Materials and Methods

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1 The Ductus Debate: Ligation in Prematurity? Willis H. Williams, M.D., Henry Gelband, M.D., Eduardo Bancalari, M.D., Charles Bauer, M.D., Otto Garcia, M.D., Dolores Tamer, M.D., and Gerard A. Kaiser, M.D. ABSTRACT This report describes 20 premature infants who have undergone surgical ligation of a patent ductus arteriosus (PDA), diagnosed solely by physical examination in all but 2 instances. There were no operative deaths. Eleven of these 20 infants had severe associated hyaline membrane disease (HMD) necessitating mechanical ventilatory support from the first or second day of life. Only 3 of these 11 infants (27%) ultimately survived to leave the hospital. In contrast, 8 of 9 premature neonates (89%) with severe congestive heart failure but without HMD were discharged alive. Surgical ligation of the PDA in a premature infant is an appropriate and successful mode of treatment when congestive heart failure is refractory to medical management. Proof is lacking, however, to establish the efficacy of PDA ligation in the premature infant with HMD. Almost twenty-five years elapsed between the successful ligation of a patent ductus arteriosus (PDA) by Gross and Hubbard in 1938 [141 and the application of this operation to premature infants with hyaline membrane disease (HMD) by Powell in 1963 [25]. Numerous publications have recently summarized the results of ductus interruption in the premature infant [3,4, 7, 9, 11, 12, 15-19, 22-24]; unfortunately, these reports have not clearly defined the indications for and usefulness of this procedure. Indications, diagnostic criteria, and timing of operation have varied widely. Randomization of patient selection has been ignored to date. The incidence of persistent patency of the duc- From the Division of Thoracic and Cardiovascular Surgery, the Department of Pediatrics, and the Division of Pediatric Cardiology, University of Miami School of Medicine and Jackson Memorial Hospital, Miami, FL. The technical assistance of Kay Allen and Sheila OMellan is gratefully acknowledged. Accepted for publication Feb 16, Address reprint requests to Dr. Kaiser, Division of Thoracic and Cardiovascular Surgery, PO Box , Miami, FL tus arteriosus in premature infants is well established [l, 2,6,8,10,13,21]. A further increased incidence is apparent in those infants surviving management of HMD and prematurity [19, 20, 27, 291. Our experience indicates relatively distinct separation in both statistical survival and the quality of survival following PDA ligation between premature infants with congestive heart failure alone and those with HMD. This observation was also alluded to by Kitterman and associates [19] in a smaller series of infants in 1972 and has recently been substantiated by Coran and his co-workers [7]. This distinction should aid in the future selection of infants most likely to benefit from ductus ligation. Materials and Methods During the three-year period between May, 1972, and April, 1975,1,640 infants were admitted to the Neonatal Intensive Care Unit at Jackson Memorial Hospital and the Department of Pediatrics of the University of Miami School of Medicine. Sixty-five percent weighed less than 2,500 gm at birth and 11% were less than 1,000 gm. Twenty-two percent were admitted primarily for the treatment of clinically and radiographically apparent HMD. The typical systolic murmur of a PDA was described in 3% at admission; murmurs subsequently became apparent in several more infants. Congestive heart failure in these infants was characterized by tachypnea, tachycardia, edema, fluid retention, progressive hepatomegaly, progressive cardiomegaly, or radiographically apparent pulmonary edema. When it was associated with bounding peripheral pulses, a hyperactive precordium, a characteristic systolic murmur, and a widened umbilical arterial pulse pressure, the presence of a PDA with a large left-to-right shunt was suspected. Medical management consisted of digitalization, fluid restriction, and intravenous adminis- 151

