Specialty Conference Participants T. ALLEN MERRITT, MD LOUIS GLUCK, MD CHARLES HIGGINS, MD WILLIAM FRIEDMAN, MD WILLIAM L. NYHAN, MD, PhD From the Department of Pediatrics and Department of Radiology, University of California, San Diego, School of Medicine, and University Hospital, San Diego.
WILLIAM L. NYHAN, MD, PH D: * Tiny premature infants, already compromised by the respiratory distress syndrome, frequently have the additional problem of a patent ductus arteriosus. We shall consider the recognition of patent ductus arteriosus within the context of seriously ill premature infants and the correlation of radiologic and clinical findings, and examine the experience at the University of California, San Diego (UCSD), with this problem. This will lead to a review of the exciting new developments in the field of prostaglandin pharmacology and their relevance to clinical management. We shall start with a consideration of the clinical problem by Dr. Gluck. Louis GLUCK, MD:t Discussion of the ductus begins not with the cardiologist but with the physician who looks after the newborn infant. It is our firm belief after a significant experience with patent ductus arteriosus that we, not cardiologists, are the ones who should make the diagnosis first. I shall try to amplify and clarify this statement. *Professor and Chairman, Department of Pediatrics. tProfessor of Pediatrics and Reproductive Medicine, Head, Division of Perinatal Medicine. Reprint requests to: William L. Nyhan, MD, PhD, Department of Pediatrics, M-009, University Hospital, P.O. Box 3548, San Diego, CA 92103.
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MARCH 1978 * 128 * 3
Refer to: Merritt TA, Gluck L, Higgins C, et al: Management of premature infants with patent ductus arteriosus (Specialty Conference). West J Med 128:212-222, Mar 1978
anagement of remature Infants rith Patent Ductus rteriosus
Historically the ductus first was mentioned in the writings of Galen in the second century AD. He dissected and described the first ductus arteriosus. It was subsequently described approximately 15 centuries later in Italy by Leonardo Botallo. The first medical concern with the ductus came in about 1900, when Gibson described the classic machinery murmur and discussed the ductus as a clinical entity. Then seven years later, in 1907, Munro described the first surgical approach, but it was not until 1938 that Gross for the first time successfully closed the ductus. There has been an understanding of the complications of patent ductus arteriosus (PDA) in premature infants-although we like to think that this is very recent-since the mid-1950's. We may perhaps get the mistaken notion that it was not until the advent of continuous positive airway pressure (CPAP) that we began to appreciate the patent ductus in small babies. However, Eric Burnard, while a Visiting Fellow at Columbia University and Babies Hospital in the mid-1950's, described patent ductus arteriosus as a complication of hyaline membrane disease. This led, in fact, to another misconception, held for a long time, that patent ductus arteriosus and consequent heart failure were "what hyaline membrane dis-
PREMATURE INFANTS ABBREVIATIONS USED IN TEXT CPAP=continuous positive airway pressure F102=forced inspiratory oxygen LA/AO=left atrial to aortic (ratio) PDA = patent ductus arteriosus RDS=respiratory distress syndrome UCSD=University of California, San Diego ease was all about." What Burnard found was that in every baby with hyaline membrane disease a definite murmur developed at some time or other. He chose to believe that respiratory distress syndrome (RDs) or hyaline membrane disease was really a complication of cardiac disease, and the theory was proposed that hyaline membrane disease represented a unique form of chronic congestive heart failure. Although the cause of the disease is not congestive failure, it is true that by the time a premature infant has lived long enough and has begun to get better, he usually will show this complication. One might state that in very small babies the incidence of patent ductus, whether significant or insignificant, must be considered 100
percent.
Although it had been known for many years that patent ductus was a major complication in very small babies, it usually was diagnosed terminally, and these infants went on to death. A major contribution of CPAP has been to keep these small babies alive. Whether or not they ultimately survived, they were now living long enough for the patent ductus to be recognized as a definite clinical entity and as an important early complication of hyaline membrane disease. In San Francisco, here at UCSD and in a few other places where CPAP techniques were in wide use, everyone began to have the same experience. The babies with RDS would continue to get better up to a point, and then they would get worse. As we improved our techniques for managing babies with RDS the early diagnosis of PDA became much more subtle. We now have a unique situation where I think the kind of mechanical support of ventilation that we give a small premature infant with RDS leaves little residual problem in the baby's lungs. As a consequence, the diagnosis of patent ductus becomes possible even on the first day of life. The hemodynamics in premature infants are somewhat different than in larger newborns. They do not have comparable
pulmonary arteriolar musculature. Systemic pressure is much lower, and in many instances we see the development of pulmonary edema very early. In current and proper management of a baby with hyaline membrane disease, the usual story is that the baby progresses to some degree of ventilatory failure. The baby is treated with mechanical ventilation, because we feel this is the least harmful way to treat ventilatory failure. The baby then begins to improve. First the fractional inspired oxygen (FIo,) can be lowered. Whereas treatment may have been started at somewhere over 60 percent FIO9, perhaps 80 or 90 percent, very promptly this can come down to perhaps 50 percent. The arterial oxygen pressure (Pao2) remains high, the baby oxygenates well and continues to improve, and ventilatory assistance can be reduced more and more. In a weaning schedule, we are ready to take the baby off the ventilator, and then we arrive at a point at which the baby does not get any better. At this time we may or may not hear a murmur of PDA, and we may or may not see changes on x-ray studies, and the pulses may or may not be bounding. The liver may or may not get larger, and the heart may or may not get bigger, but we are faced with a situation in which the baby has stopped getting better. When PDA is not a complication, the baby does get better. We use a weaning schedule and finally take the baby off the ventilator. Usually they do very well. In a baby in whom the PDA is a significant complication, the classic story is for the baby just to stop getting better. Pulmonary edema does, indeed, develop. Carbon dioxide begins to accumulate. More ventilation is required and a little more oxygen will be required. At this point, generally the baby does have some cardiomegaly. The liver may be down a bit, and on x-ray studies shunt vessels begin to be seen, along with evidence of pulmonary edema. I have emphasized the earliest findings in babies with PDA and the fact that these findings are subtle. They do not present as sudden overwhelming cardiac disease, as we have considered the ductus in years gone by. This is approached at first as a statistical variation in the way the babies should be progressing. They simply stop getting better in spite of excellent management. THE WESTERN JOURNAL OF MEDICINE
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In this situation the commonest complication to be considered is patent ductus arteriosus. DR. NYHAN: In view of the subtle early manifestations of this complication so clearly presented by Dr. Gluck it would be of interest to develop objective measures to evaluate these babies' condition. Dr. Charles Higgins has been concerned with roentgenographic approaches to the determination of when difficulties are beginning in infants, and he will discuss these aspects of the problem now. CHARLES HIGGINS, MD: * In spite of the frequency of the problem of PDA in preterm infants with RDS, surprisingly few data are available that corTABLE 1.-Criteria for the Assignment of Infants to Each of the Study Groups, and Numbers of Infants in Each Group
CLINICAL GRADES 1. Small shunt (7 infants) Intermittent murmur Normal pulses 2. Moderate shunt (11 infants) Systolic murmur Prominent pulses Infrequent episodes of apnea/bradycardia 3. Large shunt (37 infants)
Systolic/diastolic murmur Bounding pulses Multiple episodes of apnea/bradycardia Respirator dependency Hepatomegaly PLETHORA
INITIAL PULMONARY PLETHORA
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monary vascularity. Associate Professor of Radiology.
