Successful Opening of Ductus Arteriosus with Milrinone in a Newborn with Tetralogy of Fallot and Pulmonary Atresia

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1 Case report pissn eissn J Korean Soc Neonatol 2011;18: Successful Opening of Ductus Arteriosus with Milrinone in a Newborn with Tetralogy of Fallot and Pulmonary Atresia Chong Bock Won, M.D., Min Young Kim, M.D., Duk Young Choi, M.D., Hye Jung Cho, M.D., So Yeon Shim, M.D. and Dong Woo Son, M.D. Department of Pediatrics, Graduate School of Medicine, Gachon University of Medicine and Science, Incheon, Korea Tetralogy of Fallot (TOF) assumes its most severe form when accompanied by pulmonary atresia (PA). Preserving the patent ductus arteriosus to maintain pulmonary blood flow is life-saving for patients with this congenital heart disease. Milrinone, a selective phosphodiesterase III inhibitor, is a potent vasodilator. Here, we report the successful use of milrinone for a newborn infant with TOF and PA for keeping the ductus arteriosus open and thereby maintaining pulmonary circulation. Milrinone is a useful drug because of its inotropic, lusitropic, and pulmonary vasodilating effects, in addition to its ability to keep the ductus arteriosus open and its relatively mild side-effects. Case series and comparative studies will be needed in the future to verify the effectiveness of this drug. Key Words: Congenital heart disease, Tetralogy of Fallot, Pulmonary atresia, Ductus arteriosus, Milrinone, Phosphodiesterase inhibitor, Newborn Introduction Milrinone, an inhibitor of bipyridine phosphodiesterase (PDE) III, increases the level of cyclic adenosine monophosphate (camp), reinforces cardiac muscle contraction, and induces vasodilation 1). It has been used for the management of heart failure and persistent pulmonary hypertension of the neonate (PPHN) 2,3). Both we 3) and other researchers 4) have reported that infants administered milrinone have significantly larger patent ductus arteriosus (DA) diameters after the infusion was commenced. Tetralogy of Fallot (TOF) with pulmonary atresia (PA) is the most severe form of the TOF, and collateral vessels or a patent DA 5) are essential for maintaining pulmonary blood flow. We report a case of a neonate with TOF and PA who was treated with milrinone for maintaining the patent DA and pulmonary blood flow. Case report A male newborn weighing 3,330 g was delivered by a Caesarean section at 38 weeks of gestation. A possibility of ventricular septal defect (VSD) and anomalies of the great arteries were recognized in utero. The Apgar scores were 8 at 1 min and 9 at 5 min. The initial oxygen saturation recorded by pulse oximetry (SpO 2 ) was 72%, and it elevated gradually to 85% by 10 min after birth. The blood pressure (BP) was 59/27 mmhg and the heart rate was 152/min on Received: 16 September 2011, Revised: 4 October 2011, Accepted: 11 October 2011 Correspondence to: Dong Woo Son, M.D. Department of Pediatrics, Graduate School of Medicine, Gachon University of Medicine and Science, Gil Hospital, 1198 Guwol-dong, Namdong-gu, Incheon , Korea Tel: , Fax: , sondw@gilhospital.com Copyright 2011 by the Korean Society of Neonatology Published by the Korean Society of Neonatolog. All rights reserved. 365

2 366 CB Won, et al. Successful Opening of Ductus Arteriosus in Pulmonary Atresia with Milrinone admission. white blood cell count of 12,740/mm3, platelet count of The infant had no abnormalities in the head, neck, 202,000/mm3, aspartate aminotransferase (AST) of 24 U/L, abdomen, limbs, or genitalia. The neurologic findings were alanine aminotransferase (ALT) of 6 U/L, blood urea nitro within the normal ranges. Postnatal echocardiography gen (BUN) of 8.6 mg/dl and creatinine (Cr) of 0.5 mg/dl. showed large VSD and overriding of the aorta (Fig. 1) with Milrinone was administered continuously via percu PA (Fig. 2) and a patent DA. The main pulmonary artery was taneous central venous catheter (PCVC) at an infusion rate of not properly developed. However, the left and right pul µg kg-1 min-1. With the medication, the SpO2 remained monary arteries were normal in size (Fig. 3). No collateral between 90% and 92%. On day 3 of life, follow-up vessels were found, and no other specific abnormalities echocardiography showed an adequately open DA with the were found on abdominal or cranial ultrasonography. The diameter of 3.8 mm (Fig. 4). No desaturation, (i.e., SpO2 laboratory tests on admission revealed hematocrit of 47%, <80%), was noted during milrinone infusion. During the infusion of milrinone, the heart rate ranged from 135/min to 155/min, systolic BP from 55 to 70 mmhg and diastolic BP Fig. 1. Parasternal long axis view of the patient s echocardiogram. Large VSD and overriding of the aorta was shown. The outlet of the right ventricle looked atretic. But the atretic valve was not evident. Only rudimentary main pulmonary artery could be visible (arrows). Abbreviations: LA, left atrium; LV, left ventricle; Ao, aortic root; RV, right ventricle; VSD, ventricular septal defect. Fig. 3. Parasternal short axis view of the patient s echocardiogram. The diameters of the left and right pulmonary arteries were 4.1 mm and 4.6 mm, respectively. Abbreviations: LPA, left pulmonary artery; Ao, Aorta; RPA, right pulmonary artery. Fig. 2. Subcostal anatomical view of the patient s echocardiogram. By tilting the probe upward, the atretic pulmonary valve (arrow) was visible. The patient was diagnosed as TOF with PA. Abbreviations: LV, left ventricle; RA, right atrium; RV, right ventricle. Fig. 4. Parasternal short axis view of the patient s echocardiogram showing the patent ductus arteriosus. The ductus arteriosus was well maintained patent with the diameter of 3.8 mm during the continuous infusion of milrinone. Abbreviation: PDA, patent ductus arteriosus.