2 152 The Annals of Thoracic Surgery Vol 22 No 2 August 1976 tration of diuretics. Salt-poor albumin was given when total serum proteins were below 4 gm per 100 ml; anemia was corrected by administration of packed red blood cells. Umbilical arterial blood gases were monitored. Orotracheal intubation with continuous positive airway pressure or intermittent mandatory ventilation was used when ventilatory support was required. Cardiac catheterization was carried out in only 1 of these infants suspected of having a PDA, the first child in the series. An isolated aortogram was obtained in another infant, utilizing the umbilical arterial catheter, and demonstrated the ductus as described in two recent reports [7,11]. We have used the echocardiographic diameter of the left atrium compared with the diameter of the aorta, as described by Silverman [28] and Baylen [5] and their colleagues, as supportive evidence for a significant left-to-right shunt. The diagnosis of PDA was based on clinical and physical diagnostic grounds in all subsequent infants. Twenty critically ill premature neonates failing to respond to medical management of congestive heart failure and requiring mechanical ventilatory support were referred for PDA ligation. These 20 infants have been retrospectively divided into two groups: Group A consists of 11 infants with HMD, PDA, and congestive heart failure; Group B consists of 9 with a PDA associated with refractory congestive heart failure but without preexisting HMD. Respiratory distress and the need for ventilatory support were common to most infants. Weaning from the respirator had been attempted without success in those Group A infants in whom support had been required since birth. All infants in Group A were hypoxemic from birth, requiring mechanical ventilation from the first or second day of life (Fig 1). A majority of infants in Group B, without HMD, eventually deteriorated to the point of requiring mechanical ventilatory assistance (Fig 2). Whereas Group A infants required institution of ventilatory support between the first and second day of life, those in Group B were ventilated for the first time at approximately 3 weeks of age. Infants in Group A required an average of twelve days of preoperative ventilatory support; Fig 1. Time course of intubation and ventilatory support in Group A infants (HMD and congestive heartfailure). Only the top 3 infantssurvived. Note that ventilatory support was required from virtually the first day of life in all these children. (Solid dark areas = periods of intermittent positive-pressure ventilation; dotted areas = periods of continuous positive airway pressure through an orotracheal tube; M = time the murmur was first heard; Op = ductus ligation; DC = discharged alive; Died = hospital death.) Group B infants were ventilated for an average of three days preoperatively. The typical systolic murmur of a PDA in infants with elevated pulmonary arterial pressure was noted at about 1 week of age in Group A infants and somewhat later (12 days) in Group B. Other characteristics of these two groups are summarized in the Table. Anesthesia consisted of oxygen, small quantities of nitrous oxide, muscle relaxants, and manual ventilation through an orotracheal tube.

3 153 Williams et al: The Ductus Debate Y k Y + A I-, DC,, I b, DC 100 DIy8 DC I Adm bp DC I+ + k charge for surviving infants was almost identical Y OP 4 I-+ Y OP DC -EH i k k 4 Y OP DC Fig2. Time course of intubation andventilatory support in Group B infants (PDA and congestive heart failure but no HMD). Note the much later initiation of respiratory support in these infants than in Group A neonates. Only 1 hospital death occurred in thisgroup. (Key same asfor Figure 1.) The PDA was exposed through a posterolateral left transpleural thoracotomy in the third intercostal space and was doubly ligated. The thoracotomy, ductus ligation, and closure required between 10 and 20 minutes. Infants were transferred back to the Neonatal Intensive Care Unit for postoperative care. Results There were no intraoperative deaths in this series of 20 infants. Most hospital deaths occurred many days-even weeks-following operation. Two infants died within 24 hours following operation, 1 as a result of pneumothorax and the other with septicemia and central nervous system hemorrhage. Necrotizing enterocolitis, sep- DC sis, and central nervous system hemorrhage were the predominant factors in the other 9 deaths. Of the 11 infants in Group A with HMD and congestive heart failure, only 3 ultimately survived to be discharged from the hospital. Eight of the 9 infants in Group B with congestive heart failure refractory to medical management lived. The single death in this group was preventa- ble-an unrecognized pneumothorax resulting in cardiac arrest. Those infants who survived improved quickly, requiring an average of five days of postoperative ventilatory support compared with nineteen days for those who ultimately died. The average weight gain from operation until dis- to that which one would expect for normal premature infants of equivalent gestational age (Fig 3). All the surviving patients in these combined groups have progressed satisfactorily since discharge except for 1 infant, who has hydrocephalus requiring shunting. Psychometric assessment of the 11 surviving infants is in progress. Comment We have followed the conservative and noninvasive operative indications outlined by Murphy and his co-workers [231 with minor