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MARCH 1978 * 128 * 3
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relate the sequential radiographic findings with the clinical course or the echocardiographic findings. In order to obtain this type of correlation, we recently evaluated sequential radiographic findings in a group of 55 infants'with PDA in the setting of RDS, along with the clinical and echocardiographic findings.' The sequential radiographic findings we assessed were increases in pulmonary vascularity and cardiomegaly. Clinical severity was the measure of the left-to-right shunt. The echocardiographic marker of a large shunt was an 'abnormal left atrial-to-aortic ratio. In order to confirm that the radiographic findings were, in fact, due to the PDA we noted regressive changes in the pulmonary vascularity and cardiomegaly after closure of'the shunt. The 55 infants with PDA were divided into three groups, on the basis of the clinical severity of the shunt. The number of patients in each group and the criteria for inclusion in each category are indicated in Table 1. Most of the patients fell into the large shunt category. This may reflect the fact that there is a greater likelihood that in a child with a large shunt there will be sequential radiographic examinations. Figure 1 provides data on plethora and the age at which peak pulmonary vascularity was observed. The time of onset was usually between the second and sixth day. Most patients present with increase in pulmonary vascularity within the first week of life. However, the time of peak
PREMATURE INFANTS
increase in pulmonary vascularity is usually delayed until the end of the first week or during the second week. Figure 2 relates the time that a murmur was detected clinically with the radiographic appearance of increase in pulmonary vascularity. In 56 percent of the infants there was radiographic evidence of increase in pulmonary vascularity before murmur detection; that is, at least 24 hours before the clinical detection of a cardiac murmur. In 26 percent of patients there was simultaneous appearance of the murmur and increase in pulmonary vascularity. The clinical detection of a murmur occurred before the radiographic observation of pulmonary plethora in only 18 percent of these infants. There was no significant difference in the time of onset or time of peak pulmonary vascularity between those patients with small or moderatevolume shunts and those with large-volume shunts. Pulmonary edema was seen almost exclusively in patients with large-volume shunts. This was true for perihilar edema as well as generalized pulmonary edema. In only a single patient with a moderate-volume shunt was there radiographically apparent pulmonary edema. A typical radiographic sequence in a child with a large-volume shunt is portrayed in Figure 3. The radiograph on the first day of life showed a normal cardiac size, evidence of some hyaline membrane disease and some retained lung fluid.
The radiograph on the fourth day of life showed substantial pulmonary plethora, perihilar pulmonary edema, and an increase in cardiac size. This is the radiographic sequence which is observed when hemodynamically significant ductal left-to-right shunting has ensued in a patient with RDS. In order to derive numbers with which to quantitate the signs of a large-volume shunt, we compared the peak cardiothoracic ratio in the patients in each of the three groups. In infants, cardiomegaly is usually not considered to be present until the transverse cardiothoracic ratio is over 60 percent. There was only one patient with a moderate-volume shunt in whom the cardiothoracic ratio was greater than 60 percent. However, only a third of patients with largevolume shunts had cardiomegaly. Therefore, while this sign is relatively specific for a large-volume shunt, it is extremely insensitive. Moreover, there was considerable overlap in the values of the peak cardiothoracic ratio in the large-volume group when compared with the groups of smaller-sized shunts. The increase or change in cardiothoracic ratio was compared among the three groups of infants. The change in cardiothoracic ratio was calculated as the increase in this ratio between the radiograph on the first day of life, and the maximum cardiothoracic ratio. An increase in ratios of 0.05
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THE WESTERN JOURNAL OF MEDICINE
215
PREMATURE INFANTS
or greater was considered to be indicative of a large-volume shunt. In 78 percent of patients with large-volume shunts there was a cardiothoracic ratio that increased 0.05 or more. This represents at least a 10-percent increase in cardiac size. On the other hand, in only a small number of patients with moderate-volume shunts was there a significant increase in cardiothoracic ratio. The other modality for the objective evaluation of the severity of the left-to-right shunt is the echocardiographic determination of the left atrialto-aortic (LA/AO) ratio. Patients with largevolume shunts usually have a LA/AO ratio of greater than 1.0.2 In most of the patients in this group, actually in all but nine patients, there were LA/AO ratios greater than 1.0. However, in nine patients with a large-volume shunt, LA/AO ratios were less than 1.0. In other words, by echocardiographic measures, these patients would not have been considered to have large-volume shunts. In eight of these nine patients there was increase in the cardiothoracic ratio as determined by sequential thoracic radiographs. Therefore, in all but one patient with a large-volume ductal shunt, the condition would have been detected by using a combination of radiographic evaluation and sequential echocardiographic evaluation. Figure 4 illustrates the close correlation of radiographic findings with echocardiograms in a child with a large-volume left-to-right shunt. A radiograph on the eighth day of life showed pulmonary edema and large segmental pulmonary arteries with perihilar pulmonary edema, alveolar pulmonary edema in the lower lobes and a cardiothoracic ratio which had increased greater
than 0.05. An echocardiogram obtained on the same day showed that the LA/AO ratio was notably elevated. The LA/AO ratio, which was measured during systole as the ratio of the dimension of the aorta and the dimension of the left atrium, was greater than 1.4. There was clear evidence, therefore, of a large-volume left-to-right shunt. In the group of 26 patients in whom surgical operation was carried out, radiographs were evaluated on each of the postoperative days for a week following operation. After operation, the cardiothoracic ratio dropped almost immediately to within the normal range. The average decline in the ratio on the first postoperative day was 0.07 which was greater than a 12 percent decrease. By the seventh day after operation, the cardiothoracic ratio was identical to that on the first day of life. Figure 5 illustrates this process in a sequence of chest x-ray studies. On the first day of life, there was evidence of granularity throughout the lungs, indicating hyaline membrane disease, and a normal-sized heart. By day 11 there was perihilar pulmonary edema and a significant increase in cardiothoracic ratio. On the fourth postoperative day pulmonary vascularity still remained somewhat abnormal, but there had been a substantial decrease in the cardiothoracic ratio. In conclusion, pulmonary plethora may be detected by radiographic evaluation before detection of a murmur. Cardiomegaly is a relatively insensitive sign of a large-volume shunt, which was present in only a third of patient-s with largevolume left-to-right shunts. However, sequential radiographic and echocardiographic evaluation is
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216
MARCH 1978 * 128 * 3
PREMATURE INFANTS
very helpful in determining the presence of a large-volume shunt. Sequential increase in the cardiothoracic ratio was detected in 75 percent of infants with large-volume shunts. Similarly an elevated LA/AO ratio was seen in approximately 75 percent of infants with large-volume shunts. Using these two modalities together, it was possible to detect 36 of the 37 large-volume shunts in patients in this study. DR. NYHAN: Dr. Merritt compiled data on patent ductus arteriosus in order to evaluate our experience. He will summarize this for us next. T. ALLEN MERRITT, MD:* Powell3 first described the surgical ligation of a PDA in a premature infant with progressive heart failure. Until 1972 only seven such cases were reported in spite of the findings of Bumard4 that 57 percent of premature infants had murmurs characteristic of a PDA. Moss and co-workers reported right-to-left or bidirectional shunting across the ductus in eight of 63 term infants.5 Similarly, Rudolph and associates0 found large left-to-right shunts in ten infants with severe RDs. Kitterman and associates7 recommended cardiac catheterization and ligation in infants with a PDA not responsive to medical management. They proposed that ligation might be the only chance for survival in infants with progressive pulmonary disease resulting from pulmonary hyperperfusion and concomitant RDS. However, only one infant of six in their series with severe RDS and deteriorating pulmonary status survived. Medical management has limitations in patients with this problem. Fluid restriction limits caloric intake in these critically ill infants and may augment a catabolic state. F102 *Fellow in Perinatal Medicine.
