THE authors report a case of a neonate with congenital complex heart anomaly who underwent total repair with a successful outcome, with the use of a forskolin-derived, adenylyl cyclase stimulator, colforsin dalopate hydrogen chloride [HCl].

A FEMALE neonate, weighing 2,690 g, developed severe cyanosis immediately after birth, and was diagnosed as having complex heart anomaly (truncus arteriosus, interruption of aortic arch, aortopulmonary septal defect, patent ducts arteriosus, and persistent foramen ovale). Despite support with dopamine, dobutamine, and epinephrine, congestive heart failure developed. Therefore, total correction surgery was scheduled to take place on the patient's twenty-first day of life.

Anaesthesia was induced and maintained with fentanyl (25 μg/kg) and midazolam (0.3 mg/kg). Surgery was performed under the moderately hypothermic (25°C) cardiopulmonary bypass (CPB) with a total flow of 2.8 l·min−1·m2. CPB was started 55 min after the anesthetic induction. The interval from the start of CPB to the initial attempt to wean the patient from CPB with sufficient body temperature recovery (36.2°C) was 5 h and 20 min. The attempt was made to discontinue CPB with the aid of dopamine (4–8 μg·kg−1·min−1) and dobutamine (5–8 μg·kg−1·min−1). However, decreasing the bypass flow to less than 1.5 l·min−1·m−2resulted in sustained hypotension. Adding epinephrine (0.5 μg/kg/min) and isoproterenol (0.1 μg·kg−1·min−1) did not improve the patient's hemodynamics; her systemic mean arterial pressure while still on partial bypass was ≤ 30 mmHg, while her central venous pressure (CVP) was approximately 17 mmHg. The addition of an infusion of milrinone (0.5 μg·kg−1·min−1) for approximately 40 min also had no significant effect. Echocardiography (using an epicardial probe) showed an adequate surgical repair.

At this point, with the patient back on full bypass support, all inotropic agents were discontinued. We next administered a combination of colforsin dalopate HCl (0.25 μg·kg−1·min−1) and dopamine (5 μg·kg−1·min−1). The patient's CPB flow rate decreased to 1.0 l·min−1·m−2and CVP was controlled at 8–11 mmHg. Over the next 30 min, the patient's mean arterial pressure increased from 35 to 65 mmHg, and her heart rate increased from 140 to 170 beats/min. After approximately 20 min of stable conditions, CPB was successfully discontinued. Her postweaning hemodynamic parameters showed heart rate, mean systemic arterial pressure, and CVP levels in the ranges of 170–180 beats/min, 55–65 mmHg, and 11–13 mmHg, respectively. Arterial blood gas analysis did not show metabolic acidosis, hypercarbia, or hypoxemia. The surgery terminated 2 h after the CPB weaning. Hemodynamic parameters recorded after each attempt to discontinue bypass are summarized in table 1.

Table 1. Changes in Hemodynamic Parameters

Table depicts the changes in systemic, central venous pressures, and heart rate after each of the attempts to discontinue from the bypass. Parameters are depicted as pre- and after 30 min attempt values under assisted flow of 1.0 l · kg−1· m2.

Table 1. Changes in Hemodynamic Parameters
Table 1. Changes in Hemodynamic Parameters

After being transferred to the intensive care unit, the patient's heart rate continued to increase, reaching 190 beats/min. Her colforsin infusion was discontinued while dopamine was maintained. Two hours later, her mean arterial pressure decreased to 35 mmHg from 60 mmHg, her heart rate decreased to 140 beats/min from 170 beats/min, and CVP increased from 11 mmHg to 17 mmHg. An infusion of epinephrine was added, but without success. Therefore, approximately 1 h later, colforsin dalopate HCl infusion (0.25 μg·kg−1·min−1) was restarted. Mean arterial pressure and heart rate quickly increased to 65 mmHg and 178 beats/min, respectively. Colforsin was discontinued without difficulty 5 h later.

This case demonstrates the successful use of colforsin dalopate for cardiovascular support during and after CPB, even when treatment with multiple other drugs had failed.

This patient's apparent insensitiveness to exogenous catecholamines suggests that there was some degree of preoperative adrenoceptor down-regulation, either caused by her chronic congestive heart failure or related to the prolonged preoperative use of adrenergic drugs. This phenomenon has been seen both in adults with chronic heart failure 1,2and in neonates with congenital heart disease and severe cardiac dysfunction. 3 

Colforsin dalopate HCl (Adehl®Inj., Nihon Kayaku Ltd., Tokyo, Japan) is a newly available forskolin derivative in Japan. It exerts its cardiovascular effect through the direct activation of adenylyl cyclase of cardiomyocytes. 4,5Doses in the range of 0.25–0.75 ·kg−1·min−1are recommended. The major adverse effect is tachyarrhythmia (supraventricular and ventricular ectopic beats). However, all of the existing clinical data has been derived from studies of adults, and little information is available regarding its use in children.

The activation of adenylyl cyclase, which is closely linked to β-adrenoceptors, induces the generation of cellular cyclic adenosine monophosphate (cAMP). When the activation of β-adrenoceptors is severely affected, accumulation of cellular cAMP is diminished thorough the catalysis of it by the responsible phosphodiesterase 6,7In this case, we administered milrinone, phosphodiesterase inhibitor [PDEI], in combination with epinephrine and isoproterenol in large doses, but we were not able to normalize the patient's cardiac function. The fact that colforsin dalopate HCl was successful after the failure of milrinone suggests that cAMP formation, presumably caused by the down-regulated state, was of greater importance than cAMP metabolism.

In conclusion, we report a case in which the continuous infusion of colforsin dalopate HCl successfully permitted the weaning of a neonate from CPB after correction of a complex congenital cardiac defect, under conditions in which better known inotropic agents had failed.

Unverferth DA, Blanford M, Kates RE, Leier CV: Tolerance to dobutamine after a 72 hour continuous infusion. Am J Med 1980; 69: 262–6
Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB: Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 1982; 307: 205–11
Kozlik R, Kramer HH, Wicht H, Feldmann R, Netz H, Reinhardt D: Distribution of myocardial β-adrenoceptor subtypes and coupling to the adenylate cyclase in children with congenital heart disease and implications for treatment. J Clin Pharmacol 1993; 33: 588–95
Hosono M, Takahasi T, Fujita A, Fujihara R, Ishizuka O, Tatee T, Nakamura K: Cardiovascular and adenylate cyclase stimulant properties of NHK477, a novel water-soluble forskolin derivative. J Cardiovasc Pharmacol 1992; 625–34
Ishizuka O, Hosono M, Nakamura K: Profile of cardiovascular effects of NHK477, a novel forskolin derivative assessed in isolated blood-perfused dog heart preparations: Comparison with isoproterenol. J Cardiovasc Pharmacol 1992; 20: 262–6
Bohm M, Beuckelmann D, Brown L, Feiler G, Lorenz B, Nabauer M, Kamkes B, Erdmann E: Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium. Eur Heart J 1988; 9: 844–52
Feldman MD, Copelas BS, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP: Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 1987; 75: 331–9