Premature Infants with Patent Ductus Arteriosus and Res iratory Distress: Selection for mdap Ligation George S. Hall, M.D., James A. Helmsworth, M.D., J. Tracy Schreiber, M.D., Jens G. Rosenkrantz, M.D., Lester W. Martin, M.D., Barry G. Baylen, M.D., and Samuel Kaplan, M.D. ABSTRACT Operative treatment of patent ductus arteriosus (PDA) in premature infants with respiratory distress has been advocated when rapid and favorable response to medical management has not occurred. At Cincinnati Children s Hospital from September, 9, to January, 95, 8 patients with respiratory distress syndrome (RDS) and PDA underwent ductal ligation after failing to respond to intensive medical management. There were 5 survivors and deaths, for a survival rate of 5%. We have found the most reliable assessment of PDA and its response to medical management to be a reduction in left cardiac chamber size as evidenced by echocardiography. In 5 of the 8 infants who underwent ligation, echocardiography showed that they had failed to respond to medical management. Seven of the group survived. During the same period 5 infants with RDS and PDA responded favorably to medical management and showed return of left cardiac chamber size to normal by serial echocardiograms. Of these, survived and 4 died of noncardiac causes. Clinical improvement was corroborated without exception by echocardiographic demonstration of a reduction in size of the left cardiac chamber. We believe that infants who follow this course should not have ductus ligation. We contend that the choice of surgical candidates should be more selective since a survival rate of only 50% has been obtained in this and other series. Further, we have found that only 8 of 4 long-term survivors in our series are free from pulmonary disease. From the Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Cincinnati Medical Center, and the Division of Cardiology, Children s Hospital, Cincinnati, OH. Accepted for publication Feb, 96. Address reprint requests to Dr. Helmsworth, Department of Surgery, College of Medicine, University of Cincinnati Medical Center, Bethesda Ave, Cincinnati, OH 456. Patent ductus arteriosus (PDA) was originally described by Gibson in 900 [6. It was successfully treated operatively by Gross and Hubbard in 98 [, and since then surgical closure of PDA has become a commonly practiced operation. The incidence of patent ductus in the general population is 0.04% in term infants at sea level [ll] and 0.% at high altitudes [. However, patent ductus occurs in 5% of premature infants [4, 0. Many of these premature neonates also have respiratory distress syndrome (RDS)[5]. Surgical ligation of the patent ductus in such infants has been advocated in several recent reports [5,8-0,8, and the need for early diagnosis and operative intervention in those who do not show a favorable response to medical management has been stressed. Our experience at the Cincinnati Children s Hospital with this important problem [ prompted us to review our results. This experience along with a description of early diagnosis and follow-up evaluation of patent ductus by echocardiography form the basis of this report. Materials and Methods From September, 9, through January, 95, 8 infants with RDS and PDA underwent ductal ligation at the Cincinnati Children s Hospital. The clinical diagnosis of respiratory distress was made on the first day of life in all cases by the findings of apneic episodes, bradycardia, hypoxia, acidosis, and the presence of a diffuse reticulogranular pulmonary shadow on chest roentgenograms. Patent ductus was diagnosed clinically by a harsh systolic murmur that frequently extended into diastole and was most prominent over the midleft sternal border. There was also accentuation of peripheral pulses and widening of the pulse pressure. The diag- 46
4 Hall et al: Patent Ductus Arteriosus and Respiratory Distress Table. Data on the 8 Patients with Respiratory Distress Syndrome and Patent Ductus Arteriosus Approximate Postnatal Age Birth Weight Gestational Age at Operation (gm) Male Female (wk) (days) 00-99 0 4 80Ck999 5-8 8-8,000-,499 0 6- - 5,500 4 0-4 6-5 nosis was confirmed in each of the 8 infants at operation. As our experience evolved, the indications for operation varied but generally were persistence of signs of patent ductus, continued need for artificial ventilation, or worsening respiratory status as shown by serial blood gas determinations and radiographic evidence of progressive pulmonary deterioration. The composition of the group with details on weight, gestational age, and interval from birth to operation is given in Table. Twenty infants were given digitalis when the clinical diagnosis of patent ductus or congestive heart failure was made, and were given furosemide intermittently. Twenty-three patients were artificially ventilated preoperatively; this treatment started shortly after birth in most cases and was continued throughout the preoperative period, which varied from to days. Five infants did not require artificialventilation at any time prior to ductus ligation. Four of the ventilated patients demonstrated radiographic evidence of cardiomegaly. Details relating to artificial ventilation and roentgenographically demonstrated cardiomegaly are listed in Table. Echocardiography was employed during the last two years of the four-year period to evaluate patients with suspected patent ductus. Particular attention was paid to the estimated anteroposterior dimensions of the left atrium and left ventricle at the end of diastole. These