DAYl1
is usually increased and pulmonary compliance worsens as progressiVe cardiac decompensation occurs. A prolonged period of ventilation with higher pressures and increased oxygen concentrations must contribute to the pathogenesis of bronchopulmonary dysplasia. Despite these problems some centers have advocated medical management alone. Others maintain that aggressive surgical intervention is the most satisfactory approach to premature infants with a patent ductus refractory to medical management. Hall and co-workers8 have reported such disappointing results that they contend that PDA ligation cannot be justified. Mortality statistics from 1974 until 1976, a period that should coincide with recent advancements in perinatal care, ranged from an alarming 70 percent mortality to 18 percent8-18 (Table 2). Our own experience has been very different (Table 3). From January 1, 1976, until December 31, 1976, a hemodynamically significant PDA was found in 25 infants, compromising their recovery from RDs. All of these infants were managed in radiant warmers with crystalloid and colloid calculated initially as 70 ml per kg of body weight in 24 hours and subsequently adjusted to maintain a urine specific gravity between 1.010 and 1.015. Whole blood or packed red cells were given daily to maintain blood balance. Ventilation was carried out in these infants by techniques using low peak inspiratory pressures with prolongation of the inspiratory phase. Twelve infants were medically managed using fluid restriction, digitalis and diuretics. These infants were slightly heavier than the 13 infants in whom more aggressive therapy was required. In these infants the ductus was first detected at seven days of age.
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However, ventilatory support was required for an average of 16 days. In six infants surgical ligation was done and in seven others indomethacin was given as part of a prospective trial of pharmacologic closure of the ductus. This group as a whole has done well. Indeed, while these infants represented the sickest and smallest group of infants with worsening pulmonary function related to a left-to-right shunt, these infants required fewer days of ventilatory support and had few complications. During 1976 one infant with PDA died at University Hospital. This 650-gram infant died of a pulmonary hemorrhage four hours before scheduled ligation. Our mortality rate of 4 percent, therefore, compares quite favorably with those reported. Systematic follow-up has been carried out on these infants including physical examinations, neurological assessment, ophthalmologic and audiologic evaluation, and Bayley Scales of Infant Development. At 3 to 15 months of age, no differences could be appreciated between these three groups. Results of renal function studies in seven infants who received indomethacin were normal as assessed by longitudinal assessment of the creatinine and blood urea nitrogen, and analysis of urine. DR. NYHAN: Last year Dr. Friedman and his colleagues reported their experience with a new treatment, the pharmacologic closure of the ductus. Let us turn to Dr. Friedman for an update on ductal physiology and the pharmacologic approach to the PDA. WILLIAM FRIEDMAN, MD:* The ductus arteriosus is a widely patent vessel connecting the pulmonary trunk and descending aorta in fetal life. In the fetus most of the output of the right ventricle bypasses the unexpanded fetal lungs via the ductus arteriosus and enters the descending aorta where it travels to the placenta, the fetal organ of oxygenation. Until recently it was assumed that the ductus arteriosus was a passively open channel during fetal life, and that it constricted postnatally by as yet undefined molecular mechanisms in response to the abrupt rise in arterial oxygen pressure that accompanies the first breath of life. Suggestive evidence now exists that even in utero the size of the ductus arteriosus lumen may be influenced by prostaglandins. The effect of prostaglandins on the smooth muscle tone of the *Professor of Pediatrics, Chief, Division of Pediatric Car-
diology.
fetal ductus arteriosus can be seen in Figure 6. In chronically instrumented fetal lambs the administration of indomethacin, an inhibitor of prostaglandin synthesis, caused constriction of the fetal ductus arteriosus. Prostaglandin E1 infusion reverses this effect (Figure 7). The ductus arteriosus is a unique structure after birth since its patency, on the one hand, M PA
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Figure 7.-Representative experiment in which an infusion of prostaglandin E, (PGE,) restored patent ductus arteriosus (PDA) dimensions to normal after constriction had been achieved with indomethacin administration (0.1 mg per kg of body weight, intravenously). Little change was observed in main pulmonary artery (MPA) pressure during PDA dilatation and aortic pressure rose slightly. THE WESTERN JOURNAL OF MEDICINE
219
PREMATURE INFANTS
may result in cardiac decompensation and, on the other hand, may provide the only life-sustaining conduit to preserve systemic or pulmonary arterial blood flow in the presence of certain cardiac malformations. Appreciable left-to-right shunting across the patent ductus arteriosus frequently complicates the clinical course of prematurely born infants. The ductal shunt has been implicated especially in the deterioration of pulmonary function in infants with RDS in whom severe congestive heart failure is often unresponsive to therapy with digitalis and diuretics. Recently, clinical trials at the University of California, San Diego, and at the University of California, San Francisco, have shown that the ductus arteriosus in preterm infants with hyaline membrane disease and cardiopulmonary deterioration can be constricted and closed by the administration of inhibitors of prostaglandin synthesis. In our initial clinical experience with sick preterm infants to whom indomethacin was given to constrict and close the PDA, a large dose (2.5 to 5 mg per kg of body weight) of the drug was delivered orally or per rectum.19 Within 12 to 24 hours of drug administration all of the clinical symptoms and physical, radiographic and ultrasound signs attributable to a substantial left-toright shunt through a PDA had permanently disappeared. In several infants, transient renal dysfunction was shown by a rise in blood urea nitrogen and serum creatinine concentrations and a reduction in urine volume. In the initial clinical trial in San Francisco, salicylates, as well as a smaller dose of indomethacin, were utilized.19 Salicylates were; not found to be particularly effective, and the smaller doses of indomethacin were not associated with transient renal dysfunction. Prostaglandins are ubiquitous in animal tissues and appear to be formed from polyunsaturated fatty acids. These lipids act throughout the body as local mediators or modulators of physiological functions. Prostaglandins of the E type have a pronounced effect on the ductus arteriosus. It should be stated that pharmacological closure of the ductus arteriosus in preterm infants must still be considered experimental. In our experience, indomethacin was employed in an attempt to constrict and close the ductus arteriosus in preterm infants who would have otherwise undergone surgical ligation of the patent ductus arteriosus. Indomethacin was chosen because of its known potency as an inhibitor of prostaglandin synthetase and its widespread use for diverse medical 220
MARCH 1978 * 128 * 3