modifications. The presence of a PDA was suspected from auscultation several days before surgical intervention. Congestive heart failure unresponsive to digitalis and diuretics was apparent radiographically by cardiomegaly, increased pulmonary vascular markings, perihilar prominence, and in some cases frank pulmonary edema. Arterial blood gases indicated a progressively rising carbon dioxide tension. Two infants did not require ventilatory support until a short time before operation. Peripheral edema, periorbital edema, and hepatomegaly were present in some of these patients, although we have usually intervened surgically prior to the onset of these late manifestations of congestive heart failure. Based on our experience with these 20 premature infants, we see no need for cardiac catheterization. The high incidence of complica-

4 154 The Annals of Thoracic Surgery Vol 22 No 2 August 1976 Data on 20 Patients with Patent Ductus Arteriosus and Congestive Heart Failure Group A: Group B: HMD & CHF CHF Only Factor Survivors Deaths (N = 3) (N = 8) Survivors Deaths (N = 8) (N = 1) Sex Gestation (wk) Birth weight (kg) First day of respiratory support Preop respiratory support (days) Day murmur first heard Age at operation (days) Weight at operation (kg) Postop respiratory support (days) Postop hospitalization (days) Weight gain per day (gm) Weight at discharge or death (kg) Age at discharge or death (days) 2WlF ( ) 1 17 (10-23) 9 (4-15) 18 (14-23) 1.4 ( ) 5 (1-10) 59 (48-65) 21 (14-27) 2.7 ( ) 77 (71-83) 2M16F 31 (28-33) 1.3 ( ) 1.5 (1-3) 11 (4-16) 6 (2-9) 12 (8-16) 1.2 ( ) 19 (0-56) 33 (1-159) 7 (0-20) 1.4 ( ) 46 (10-175) 3W5F 30 (25-32) 1.2 ( ) 24 (1-51) 3 (1-11) 12 (1-28) 28 (16-51) 1.2 ( ) 2 (W 40 (19-71) 23 (9-36) 2.1 ( ) 68 (44-100) F HMD = hyaline membrane disease; CHF = congestive heart failure. Ranges in parentheses. tions following catheterization described by Horsley and colleagues [161 and the low incidence of associated anomalies found by Edmunds [lll and Zachman [291 and their associates support our conservative approach. Ligation of the PDA in each of these 20 infants resulted in obliteration of the murmur with no instance of recurrence. No other cardiac defects have been demonstrated among the survivors; no other cardiac anomalies were found in those infants who died and in whom postmortem examination was performed. When clinical findings are typical, cardiac catheterization is unnecessary and would add potential complication and delay. The role of the patent ductus in the evolution of HMD remains undefined. Least tenable is the concept that ductus patency allows "decompression'' of a hypertensive pulmonary vascular bed by means of a right-to-left shunt. Rudolph and colleagues [26] demonstrated low pulmonary and systemic arterial pressure in catheterizations performed on critically ill premature infants with HMD. Most of these infants had a predominant left-to-right shunt, although a mixed shunt was apparent in some. The indicator-dilution studies done by Coran and associates [71 support the data of Rudolph's group, the infants having had significant leftto-right shunts through the PDA. The changing character of the ductus murmur reflects alterations in relative pulmonary and systemic vascular resistances, and perhaps changes in the ductus lumen itself. We lack hemodynamic proof of the magnitude of the left-to-right shunt in the infants described in this report, but all clinical findings point to a large aortic runoff into the pulmonary vascular bed. It is unlikely that the role of the patent ductus in HMD can be resolved until noninvasive diagnostic methods establish the time course of in-

5 155 Williams et al: The Ductus Debate / / A6E IN DAYS Fig3. Weightgain beforeand afterpda ligation in premature infants with respiratory distress syndrome. Note the marked weightgain following PDA ligation in thesurviving infants. (The points along the vertical axis indicate birth weights. The point at which the slope changes represents age and weight at operation. The right end of each line shows weight and age at discharge.) creasing pulmonary blood flow and rising left atrial pressure. A multiinstitutional, randomized prospective study will be required before the therapeutic role of ductus ligation in premature infants with HMD can be established. In contrast, ductus ligation should be carried out in the premature infant with congestive heart failure refractory to medical management who requires ventilatory assistance. The operative risk is low, and the heart failure can be controlled and the infant rapidly weaned from mechanical ventilatory support. Follow-up suggests nearly normal subsequent growth and development. The low immediate operative mortality reported for premature infants with HMD and a PDA must not itself