chambers were considered enlarged when their measurements exceeded the mean plus standard deviations for groups of infants studied at this institution with similar weights who did not have PDA [. Fifteen infants in this group of 8 underwent echocardiographic estimation of left atrial and ventricular size. During the same period, 5 additional infants with RDS and the clinical diagnosis of PDA had echocardiograms and did not undergo ductal ligation, having improved clinically on medical management. This group of infants was used in our study to augment the data relative to left atrial and ventricular size and the influence of changes in these dimensions on indications for ductal ligation. Table. Details on Artificial Ventilation and Cardiomegaly in Patients Day of Life Preoperative Artificial Ventilation Radiographic Ventilation Time Evidence of Was Initiated (days) Cardiomegaly 5 5 8 4 9 0 5 5 4 0 0 4 4 6 6
48 The Annals of Thoracic Surgery Vol No August 96 Results Thirteen of the 8 babies (46%) undergoing ductal ligation died during initial hospitalization. Postmortem examination was obtained in 8 of them. Times of death are given in Table along with mortality rates by birth weight. Causes of in-hospital death included: bronchopulmonary problems (6 infants); pneumonia or progressive RDS or both ( infants); intracranial hemorrhage ( infants); necrotizing enterocolitis ( infant); and sepsis ( infant). In several cases multiple causes were recognized. No deaths were directly attributed to operation. Surgical complications among the babies dying in the hospital were confined to patient who had acute hemorrhage from a small aortic branch with resultant transient shock. Of the 5 infants discharged from the hospital alive, none had significant surgical complications. These babies were discharged 40 to 65 days postoperatively. Seven appeared to have significant residual pulmonary disease after discharge (roentgenographic changes consistent with bronchopulmonary dysplasia or chronic cor pulmonale necessitating digitalis therapy). One of these infants subsequently died 0 days postoperatively of acute respiratory insufficiency secondary to preexisting severe subglottic stenosis. Of the remaining 4 patients still alive at this time, 8 are free from pulmonary symptoms and 6 appear to have significant chronic lung disease. Of the 5 infants who underwent echocardiography with subsequent ductal ligation, all showed persistent enlargement of the left cardiac chamber in the preoperative period, and all were judged at operation to have a PDA of significant size. Of the 5 infants undergoing Table. Details on the Hospital Deaths Time of In- Death Birth Weight No. of Hospital (days (gm) Infants Deaths postop) 00-99 0 800-999 4, 5,000-,499 9-0 5,500 6, echocardiography whose patent ductus was managed medically, all showed an initially enlarged left cardiac chamber that returned to normal with one to two weeks of medical therapy. Eleven of these infants improved and were discharged from the hospital with still showing evidence of persistent patent ductus. Four of the 5 died 0 to 0 days after beginning medical therapy. In of them postmortem examination demonstrated that the ductus was closed. The other did not undergo postmortem examination, but it was certain that they died of noncardiac causes. Comment Successful ligation of a PDA in the presence of RDS was described by Powell in 96 [4]. Since that time, several reports have supported operative intervention as a means of relieving respiratory distress and preventing bronchopulmonary dysplasia 5, 8-0, 8. Our patients have closely corresponded to those in other large groups reported. The premature infants we evaluated had RDS and gestational ages of 5 to 5 weeks with the majority at about 0 weeks. Their birth weights ranged from 00 to,00 gm with the majority being below,000 gm. The overall sex ratio has been approximately equal. This differs from the usual groups of patients with patent ductus without prematurity and RDS, in which a greater female-to-male ratio has been seen. The diagnosis of RDS was made on the first day of life. The presence of appropriate clinical findings led to the identification of an associated patent ductus. Chest roentgenograms and electrocardiographic findings were of little value in early diagnosis. Cardiac catheterization has established the diagnosis with a high degree of accuracy. However, occasional complications and the low incidence of associated cardiac anomalies has led to infrequent use of this method in most medical centers. Thibeault and co-workers [ have recently demonstrated patent ductus in 46 premature infants with RDS by single-film aortography. The estimated left-to-right shunt through the ductus by aortogram correlated well with the heart size and the clinical diagnosis of heart failure. In 4 infants with heart failure the