indications in the adult population. It should be recognized, however, that there exists a large family of drugs that have been shown to interfere with the synthesis of prostaglandins. Studies have not yet been done to identify the single agent with an especially selective action upon the smooth muscle of the ductus arteriosus and little or no action upon other organ systems. In the combined experience at UCSD and affiliated hospitals, indomethacin has been employed in 33 premature infants. Birth weight ranged from 720 to 2,480 grams. In the 33 infants to whom indomethacin was administered, surgical ligation would otherwise have been done for the PDA. In these infants, therefore, the ductal shunt was responsible for deterioration of pulmonary function, or severe congestive heart failure was unresponsive to administration of digitalis and diuretics. Rarely, severe episodes of apnea and bradycardia provided the indication for closure of the ductus. Each infant was evaluated serially, by the usual clinical and radiographic techniques, and also by analysis of the ultrasound assessment of left atrial and left ventricular dimensions, since the latter determinations have been shown to reflect accurately the augmentation of pulmonary arterial blood flow secondary to left-to-right shunt distal to the atrioventricular valves. In 32 of the 33 infants, the PDA constricted promptly and signs and 'symptoms were alleviated. In only one infant did the ductus fail to constrict sufficiently to alleviate symptoms, and surgical ligation was required in this infant. In many infants the PDA appeared to reopen between 5 and 14 days after initial drug-induced constriction. One of these babies became sufficiently symptomatic so that indomethacin was administered again with success. The other infants in whom the ductus reopened were asymptomatic and ultimately the PDA'S closed spontaneously. Three of the 33 infants died in the hospital of problems unrelated to ductal patency. The causes were pulmonary hemorrhage in a 720-gram baby, sepsis in a 1,200-gram baby and a combination of pneumonia and myocardial infarction in a 1,300-gram infant. Therefore, infants who ordinarily would have undergone ductal ligation were spared a thoracotomy by indomethacin treatment. Because transient renal dysfunction was observed initially in premature infants in whom indomethacin was being given to inhibit prostaglandin synthesis, and constrict PDA's, a study was undertaken in 14 newborn lambs between one and
PREMATURE INFANTS
six days of age to examine the influence of high and low doses of indomethacin on renal blood flow, glomerular filtration rate and urine flow. The high-dose group received 7.5 mg per kg of body weight of indomethacin intravenously, while the low-dose group received 0.2 mg per kg of body weight of indomethacin intravenously. Each animal served as its own control and each group of animals was compared with a separate control group matched for age and weight in which indomethacin was not administered. The indices of renal function were studied using iodohippurate sodium I 131 and inulin C 14 clearances in conscious, chronically instrumented lambs. Both high and low doses of indomethacin reduced renal blood flow significantly at four hours, but only in the high-dose animals was blood flow significantly lower than in the control group at 12 and 24 hours. Levels of prostaglandin E determined by radioimmunoassay correlated directly with alterations in renal blood flow. Glomerular filtration rate was unaltered in all groups; urine flow was significantly lower than in the control group at 24 hours only in the high-dose indomethacin group. The filtration fraction rose notably at 12 hours in both high and low dose indomethacin groups. These data suggest that the renal dysfunction observed transiently in some premature infants may be dose-related and support the need to monitor renal function, when indomethacin is administered to preterm infants. Various experimental approaches have been made in several animal species to elucidate the contractile response of ductus arteriosus smooth muscle. The isolated ductus arteriosus has been analyzed extensively with respect to its responses to oxygen, neurotransmitters, various mediators and hormones. We believe that multiple problems exist with an in vitro analysis of the reactivity of smooth muscles of the ductus arteriosus. Accordingly, in association with Drs. Stanley Kirkpatrick and Morton 'Printz, 42 studies were done from one to twenty-seven days postoperatively in 14 fetal lambs instrumented chronically with PDA sonomicrometer dimension crystals and with pressures determined in the main pulmonary artery and the ascending and descending aorta. Animals were operated on for implantation of the catheters and crystals between 95 and 120 days gestation. This approach to the study of the fetal ductus allows for direct serial measurements of the caliber of the ductus itself, as well as of pressure on all sides of the ductus. Drugs can be infused through
a catheter implanted chronically in the superior vena cava so as not to disrupt the monitoring of periductal pressures. The ductus was dilated maximally in utero. Experiments in which prostaglandin E1 and E2 were infused intravenously in graded doses up to 1 mg per kg of body weight did not result in altered ductal dimensions. Infusion of prostaglandin F2 over this same concentration range had no influence on the ductus. We found that alpha and beta adrenergic agonists (methoxamine and norepinephrine, respectively) and adrenergic (phentolamine and propranolol) and cholinergic (atropine) antagonists had no influence on ductal caliber. Acetylcholine infusions caused a mild reduction in ductal dimensions and internal cross sectional area, but concurrently lowered both pulmonary and systemic pressures. Therefore, it was difficult to distinguish between the hydrostatic influence of hypotension on ductal caliber and the direct effect of acetylcholine. Neither angiotensin 1 nor angiotensin 2 infusion, nor blockade of conversion of angiotensin 1 to 2 with the Squibb experimental compound SQ2088 1 influenced the dimensions of the ductus. A major finding of these studies was that inhibition of prostaglandin synthesis by a single intravenous dose of as little as 0.01 mg per kg of body weight of indomethacin caused significant PDA constriction. As anticipated, ductal constriction was accompanied by an elevation of main pulmonary arterial pressure with little change in systemic pressures. Infusions of prostaglandin E1 and E2 always reversed the constriction and returned ductal caliber to control dimensions. The responses to indomethacin were accompanied by striking reductions in circulating prostaglandin E2 levels measured by radioimmun'oassay. It has not yet been determined if ductal reactivity may be more importantly associated with alterations in prostaglandin synthetase activity within the ductus itself or with changes in circulating prostaglandin levels. Of major interest was the' finding of a direct correlation, after fetal administration of indomethacin, between fetal and maternal circulating levels of prostaglandins. These preliminary experimental findings suggest that the prostaglandins may directly influence ductal caliber, and suggest certainly that past theories concerning the mechanisms of spontaneous or delayed ductal constriction must be revised. The combination of clinical experience and the results of animal experimentation has led to our THE WESTERN JOURNAL OF MEDICINE
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current approach to the nonsurgical treatment of preterm infants with threatening PDA. The pretreatment evaluation of infants in whom indomethacin is to be employed is to uncover problems related to bilirubin metabolism, coagulation and renal function. A single dose of indomethacin (0.2 mg per kg of body weight) is then administered intravenously. A meticulous serial assessment is undertaken of cardiopulmonary and clinical status, and laboratory measurements are done to detect bleeding, displacement of bilirubin from albumin, and renal function. Rapid changes in oxygen requirements and the theoretical possibility of retinal arterial vasoconstriction require analysis. If evidence exists that constriction of the ductus has been inadequate, the same dose' of indomethacin may be repeated at 12- to 24-hour intervals. If ductal left-to-right shunting remains uncontrolled after a total dose of 0.6 mg per kg of body weight has been administered, then the infant may be considered a candidate for operative ligation. In addition, if after initial closure, the subsequent clinical course indicates that the PDA has reopened and produces cardiopulmonary difficulties, the treatment regimen may be repeated. We currently employ an experimental intravenously given preparation of indomethacin in our clinical studies which insures delivery of the desired dose. It should be recognized that an orally given suspension or solution of uniform composition does not exist commercially and that potential problems in dosimetry and absorption have not been evaluated critically when the drug is delivered through a nasogastric tube to preterm infants. In our view, the high morbidity and mortality of premature infants with PDA provides abunda'nt justification for pursuing nonsurgical methods to alter the course of this common problem. One of the major aims of continued clinical studies in this area is to assess the potential complications
