beam and the ascending aorta was kept below IO”. The flow-velocity-integral (FVI) was measured using the envelope technique. The diameter of the aortic root (d) was measured at the base of aortic valve using two-dimensional echocardiography. Stroke volume (SV) was calculated as: SV=FVI
* d2/4 * 3.14
Cardiac index (CI) was then calculated CI=HR
Table1. Concomitant
catecholamine
therapy (pg/kg per min)
Patient
Epinephrine
Dobutamine
Dopamine
Norepinephrine
1 2 3 4 5 6 7 8 9 IO 11 I2 13 I4 15 I6
1.1 I.2 2.0 1.2 2.0 2.5 1.4 1.8 1.6 I.8 1.6 I.6 1.5 I.5 1.6 2.0
20 20 20 20 20 10 20 I5 20 15 20 15 15 20 20 IO
5.0 2.5 15.0 5.0 5.0 5.0 15.0 5.0 5.0 5.0 5.0 15.0 5.0 25.0 5.0
-
Table2. Demographic Patient 1 2 3 4 5 6 7 8 9 10 11 12 I3 14 I5 16
Age (days)
2 4 4 2 4 3 5 5 12 6
0.8 _ _ 1 0.6 -
data Weight (kg)
Sex
BSA (m2)
3.52 3.05 3.65 3.12 2.82 3.62 3.54 3.20 2.93 3.64 3.46 3.21 2.71 3.25 3.96 3.12
M F F M F M M M M F F M F M F M
0.240 0.200 0.250 0.260 0.190 0.240 0.230 0.220 0.200 0.240 0.230 0.220 0.190 0.220 0.250 0.220
as:
* SV * BSA-’
(HR - heart rate, BSA - body surface area). Stroke volume index (SVI) and systemic vascular resistance (SVR) were calculated according to standard formulae. The study was approved by the local committee for human research. The parent/guardian has given informed consent to participate in the study.
Statistical analysis Haemodynamic parameters were compared using the Wilcoxon test for paired data. P
Surg (1992) 6:311-317
0 Springer-Verlag
1992
Enoximone in newborns with refractory postoperative low-output states (LOS) G. Hausdorf I, N. Friedel I, E Berdjis ‘, H. A. Dieterich 2, J. J. Fell 2, H. T. DreDler 2, A. Werneyer ‘, R. Hetzer I, and P. E. Lange ’ 1 German Heart Center, Berlin, FRG * Mere11 Dow Research Institute, Riisselsheim,
FRG
Abstract. Enoximone was administered to 16 newborns with postoperative, catecholamine-refractory cardiac low-output states in addition to high-dose catecholamlne treatment. Haemodynamic changes were assessed at baseline and during treatment. Haemodynamic parameters were improved in 12 newborns (“responders”), 9 of these survived. Three responders died; one from cardiac low+utput and 2 from uncorrectable congenital heart disease verified by autopsy. Four newborns did not respond to enoximone therapy (“non-responders”) and died. The haemodynamic effects of enoximone were characterized by an increase in cardiac index (+ 160%, P < 0.0008), and a fall in right (- 26%, P < 0.0004) and left (- 34%, P < 0.003) atria1 pressures. It is concluded that enoximone can be an effective agent in the treatment of cardiac low-output states refractory to high-dose catecholamines in neonates up to 7 months old. [Eur J Cardio-thorac Surg (1992) 6:311-3171 Key words: Congenital Neonates
heart disease - Postoperative
cardiac low-output
Surgical repair and palliative surgery in neonates with congenital heart disease carries the risk of postoperative cardiac low-output syndrome caused by inadequate adaptation to postoperative loading conditions. However, adaptation occurs within days by means of growth and hypertrophy of cardiac muscle. Thus, pharmacological “bridging” until the heart has adapted to the changes in load is of increasing importance for postoperative intensive care medicine in this age group. Enoximone is a new imidazolone derivative which selectively inhibits phosphodiesterase (PDE) III [9,21,22]. It increases the concentration of intracellular CAMP and leads to increased myocardial contractility by increasing intracellular free calcium ion concentration by influx through slow calcium channels. The major advantage of enoximone compared to catecholamines is that the principal mechanism of action of the PDE inhibitor is independent of adrenergic cardiac receptors. However, its effectiveness depends on intracellular CAMP and therefore stimulation of cardiac /3-receptors increases its effectiveness. Despite this, p-receptor down-regulation [5] does not occur due to PDE inhibitors. Furthermore, enoxi-
Received for publication: Accepted for publication:
August 19, 1991 January 6, 1992
state - Catecholamines
- Enoximone
-
mone does not lead to an increase in heart rate, while the increase of myocardial oxygen consumption is controversial [12, 14, 161. In addition, it is a vasodilator [I]. The mechanism of vasodilatation is thought to be inhibition of myosinkinase by CAMP. Enoximone has been shown to be effective in the treatment of sustained cardiac pump failure where traditional treatment with catecholamines was ineffective [7,8, 10,171. Its use in adult pretransplant patients has also shown promising results [3,4,6, 19,221. Duffet et al. [l 11 successfully used enoximone for cardiac recompensation in a 16-month-old girl with congenital cardiomyopathy refractory to treatment with catecholamines and digitalis. Cardiac function increased and clinical symptoms improved i.e. dyspnoea decreased so that successful cardiac transplantation could be performed after 3 days of therapy [Ill. Experience with enoximone in neonatal cardiac surgery is limited. Schranz et al. showed that intravenous enoximone led to acute haemodynamic improvement in 6 children suffering from postoperative heart failure. Twenty-five children between the ages of 3 days and 14 years who underwent cardiac surgery were included in a pilot study by Jayais [15]. They were treated with enoximone or a combination of enoximone and dopamine postoperatively. Enoximone was well tolerated by all children and haemodynamic parameters improved significantly.