49 Hall et al: Patent Ductus Arteriosus and Respiratory Distress ductus was demonstrated before a murmur appeared. Echocardiography has proved to be a most dependable, safe, and rapid method of diagnosing a PDA in infants with RDS [,,6. Left cardiac chamber enlargement is frequently found at the time a murmur is first heard. Serial evaluations are easily obtained, and a return of the left cardiac chamber size to normal with successful medical management or following ductal ligation has been consistently observed [. The Figure illustrates changes in dimensions in an infant who had abnormal preoperative measurements. The indications for ductal ligation in babies with RDS have been failure of medical therapy to control congestive failure and deterioration of pulmonary function (increasing carbon dioxide retention, hypoxemia, and reduction in pulmonary compliance) [5,8-,8. In a recent report by Gay and associates [5], there were 0 survivors and 4 deaths in a group of respiratordependent infants with PDA and RDS treated by ductal ligation, a 68% survival rate. In contrast, 5 infants not requiring artificial ventilation received ligation of the ductus with only death, which was related to operation. Gay and his associates concluded that ductal ligation should be performed within 4 days of diagnosis to prevent bronchopulmonary dysplasia if a positive The left atrial dimension (LAD) is reduced by one-third following ductal ligation in an infant. (MV = mitral valve; LAW = left atrial wall; Ao = aortic outflow tract.) response to medical management is not obtained. In a similar series reported by Zachman and colleagues [8] a 60% incidence of bronchopulmonary dysplasia was found in the babies who died. The survival rate in our group (50) is similar to the rates given in other reports [5, 8. However, the overall results in terms of mortality and quality of life among survivors have been unsatisfactory in our experience. Over the long term, 6 of our 4 long-term survivors have chronic lung disease, many with cor pulmonale. These results indicate that at present there is insufficient information on which to base proper patient selection for ligation. Apparently, many infants are operated on after irreversible effects have occurred in a compromised respiratory system. The exact mechanism by which a patent ductus affects pulmonary mechanics, gas exchange, and the development of bronchopulmonary dysplasia remains to be clarified. It is suspected that further pulmonary damage occurs after large left-to-right ductal shunts have caused left heart failure. Volume overload of the left atrium produces elevation of pulmonary venous and capillary pressures with resultant alveolar transudation and hypoventilation. A serious ventilationlperfusion disorder occurs, with reduction of lung compliance. This ultimately results in decreased oxygenation and further impairment of the stressed left ventricle. Prevention of these complications will likely depend on earlier recognition and ligation of the patent ductus that is shunting a large volume Preoperative 4 hr Postoperative
50 The Annals of Thoracic Surgery Vol No August 96 from left to right. It may be necessary to employ special methods for recognition. For example, aortography quite often can demonstrate a patent ductus before a murmur is evident. Certainly, earlier use of echocardiography shows much promise for demonstrating left chamber enlargement associated with patent ductus before clinical signs of cardiac decompensation occur [, 6. It should be possible to perform ductal ligation prior to the development of irreversible pulmonary changes. One would hope that an increase in immediate survival and preservation of cardiopulmonary function in the long term could then be accomplished in these seriously ill infants. References. Anderson RC: Causative factors underlying congenital heart malformations: I. Patent ductus arteriosus. Pediatrics 4:4, 954. Baylen D: Critically ill prematures with patent ductus arteriosus and respiratory disease. J Pediatr 86:4, 95. Baylen B, Meyer RA, Kaplan S: Echocardiographic assessment of prematures with respiratory distress syndrome (abstract). Pediatr Res 8: 4, 94 4. Danilowicz 0, Rudolph AM, Hoffman JIE: Delayed closure of the ductus arteriosus in premature infants. Pediatrics :4, 966 5. Gay JH, Daily WJR, Meyer BHP, et al: Ligation of the patent ductus arteriosus in premature infants: report of 45 cases. J Pediatr Surg 8:6, 9 6. Gibson GA: Clinical lectures on circulatory affections: Lecture. Persistence of the arterial duct and its diagnosis. Edinburgh Med J 8:, 900. Gross RE, Hubbard JP: Surgical ligation of a patent ductus arteriosus: report of first successful case. JAMA :9, 99 8. Gupta JM, Fisk GC, Wright JA: Ductus ligation in the respiratory distress syndrome. J Thorac Cardiovasc Surg 6:64, 9 9. Horsley BL, Lerberg DB, Allen AC, et al: Respiratory distress from patent ductus arteriosus in the premature newborn. Ann Surg :806, 9 0. Kitterman JA, Edmunds LH, Gregory GA, et al: Patent ductus arteriosus in premature infants. N Engl J Med 8:4, 9. Lees MH: Patent ductus arteriosus in premature infants-a diagnostic and therapeutic dilemma (commentary). J Pediatr 86:, 95. Neal WA, Bersinger FB, Hunt CE, et al: Patent ductus arteriosus complicating respiratory distress syndrome. J Pediatr 86:, 95. Penaloza D, Arias-Stella J, Sime F, et al: The heart and pulmonary circulation at high altitudes: physiological, anatomical, and clinical observations. Pediatrics 4:568, 964 4. Powell ML: Patent ductus arteriosus in premature infants. Med J Aust :58, 96 5. Siassi B, Emmanouilides GC, Cleveland RJ, et al: Patent ductus arteriosus complicating prolonged assisted ventilation in the respiratory distress syndrome. J Pediatr 4:, 969 6. Silverman NH, Lewis AB, Heymann MA, et al: Echocardiographic assessment in ductus arteriosus shunt in premature infants. Circulation 50:8, 94. Thibeault DW, Emmanouilides GC, Nelson RJ, et al: Patent ductus arteriosus complicating the respiratory distress syndrome in preterm infants. J Pediatr 86:0, 95 8. Zachman RD, Steinmatz GA, Botham RJ, et al: Incidence and treatment of the patent ductus arteriosus in the ill premature neonate. Am Heart J 8:69, 94