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of the pharmacological approach to constriction and closure of the PDA. It is hoped to provide more appropriate guidelines for the optimal timing of therapeutic intervention. If results of clinical studies confirm our earlier observations, it will be appropriate to use these agents in infants early in the course of hyaline membrane disease with associated PDA. REFERENCES 1. Higgins CB, Rausch J, Friedman WF, et al: Patent ductus arteriosus in preterm infants with idiopathic respiratory distress syndrome-Radiographic and echo-cardiographic evaluation. Radiology (in press) 1977 2. Sahn DJ, Vaucher U, Williams DE, et al: Echocardiographic detection of large left-to-right shunts and cardiomyopathies in infants and children. Am J Cardiol 38:73-79, 1976 3. Powell ML: Patent ductus arteriosus in premature infants. Med J Australia 2:58-60, 1963 4. Barnard ED: A murmur that may arise from the ductus arteriosus in the human body. Proc R Soc Med 52:77-78, 1959 5. Moss AJ, Emmanouilides GC, Duffie ER: Closure of the ductus arteriosus in the newborn infant. Pediatrics 32:25-30, 1963 6. Rudolph AM, Drorbaugh JE, Auld PAM, et al: Studies on the circulation in the neonatal period: The circulation in the respiratory distress syndrome. Pediatrics 27:551-566, 1961 7. Kitterman JA, Edmunds LH, Gregory GA, et al: Patent ductus arteriosus in premature infants: Incidence, relation to pulmonary disease and management. N Engl J Med 287:473-477, 1972 8. Hall GS, Helmisworth JA, Schreiber JT, et al: Premature infants with patent ductus arteriosus and respiratory disease: Selection for ductal ligation. Ann Thorac Surg 22:146-150, 1976 9. Murphy DA, Outerbridge E, Stern L, et al: Management of premature infants with patent ductus arteriosus, J Thorac Cardiovasc Surg 67:221-228, 1974 10. Zachman RD, Steinmetz G, Botham R, et al: Incidence and treatment of the patent ductus arteriosus in the ill premature neonate. Am Heart J 87:6974699, 1974 11. Kilman JW, Kokos GS, Williams TE Jr, et al: Ligation of patent ductus arteriosus for persistent respiratory distress syndrome in premature infants. J Pediatr Surg 9:227-231, 1974 12. Thibeault DW, Emmanouilides GC, Nelson RJ, et al: Patent ductus arteriosus complicating the respiratory distress syndrome in preterm infants. J Pediat 86:120-126, 1975 13. Neal WA, Bessinger FB, Hunt CE, et al: Patent ductus arteriosus complicating respiratory distress syndrome. J Pediatr 86:127-131, 1975 14. Rittenhouse EA, Doty DB, Laurer RM, et al: Patent ductus arteriosus in premature infants: Indications for surgery. J Thorac Cardiovasc Surg 71:187-194, 1976 15. Nelson RJ, Thibeault DW, Emmanouilides GC, et al: Improving the results of ligation of patent ductus arteriosus in small preterm infants. J Thorac Cardiovasc Surg 71:169-178, 1976 16. Williams WH, Gelband H, Bancalari E, et al: The ductus debate: Ligation in prematurity? Ann Thorac Surg 22:151-156, 1976 17. Clarke D, Paton B, Way G, et al: Patent ductus arteriosus ligation and respiratory distress syndrome in premature infants. Ann Thorac Surg 22:138-145, 1976 18. Levitsky S, Fisher E, Vidyasagar D, et al: Interruption of patent ductus arteriosus in premature infants with respiratory distress syndrome. Ann Thorac Surg 22:131-137, 1976 19. Friedman WF, Hirschklau MJ, Printz MP, et al: Pharmacological closure of patent ductus arteriosus in the premature infant. N Eng J Med 295:526-533, 1976 20. Heymann MA, Rudolph AM, Silverman NH: Closure of the ductus arteriosus in premature infants by inhibition of progstaglandin synthesis. N Engl J Med 295:530-533, 1976
WILLIAM L. NYHAN, MD, PH D: * Tiny premature infants, already compromised by the respiratory distress syndrome, frequently have the additional problem of a patent ductus arteriosus. We shall consider the recognition of patent ductus arteriosus within the context of seriously ill premature infants and the correlation of radiologic and clinical findings, and examine the experience at the University of California, San Diego (UCSD), with this problem. This will lead to a review of the exciting new developments in the field of prostaglandin pharmacology and their relevance to clinical management. We shall start with a consideration of the clinical problem by Dr. Gluck. Louis GLUCK, MD:t Discussion of the ductus begins not with the cardiologist but with the physician who looks after the newborn infant. It is our firm belief after a significant experience with patent ductus arteriosus that we, not cardiologists, are the ones who should make the diagnosis first. I shall try to amplify and clarify this statement. *Professor and Chairman, Department of Pediatrics. tProfessor of Pediatrics and Reproductive Medicine, Head, Division of Perinatal Medicine. Reprint requests to: William L. Nyhan, MD, PhD, Department of Pediatrics, M-009, University Hospital, P.O. Box 3548, San Diego, CA 92103.
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Refer to: Merritt TA, Gluck L, Higgins C, et al: Management of premature infants with patent ductus arteriosus (Specialty Conference). West J Med 128:212-222, Mar 1978
anagement of remature Infants rith Patent Ductus rteriosus
Historically the ductus first was mentioned in the writings of Galen in the second century AD. He dissected and described the first ductus arteriosus. It was subsequently described approximately 15 centuries later in Italy by Leonardo Botallo. The first medical concern with the ductus came in about 1900, when Gibson described the classic machinery murmur and discussed the ductus as a clinical entity. Then seven years later, in 1907, Munro described the first surgical approach, but it was not until 1938 that Gross for the first time successfully closed the ductus. There has been an understanding of the complications of patent ductus arteriosus (PDA) in premature infants-although we like to think that this is very recent-since the mid-1950's. We may perhaps get the mistaken notion that it was not until the advent of continuous positive airway pressure (CPAP) that we began to appreciate the patent ductus in small babies. However, Eric Burnard, while a Visiting Fellow at Columbia University and Babies Hospital in the mid-1950's, described patent ductus arteriosus as a complication of hyaline membrane disease. This led, in fact, to another misconception, held for a long time, that patent ductus arteriosus and consequent heart failure were "what hyaline membrane dis-
PREMATURE INFANTS ABBREVIATIONS USED IN TEXT CPAP=continuous positive airway pressure F102=forced inspiratory oxygen LA/AO=left atrial to aortic (ratio) PDA = patent ductus arteriosus RDS=respiratory distress syndrome UCSD=University of California, San Diego ease was all about." What Burnard found was that in every baby with hyaline membrane disease a definite murmur developed at some time or other. He chose to believe that respiratory distress syndrome (RDs) or hyaline membrane disease was really a complication of cardiac disease, and the theory was proposed that hyaline membrane disease represented a unique form of chronic congestive heart failure. Although the cause of the disease is not congestive failure, it is true that by the time a premature infant has lived long enough and has begun to get better, he usually will show this complication. One might state that in very small babies the incidence of patent ductus, whether significant or insignificant, must be considered 100
percent.