312
The purpose of the present study was to determine whether enoximone could be helpful in the management of newborns with postoperative low-output states refractory to conventional treatment with catecholamines. Material and methods Sixteen neonates were included in this study. The criteria of the study protocol were: low cardiac output syndrome despite high dose catecholamine therapy (Table I), optimal preload, cardiac index below 2.0 l/min per m’, central venous oxygen saturation below 45%. Individual patient demographic and surgical data are summarized in Tables 2 and 3. The mortality in all patients was clinically judged to be higher than 80% but this judgement was based on clinical experience only. A positive response to enoximone treatment was defined as an increase in cardiac index by more than 20%. Enoximone was administered intravenously in addition to high dose catecholamine therapy (Table 1) with a loading dose of 1.0 mg/ kg over IO min, followed by an infusion of 10 ug/kg per min, 30 min after the bolus dose. Haemodynamic parameters were assessed at baseline, before enoximone was administered, 30 min after administration of the loading dose (i.e. before the infusion was started) and 30-60 min after onset of the infusion. The following parameters were measured: CI = cardiac index; MAP = mean arterial pressure in the femoral artery; RAPm = mean right atria1 pressure; LAPm = mean left atria1 pressure; AVDO, = arterio-venous oxygen difference; HR = heart rate. The AVDO, was calculated as follows: AVDO, = (arterial O,content) - (venous O,-content) were comprised of O,-content = O,saturation. 1.34. Hb+0.0031 . PO,. Cardiac index was calculated using PW Doppler echocardiography of the aorta, as previously described [13]. Blood flow in the pulmonary artery was measured only in patient 15 due to turbulent flow in the ascending aorta. In all other patients, Doppler flow was measured in the ascending aorta, just beyond the aortic valve. The angle between the ultrasound beam and the ascending aorta was kept below IO”. The flow-velocity-integral (FVI) was measured using the envelope technique. The diameter of the aortic root (d) was measured at the base of aortic valve using two-dimensional echocardiography. Stroke volume (SV) was calculated as: SV=FVI
* d2/4 * 3.14
Cardiac index (CI) was then calculated CI=HR
Table1. Concomitant
catecholamine
therapy (pg/kg per min)
Patient
Epinephrine
Dobutamine
Dopamine
Norepinephrine
1 2 3 4 5 6 7 8 9 IO 11 I2 13 I4 15 I6
1.1 I.2 2.0 1.2 2.0 2.5 1.4 1.8 1.6 I.8 1.6 I.6 1.5 I.5 1.6 2.0
20 20 20 20 20 10 20 I5 20 15 20 15 15 20 20 IO
5.0 2.5 15.0 5.0 5.0 5.0 15.0 5.0 5.0 5.0 5.0 15.0 5.0 25.0 5.0
-
Table2. Demographic Patient 1 2 3 4 5 6 7 8 9 10 11 12 I3 14 I5 16
Age (days)
2 4 4 2 4 3 5 5 12 6
0.8 _ _ 1 0.6 -
data Weight (kg)
Sex
BSA (m2)
3.52 3.05 3.65 3.12 2.82 3.62 3.54 3.20 2.93 3.64 3.46 3.21 2.71 3.25 3.96 3.12
M F F M F M M M M F F M F M F M
0.240 0.200 0.250 0.260 0.190 0.240 0.230 0.220 0.200 0.240 0.230 0.220 0.190 0.220 0.250 0.220
as:
* SV * BSA-’
(HR - heart rate, BSA - body surface area). Stroke volume index (SVI) and systemic vascular resistance (SVR) were calculated according to standard formulae. The study was approved by the local committee for human research. The parent/guardian has given informed consent to participate in the study.
Statistical analysis Haemodynamic parameters were compared using the Wilcoxon test for paired data. P