lead to the conclusion that ductus ligation is appropriate therapy. Proof of the efficacy of this procedure is lacking. While there are those who argue for earlier ductus ligation, even before the murmur and hyperdynamic circulatory signs of a large left-to-right shunt appear 171, we, like others, have seen infants with HMD and an unequivocal PDA in whom the PDA closed without operation. Until definitive data are available, we advocate ductus ligation only in those premature infants who are ventilator dependent, demonstrate deteriorating pulmonary compliance, and, because of progressive congestive heart failure, retain fluid to a degree that forces their daily caloric intake below the minimum requirement necessary for anabolic weight gain. It is difficult to conceive of any beneficial role for the large PDA in these critically ill infants. The possibility remains that early PDA ligation may offer more benefit than waiting until the later, severe stage of the disease, References 1. Anderson RC: Causative factors underlying congenital heart malformations: I. Patent ductus arteriosus. Pediatrics 14:143, Auld PAM: Delayed closure of the ductus arteriosus. J Pediatr 69:61, Bahnson HT: Managing patent ductus in premature newborns with RDS. Contemp Surg 7:37, Bauersfeld SR, Adkins PC, Kent EM: Patent ductus arteriosus in infancy. J Thorac Surg 33:123, Baylen BG, Meyer RA, Kaplan S, et al: The critically ill premature infant with patent ductus arteriosus and pulmonary disease-an echocardiographic assessment. J Pediatr 86:423, Blancquaert A, Van Den Bogaert-Van Heesvelde AM: Ductus arteriosus with fatal evolution in the first week of life. Acta Paediatr Belg 28:5, Coran AG, Cabal L, Siassi B, et al: Surgical closure of patent ductus arteriosus in the premature infant with respiratory distress. J Pediatr Surg 10:399, Danilowicz D, Rudolph AM, Hoffman JIE: Delayed closure of the ductus arteriosus in premature infants. Pediatrics 37:74, Decancq HG Jr: Repair of patent ductus arteriosus in 1,417 gram infant. Am J Dis Child 106:402, Dunn PM, Speidel BD: Use of oxygen to close patent ductus arteriosus in preterm infants. Lancet 2:333, Edmunds LH Jr, Gregory GA, Heymann MA, et al: Surgical closure of the ductus arteriosus in premature infants. Circulation 48:856, Gay JH, Daily WJR, Meyer BHP, et al: Ligation of the patent ductus arteriosus in premature infants: report of 45 cases. J Pediatr Surg 8:677, Girling DJ, Hallidie-Smith KA: Persistent ductus

6 156 The Annals of Thoracic Surgery Vol 22 No 2 August 1976 arteriosus in ill and premature babies. Arch Dis Child 46:177, Gross RE, Hubbard JP: Surgical ligation of a patent ductus arteriosus. JAMA 112:729, Gupta JM, Van Vliet PKJ, Fisk GC, et al: Ductus ligation in respiratory distress syndrome. J Thorac Cardiovasc Surg 63:642, Horsley BL, Lerberg DB, Allen AC, et al: Respiratory distress from patent ductus arteriosus in the premature newborn. Ann Surg , Jegier W, Karne G, Stern L: Operative treatment of patent ductus arteriosus complicating respiratory distress syndrome of the premature (abstract). Can Med Assoc J 98:105, Kilman JW, Kakos GS, Williams TE Jr, et al: Ligation of patent ductus arteriosus for persistent respiratory distress syndrome in premature infants. J Pediatr Surg 9:277, Kitterman JA, Edmunds LH Jr, Gregory GA, et al: Patent ductus arteriosus in premature infants: incidence, relation to pulmonary disease and management. N Engl J Med 287:473, Krovetz LJ, Rowe RD: Patent ductus, prematurity and pulmonary disease. N Engl J Med 287:513, Lees MH: Commentary: patent ductus arteriosus in premature infants-a diagnostic and therapeutic dilemma. J Pediatr 86:132, Lewis CE Jr, Coen RW, Talbot W, et al: Early surgical intervention in premature infants with respiratory distress and patent ductus arteriosus. Am J Surg 128:829, Murphy DA, Outerbridge E, Stern L, et al: Management of premature infants with patent ductus arteriosus. J Thorac Cardiovasc Surg 67:221, Neal WA, Bessinger FB Jr, Hunt CE, et al: Patent ductus arteriosus complicating respiratory distress syndrome. J Pediatr 86:127, Powell ML: Patent ductus arteriosus in premature infants. Med J Aust 2:58, Rudolph AM, Drorhaugh JE, Auld AM, et al: Studies on the circulation in the neonatal period: the circulation in the respiratory distress syndrome. Pediatrics 27:551, Siassi B, Emmanouilides GC, Cleveland RJ, et al: Patent ductus arteriosus complicating prolonged assisted ventilation in respiratory distress syndrome. J Pediatr 74:11, Silverman NH, Lewis AB, Heymann MA, et al: Echocardiographic assessment of ductus arteriosus shunt in premature infants. Circulation , Zachman RD, Steinmetz GP, Botham RJ, et al: Incidence and treatment of the patent ductus arteriosus in the ill premature neonate. Am Heart J 87:697, 1974