Although it had been known for many years that patent ductus was a major complication in very small babies, it usually was diagnosed terminally, and these infants went on to death. A major contribution of CPAP has been to keep these small babies alive. Whether or not they ultimately survived, they were now living long enough for the patent ductus to be recognized as a definite clinical entity and as an important early complication of hyaline membrane disease. In San Francisco, here at UCSD and in a few other places where CPAP techniques were in wide use, everyone began to have the same experience. The babies with RDS would continue to get better up to a point, and then they would get worse. As we improved our techniques for managing babies with RDS the early diagnosis of PDA became much more subtle. We now have a unique situation where I think the kind of mechanical support of ventilation that we give a small premature infant with RDS leaves little residual problem in the baby's lungs. As a consequence, the diagnosis of patent ductus becomes possible even on the first day of life. The hemodynamics in premature infants are somewhat different than in larger newborns. They do not have comparable
pulmonary arteriolar musculature. Systemic pressure is much lower, and in many instances we see the development of pulmonary edema very early. In current and proper management of a baby with hyaline membrane disease, the usual story is that the baby progresses to some degree of ventilatory failure. The baby is treated with mechanical ventilation, because we feel this is the least harmful way to treat ventilatory failure. The baby then begins to improve. First the fractional inspired oxygen (FIo,) can be lowered. Whereas treatment may have been started at somewhere over 60 percent FIO9, perhaps 80 or 90 percent, very promptly this can come down to perhaps 50 percent. The arterial oxygen pressure (Pao2) remains high, the baby oxygenates well and continues to improve, and ventilatory assistance can be reduced more and more. In a weaning schedule, we are ready to take the baby off the ventilator, and then we arrive at a point at which the baby does not get any better. At this time we may or may not hear a murmur of PDA, and we may or may not see changes on x-ray studies, and the pulses may or may not be bounding. The liver may or may not get larger, and the heart may or may not get bigger, but we are faced with a situation in which the baby has stopped getting better. When PDA is not a complication, the baby does get better. We use a weaning schedule and finally take the baby off the ventilator. Usually they do very well. In a baby in whom the PDA is a significant complication, the classic story is for the baby just to stop getting better. Pulmonary edema does, indeed, develop. Carbon dioxide begins to accumulate. More ventilation is required and a little more oxygen will be required. At this point, generally the baby does have some cardiomegaly. The liver may be down a bit, and on x-ray studies shunt vessels begin to be seen, along with evidence of pulmonary edema. I have emphasized the earliest findings in babies with PDA and the fact that these findings are subtle. They do not present as sudden overwhelming cardiac disease, as we have considered the ductus in years gone by. This is approached at first as a statistical variation in the way the babies should be progressing. They simply stop getting better in spite of excellent management. THE WESTERN JOURNAL OF MEDICINE
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In this situation the commonest complication to be considered is patent ductus arteriosus. DR. NYHAN: In view of the subtle early manifestations of this complication so clearly presented by Dr. Gluck it would be of interest to develop objective measures to evaluate these babies' condition. Dr. Charles Higgins has been concerned with roentgenographic approaches to the determination of when difficulties are beginning in infants, and he will discuss these aspects of the problem now. CHARLES HIGGINS, MD: * In spite of the frequency of the problem of PDA in preterm infants with RDS, surprisingly few data are available that corTABLE 1.-Criteria for the Assignment of Infants to Each of the Study Groups, and Numbers of Infants in Each Group
CLINICAL GRADES 1. Small shunt (7 infants) Intermittent murmur Normal pulses 2. Moderate shunt (11 infants) Systolic murmur Prominent pulses Infrequent episodes of apnea/bradycardia 3. Large shunt (37 infants)
Systolic/diastolic murmur Bounding pulses Multiple episodes of apnea/bradycardia Respirator dependency Hepatomegaly PLETHORA
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relate the sequential radiographic findings with the clinical course or the echocardiographic findings. In order to obtain this type of correlation, we recently evaluated sequential radiographic findings in a group of 55 infants'with PDA in the setting of RDS, along with the clinical and echocardiographic findings.' The sequential radiographic findings we assessed were increases in pulmonary vascularity and cardiomegaly. Clinical severity was the measure of the left-to-right shunt. The echocardiographic marker of a large shunt was an 'abnormal left atrial-to-aortic ratio. In order to confirm that the radiographic findings were, in fact, due to the PDA we noted regressive changes in the pulmonary vascularity and cardiomegaly after closure of'the shunt. The 55 infants with PDA were divided into three groups, on the basis of the clinical severity of the shunt. The number of patients in each group and the criteria for inclusion in each category are indicated in Table 1. Most of the patients fell into the large shunt category. This may reflect the fact that there is a greater likelihood that in a child with a large shunt there will be sequential radiographic examinations. Figure 1 provides data on plethora and the age at which peak pulmonary vascularity was observed. The time of onset was usually between the second and sixth day. Most patients present with increase in pulmonary vascularity within the first week of life. However, the time of peak
PREMATURE INFANTS
increase in pulmonary vascularity is usually delayed until the end of the first week or during the second week. Figure 2 relates the time that a murmur was detected clinically with the radiographic appearance of increase in pulmonary vascularity. In 56 percent of the infants there was radiographic evidence of increase in pulmonary vascularity before murmur detection; that is, at least 24 hours before the clinical detection of a cardiac murmur. In 26 percent of patients there was simultaneous appearance of the murmur and increase in pulmonary vascularity. The clinical detection of a murmur occurred before the radiographic observation of pulmonary plethora in only 18 percent of these infants. There was no significant difference in the time of onset or time of peak pulmonary vascularity between those patients with small or moderatevolume shunts and those with large-volume shunts. Pulmonary edema was seen almost exclusively in patients with large-volume shunts. This was true for perihilar edema as well as generalized pulmonary edema. In only a single patient with a moderate-volume shunt was there radiographically apparent pulmonary edema. A typical radiographic sequence in a child with a large-volume shunt is portrayed in Figure 3. The radiograph on the first day of life showed a normal cardiac size, evidence of some hyaline membrane disease and some retained lung fluid.