3 J Korean Soc Neonatol 2011;18: from 30 to 42 mmhg. The results of the laboratory tests on day 4 of life revealed hematocrit of 39.9%, white blood cell count of 9,100/mm 3, platelet count of 255,000/mm 3, AST of 34 U/L, ALT of 15 U/L, BUN of 5.1 mg/dl and Cr of 0.2 mg/ dl. There were no side effects of milrinone, such as fluctuation of BP, tachycardia, dysrhythmia, thrombocytopenia, or changing of the renal function, during the infusion. On day 5 of life, the patient was transferred to a cardiac surgeon for a shunt operation. Discussion In TOF with PA, the pulmonary valve is atretic, and the pulmonary trunk may be hypoplastic or atretic as well. As the pulmonary valve is atretic, the entire right ventricular output should be ejected into the aorta. To maintain the pulmonary blood flow, collateral vessels, such as major aortopulmonary collateral arteries (MAPCAs) or a patent DA, should be needed. The degree of development of the branch pulmonary arteries decides the ultimate prognosis. If both of branch pulmonary arteries are severely hypoplastic and fail to grow after a palliative shunt procedure like Blalock-Taussig shunt, heart-lung transplantation may be the only option 5). The DA is a normal and essential fetal structure. Abnormalities develop if it remains patent after the neonatal period. In fetal life, the most important factors for patency of the DA are a relatively low fetal oxygen tension and cyclooxygenase-mediated products of arachidonic acid metabolism (primarily prostaglandin [PGE 2 ] and prostacyclin [PGI 2 ]). PGE 2 and PGI 2 are produced locally and circulating in the fetus. PGE 2 and PGI 2 cause vasodilation of the DA by interacting with ductal prostanoid receptors. The production of PGE 2 and PGI 2 is increased by the placenta. Also, their degradation is decreased in the fetal lung. Both of the mechanisms make the levels of circulating PGE 2 and PGI 2 high in the fetus 6). In newborns with various forms of PA, pulmonary blood flow can be almost entirely absent. Therefore, keeping the DA open is critical. Alprostadil, a potent vasodilator also known as prostaglandin E1, is the most common drug used to maintain DA patency. The side-effects of alprostadil include fever, hypotension, rhythm disturbance, inhibition of platelet aggregation, cortical proliferation of long bones with long-term infusion, apnea, and sudden cardiac arrest 7,8). For the current patient, we chose milrinone to maintain pulmonary circulation via the DA to avoid the side-effects of alprostadil. The size of the DA remained the same, and the SpO 2 was stable during milrinone infusion in this patient, with no side-effects. The effects of PDE inhibitors include increasing intracellular camp levels and cardiac contractility, inducing mild systemic vasodilation, and reducing myocardial oxygen consumption 9). PDE inhibitors induce vasodilation by delivering calcium to the sarcoplasmic reticulum 10). They have an inotropic effect mediated by the trans-sarcolemmal flow of calcium 11). Further, they exhibit a lusitropic effect by promoting the dissociation of the actin-myosin complex 12). Milrinone is a selective PDE III inhibitor that has been reported to induce vasodilation of the pulmonary vessels in the PPHN 3). The side-effects of milrinone in infants include arrhythmia, fluctuation of BP, derangement of the renal function, and thrombocytopenia 2,13,14). None of these sideeffects were found in the present case. In a randomized trial of milrinone versus a placebo for the prevention of low systemic blood flow in very preterm infants, the infants randomized for milrinone had significantly larger DA diameters after infusion was commenced. The overall incidence of patent DAs treated with indomethacin was 81% for the milrinone group and 69% for the placebo group, and this difference was not significant 4). In one animal study, milrinone was found to dilate the DA postnatally in a dose-dependent manner. Further, it prevented indomethacin-induced fetal DA constriction 15). We have previously reported the use of milrinone for the treatment of PPHN 3). We have also been using milrinone for pulmonary hypertension, and have found that the DA opens widely after milrinone infusion. In several cases, we effectively used milrinone to keep the DA open in TOF patients (not published). But, there has been no report of the use of