The radiograph on the fourth day of life showed substantial pulmonary plethora, perihilar pulmonary edema, and an increase in cardiac size. This is the radiographic sequence which is observed when hemodynamically significant ductal left-to-right shunting has ensued in a patient with RDS. In order to derive numbers with which to quantitate the signs of a large-volume shunt, we compared the peak cardiothoracic ratio in the patients in each of the three groups. In infants, cardiomegaly is usually not considered to be present until the transverse cardiothoracic ratio is over 60 percent. There was only one patient with a moderate-volume shunt in whom the cardiothoracic ratio was greater than 60 percent. However, only a third of patients with largevolume shunts had cardiomegaly. Therefore, while this sign is relatively specific for a large-volume shunt, it is extremely insensitive. Moreover, there was considerable overlap in the values of the peak cardiothoracic ratio in the large-volume group when compared with the groups of smaller-sized shunts. The increase or change in cardiothoracic ratio was compared among the three groups of infants. The change in cardiothoracic ratio was calculated as the increase in this ratio between the radiograph on the first day of life, and the maximum cardiothoracic ratio. An increase in ratios of 0.05
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THE WESTERN JOURNAL OF MEDICINE
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PREMATURE INFANTS
or greater was considered to be indicative of a large-volume shunt. In 78 percent of patients with large-volume shunts there was a cardiothoracic ratio that increased 0.05 or more. This represents at least a 10-percent increase in cardiac size. On the other hand, in only a small number of patients with moderate-volume shunts was there a significant increase in cardiothoracic ratio. The other modality for the objective evaluation of the severity of the left-to-right shunt is the echocardiographic determination of the left atrialto-aortic (LA/AO) ratio. Patients with largevolume shunts usually have a LA/AO ratio of greater than 1.0.2 In most of the patients in this group, actually in all but nine patients, there were LA/AO ratios greater than 1.0. However, in nine patients with a large-volume shunt, LA/AO ratios were less than 1.0. In other words, by echocardiographic measures, these patients would not have been considered to have large-volume shunts. In eight of these nine patients there was increase in the cardiothoracic ratio as determined by sequential thoracic radiographs. Therefore, in all but one patient with a large-volume ductal shunt, the condition would have been detected by using a combination of radiographic evaluation and sequential echocardiographic evaluation. Figure 4 illustrates the close correlation of radiographic findings with echocardiograms in a child with a large-volume left-to-right shunt. A radiograph on the eighth day of life showed pulmonary edema and large segmental pulmonary arteries with perihilar pulmonary edema, alveolar pulmonary edema in the lower lobes and a cardiothoracic ratio which had increased greater
than 0.05. An echocardiogram obtained on the same day showed that the LA/AO ratio was notably elevated. The LA/AO ratio, which was measured during systole as the ratio of the dimension of the aorta and the dimension of the left atrium, was greater than 1.4. There was clear evidence, therefore, of a large-volume left-to-right shunt. In the group of 26 patients in whom surgical operation was carried out, radiographs were evaluated on each of the postoperative days for a week following operation. After operation, the cardiothoracic ratio dropped almost immediately to within the normal range. The average decline in the ratio on the first postoperative day was 0.07 which was greater than a 12 percent decrease. By the seventh day after operation, the cardiothoracic ratio was identical to that on the first day of life. Figure 5 illustrates this process in a sequence of chest x-ray studies. On the first day of life, there was evidence of granularity throughout the lungs, indicating hyaline membrane disease, and a normal-sized heart. By day 11 there was perihilar pulmonary edema and a significant increase in cardiothoracic ratio. On the fourth postoperative day pulmonary vascularity still remained somewhat abnormal, but there had been a substantial decrease in the cardiothoracic ratio. In conclusion, pulmonary plethora may be detected by radiographic evaluation before detection of a murmur. Cardiomegaly is a relatively insensitive sign of a large-volume shunt, which was present in only a third of patient-s with largevolume left-to-right shunts. However, sequential radiographic and echocardiographic evaluation is
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216
MARCH 1978 * 128 * 3
PREMATURE INFANTS
very helpful in determining the presence of a large-volume shunt. Sequential increase in the cardiothoracic ratio was detected in 75 percent of infants with large-volume shunts. Similarly an elevated LA/AO ratio was seen in approximately 75 percent of infants with large-volume shunts. Using these two modalities together, it was possible to detect 36 of the 37 large-volume shunts in patients in this study. DR. NYHAN: Dr. Merritt compiled data on patent ductus arteriosus in order to evaluate our experience. He will summarize this for us next. T. ALLEN MERRITT, MD:* Powell3 first described the surgical ligation of a PDA in a premature infant with progressive heart failure. Until 1972 only seven such cases were reported in spite of the findings of Bumard4 that 57 percent of premature infants had murmurs characteristic of a PDA. Moss and co-workers reported right-to-left or bidirectional shunting across the ductus in eight of 63 term infants.5 Similarly, Rudolph and associates0 found large left-to-right shunts in ten infants with severe RDs. Kitterman and associates7 recommended cardiac catheterization and ligation in infants with a PDA not responsive to medical management. They proposed that ligation might be the only chance for survival in infants with progressive pulmonary disease resulting from pulmonary hyperperfusion and concomitant RDS. However, only one infant of six in their series with severe RDS and deteriorating pulmonary status survived. Medical management has limitations in patients with this problem. Fluid restriction limits caloric intake in these critically ill infants and may augment a catabolic state. F102 *Fellow in Perinatal Medicine.
DAYl1
is usually increased and pulmonary compliance worsens as progressiVe cardiac decompensation occurs. A prolonged period of ventilation with higher pressures and increased oxygen concentrations must contribute to the pathogenesis of bronchopulmonary dysplasia. Despite these problems some centers have advocated medical management alone. Others maintain that aggressive surgical intervention is the most satisfactory approach to premature infants with a patent ductus refractory to medical management. Hall and co-workers8 have reported such disappointing results that they contend that PDA ligation cannot be justified. Mortality statistics from 1974 until 1976, a period that should coincide with recent advancements in perinatal care, ranged from an alarming 70 percent mortality to 18 percent8-18 (Table 2). Our own experience has been very different (Table 3). From January 1, 1976, until December 31, 1976, a hemodynamically significant PDA was found in 25 infants, compromising their recovery from RDs. All of these infants were managed in radiant warmers with crystalloid and colloid calculated initially as 70 ml per kg of body weight in 24 hours and subsequently adjusted to maintain a urine specific gravity between 1.010 and 1.015. Whole blood or packed red cells were given daily to maintain blood balance. Ventilation was carried out in these infants by techniques using low peak inspiratory pressures with prolongation of the inspiratory phase. Twelve infants were medically managed using fluid restriction, digitalis and diuretics. These infants were slightly heavier than the 13 infants in whom more aggressive therapy was required. In these infants the ductus was first detected at seven days of age.
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Figure 5.-Progression of roentgenographic findings in a patient with respiratory distress syndrome i in whom pulmonary edema developed which resolved following operative closure of a patent ductus arteriosus. THE WESTERN JOURNAL OF MEDICINE
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However, ventilatory support was required for an average of 16 days. In six infants surgical ligation was done and in seven others indomethacin was given as part of a prospective trial of pharmacologic closure of the ductus. This group as a whole has done well. Indeed, while these infants represented the sickest and smallest group of infants with worsening pulmonary function related to a left-to-right shunt, these infants required fewer days of ventilatory support and had few complications. During 1976 one infant with PDA died at University Hospital. This 650-gram infant died of a pulmonary hemorrhage four hours before scheduled ligation. Our mortality rate of 4 percent, therefore, compares quite favorably with those reported. Systematic follow-up has been carried out on these infants including physical examinations, neurological assessment, ophthalmologic and audiologic evaluation, and Bayley Scales of Infant Development. At 3 to 15 months of age, no differences could be appreciated between these three groups. Results of renal function studies in seven infants who received indomethacin were normal as assessed by longitudinal assessment of the creatinine and blood urea nitrogen, and analysis of urine. DR. NYHAN: Last year Dr. Friedman and his colleagues reported their experience with a new treatment, the pharmacologic closure of the ductus. Let us turn to Dr. Friedman for an update on ductal physiology and the pharmacologic approach to the PDA. WILLIAM FRIEDMAN, MD:* The ductus arteriosus is a widely patent vessel connecting the pulmonary trunk and descending aorta in fetal life. In the fetus most of the output of the right ventricle bypasses the unexpanded fetal lungs via the ductus arteriosus and enters the descending aorta where it travels to the placenta, the fetal organ of oxygenation. Until recently it was assumed that the ductus arteriosus was a passively open channel during fetal life, and that it constricted postnatally by as yet undefined molecular mechanisms in response to the abrupt rise in arterial oxygen pressure that accompanies the first breath of life. Suggestive evidence now exists that even in utero the size of the ductus arteriosus lumen may be influenced by prostaglandins. The effect of prostaglandins on the smooth muscle tone of the *Professor of Pediatrics, Chief, Division of Pediatric Car-
diology.