4 368 CB Won, et al. Successful Opening of Ductus Arteriosus in Pulmonary Atresia with Milrinone milrinone for the purpose of opening the DA. To the best of our knowledge and according to a literature review, this is the first report of the successful use of milrinone in a neonate with TOF and PA. Milrinone improves pulmonary hypertension in PPHN patients 3) and the low-cardiac-output state in infants after cardiac surgery 2). Recently, it has been shown to be useful in the management of postsurgical duct ligation myocardial failure 16). For preterm and term infants, very limited reported data is available on the role of milrinone in improving circulation. One study showed that milrinone did not prevent low systemic blood flow during the first 24 hours in very preterm infants 4). Milrinone has been recommended for use in preterm infants who have normal blood pressure but low cardiac output, because of its effects in decreasing afterload and improving cardiac contractility 17). Milrinone might effectively maintain DA patency, increase pulmonary circulation by dilating the pulmonary vessels, and restore cardiac output by improving cardiac contractility and reducing the afterload. Therefore, we believe that milrinone may be more beneficial for certain congenital heart diseases for which maintaining DA patency is critical, such as TOF and PA, as in the present case. We report a successful case of maintaining the patency of DA in a newborn with TOF and PA. Milrinone might be effective for treating certain types of congenital heart diseases that require DA patency to be maintained for adequate pulmonary blood flow. Its advantages could be its inotropic and lusitropic effects and its pulmonary vasodilatory effects, along with limited severe side-effects. To confirm the efficacy of milrinone, further case series and comparative studies are needed in the future. 한글요약 폐동맥폐쇄가동반된팔로네증은팔로네증중에가장심한형태이다. 이런종류의선천성심질환에서폐혈액순환을지속하기위하여동맥관개존을유지하는것은생명을구하는매우중요한치료이다. Milrinone 은선택적인산이에스테르효소 3 억제제이며강력한혈관확장제로알려져있다. 저자들은폐동맥 폐쇄가동반된팔로네증신생아에서폐순환을지속시키기위하여동맥관개방을유지하는치료로 milrinone 을성공적으로사용한증례를보고한다. Milrinone 은동맥관개방효과뿐아니라, 심근수축촉진, 이완촉진, 폐혈관확장효과가있으며부작용은심하지않아더이로운치료방법이될가능성이있다. Milrinone 의치료효과를밝히기위하여더많은치료증례조사와타약제와의비교연구등이필요하다. References 1) Hayes JS, Bowling N, Boder GB, Kauffman R. Molecular basis for the cardiovascular activities of amrinone and AR-L57. J Pharmacol Exp Ther 1984;230: ) Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL. Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 1995;23: ) In DK, Yang SW, Hong HJ, Choi DY, Sun YH, Ryoo E, et al. Experience of milrinone treatment for persistent pulmonary hypertension of the newborn. J Korean Soc Neonatol 2006;13: ) Paradisis M, Evans N, Kluckow M, Osborn D. Randomized trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants. J Pediatr 2009;154: ) Bernstein D. Tetralogy of Fallot with pulmonary atresia. In: Kliegman RM, Stanton BF, St Geme III JW, Schor NF, Behrman RE, editors. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Elsevier Saunders, 2011: ) Schneider DJ, Moore JW. Patent ductus arteriosus. Circulation 2006;114: ) Kaufman MB, El-Chaar GM. Bone and tissue changes following prostaglandin therapy in neonates. Ann Pharmacother 1996;30:269-74, ) Lewis AB, Freed MD, Heymann MA, Roehl SL, Kensey RC. Side effects of therapy with prostaglandin E1 in infants with critical congenital heart disease. Circulation 1981;64: ) Jentzer JH, Lejemtel TH, Sonnenblick EH, Kirk ES. Beneficial effect of amrinone on myocardial oxygen consumption during acute left ventricular failure in dogs. Am J Cardiol 1981;48: ) LeJemtel TH, Scortichini D, Levitt B, Sonnenblick EH. Effects of phosphodiesterase inhibition on skeletal muscle vasculature. Am J Cardiol 1989;63:27A-30A. 11) Silver PJ, Harris AL, Canniff PC, Lepore RE, Bentley RG, Hamel LT, et al. Phosphodiesterase isozyme inhibition, activation of the camp system, and positive inotropy mediated by milrinone in isolated guinea pig cardiac muscle. J Cardiovasc Pharmacol 1989;13: ) Wynands JE. Amrinone: is it the inotrope of choice? J Cardiothorac Anesth 1989;3(6 Suppl 2): ) Ramamoorthy C, Anderson GD, Williams GD, Lynn AM. Pharmacokinetics and side effects of milrinone in infants and children

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