fetal ductus arteriosus can be seen in Figure 6. In chronically instrumented fetal lambs the administration of indomethacin, an inhibitor of prostaglandin synthesis, caused constriction of the fetal ductus arteriosus. Prostaglandin E1 infusion reverses this effect (Figure 7). The ductus arteriosus is a unique structure after birth since its patency, on the one hand, M PA
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Figure 6.-Representative experiment in which indomethacin produced profound constriction of the fetal ductus arteriosus. Dimensions of the patent ductus arteriosus (PDA) were measured directly with sonomicrometer crystals while pressures were recorded simultaneously from the fetal ascending aorta, main pulmonary artery (MPA), and descending aorta (desc. Ao). The constriction is best appreciated in the lower panel. A rise in main pulmonary arterial pressure was associated with ductal constriction. PETAL LAMB
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Figure 7.-Representative experiment in which an infusion of prostaglandin E, (PGE,) restored patent ductus arteriosus (PDA) dimensions to normal after constriction had been achieved with indomethacin administration (0.1 mg per kg of body weight, intravenously). Little change was observed in main pulmonary artery (MPA) pressure during PDA dilatation and aortic pressure rose slightly. THE WESTERN JOURNAL OF MEDICINE
219
PREMATURE INFANTS
may result in cardiac decompensation and, on the other hand, may provide the only life-sustaining conduit to preserve systemic or pulmonary arterial blood flow in the presence of certain cardiac malformations. Appreciable left-to-right shunting across the patent ductus arteriosus frequently complicates the clinical course of prematurely born infants. The ductal shunt has been implicated especially in the deterioration of pulmonary function in infants with RDS in whom severe congestive heart failure is often unresponsive to therapy with digitalis and diuretics. Recently, clinical trials at the University of California, San Diego, and at the University of California, San Francisco, have shown that the ductus arteriosus in preterm infants with hyaline membrane disease and cardiopulmonary deterioration can be constricted and closed by the administration of inhibitors of prostaglandin synthesis. In our initial clinical experience with sick preterm infants to whom indomethacin was given to constrict and close the PDA, a large dose (2.5 to 5 mg per kg of body weight) of the drug was delivered orally or per rectum.19 Within 12 to 24 hours of drug administration all of the clinical symptoms and physical, radiographic and ultrasound signs attributable to a substantial left-toright shunt through a PDA had permanently disappeared. In several infants, transient renal dysfunction was shown by a rise in blood urea nitrogen and serum creatinine concentrations and a reduction in urine volume. In the initial clinical trial in San Francisco, salicylates, as well as a smaller dose of indomethacin, were utilized.19 Salicylates were; not found to be particularly effective, and the smaller doses of indomethacin were not associated with transient renal dysfunction. Prostaglandins are ubiquitous in animal tissues and appear to be formed from polyunsaturated fatty acids. These lipids act throughout the body as local mediators or modulators of physiological functions. Prostaglandins of the E type have a pronounced effect on the ductus arteriosus. It should be stated that pharmacological closure of the ductus arteriosus in preterm infants must still be considered experimental. In our experience, indomethacin was employed in an attempt to constrict and close the ductus arteriosus in preterm infants who would have otherwise undergone surgical ligation of the patent ductus arteriosus. Indomethacin was chosen because of its known potency as an inhibitor of prostaglandin synthetase and its widespread use for diverse medical 220
MARCH 1978 * 128 * 3
indications in the adult population. It should be recognized, however, that there exists a large family of drugs that have been shown to interfere with the synthesis of prostaglandins. Studies have not yet been done to identify the single agent with an especially selective action upon the smooth muscle of the ductus arteriosus and little or no action upon other organ systems. In the combined experience at UCSD and affiliated hospitals, indomethacin has been employed in 33 premature infants. Birth weight ranged from 720 to 2,480 grams. In the 33 infants to whom indomethacin was administered, surgical ligation would otherwise have been done for the PDA. In these infants, therefore, the ductal shunt was responsible for deterioration of pulmonary function, or severe congestive heart failure was unresponsive to administration of digitalis and diuretics. Rarely, severe episodes of apnea and bradycardia provided the indication for closure of the ductus. Each infant was evaluated serially, by the usual clinical and radiographic techniques, and also by analysis of the ultrasound assessment of left atrial and left ventricular dimensions, since the latter determinations have been shown to reflect accurately the augmentation of pulmonary arterial blood flow secondary to left-to-right shunt distal to the atrioventricular valves. In 32 of the 33 infants, the PDA constricted promptly and signs and 'symptoms were alleviated. In only one infant did the ductus fail to constrict sufficiently to alleviate symptoms, and surgical ligation was required in this infant. In many infants the PDA appeared to reopen between 5 and 14 days after initial drug-induced constriction. One of these babies became sufficiently symptomatic so that indomethacin was administered again with success. The other infants in whom the ductus reopened were asymptomatic and ultimately the PDA'S closed spontaneously. Three of the 33 infants died in the hospital of problems unrelated to ductal patency. The causes were pulmonary hemorrhage in a 720-gram baby, sepsis in a 1,200-gram baby and a combination of pneumonia and myocardial infarction in a 1,300-gram infant. Therefore, infants who ordinarily would have undergone ductal ligation were spared a thoracotomy by indomethacin treatment. Because transient renal dysfunction was observed initially in premature infants in whom indomethacin was being given to inhibit prostaglandin synthesis, and constrict PDA's, a study was undertaken in 14 newborn lambs between one and
PREMATURE INFANTS
six days of age to examine the influence of high and low doses of indomethacin on renal blood flow, glomerular filtration rate and urine flow. The high-dose group received 7.5 mg per kg of body weight of indomethacin intravenously, while the low-dose group received 0.2 mg per kg of body weight of indomethacin intravenously. Each animal served as its own control and each group of animals was compared with a separate control group matched for age and weight in which indomethacin was not administered. The indices of renal function were studied using iodohippurate sodium I 131 and inulin C 14 clearances in conscious, chronically instrumented lambs. Both high and low doses of indomethacin reduced renal blood flow significantly at four hours, but only in the high-dose animals was blood flow significantly lower than in the control group at 12 and 24 hours. Levels of prostaglandin E determined by radioimmunoassay correlated directly with alterations in renal blood flow. Glomerular filtration rate was unaltered in all groups; urine flow was significantly lower than in the control group at 24 hours only in the high-dose indomethacin group. The filtration fraction rose notably at 12 hours in both high and low dose indomethacin groups. These data suggest that the renal dysfunction observed transiently in some premature infants may be dose-related and support the need to monitor renal function, when indomethacin is administered to preterm infants. Various experimental approaches have been made in several animal species to elucidate the contractile response of ductus arteriosus smooth muscle. The isolated ductus arteriosus has been analyzed extensively with respect to its responses to oxygen, neurotransmitters, various mediators and hormones. We believe that multiple problems exist with an in vitro analysis of the reactivity of smooth muscles of the ductus arteriosus. Accordingly, in association with Drs. Stanley Kirkpatrick and Morton 'Printz, 42 studies were done from one to twenty-seven days postoperatively in 14 fetal lambs instrumented chronically with PDA sonomicrometer dimension crystals and with pressures determined in the main pulmonary artery and the ascending and descending aorta. Animals were operated on for implantation of the catheters and crystals between 95 and 120 days gestation. This approach to the study of the fetal ductus allows for direct serial measurements of the caliber of the ductus itself, as well as of pressure on all sides of the ductus. Drugs can be infused through
a catheter implanted chronically in the superior vena cava so as not to disrupt the monitoring of periductal pressures. The ductus was dilated maximally in utero. Experiments in which prostaglandin E1 and E2 were infused intravenously in graded doses up to 1 mg per kg of body weight did not result in altered ductal dimensions. Infusion of prostaglandin F2 over this same concentration range had no influence on the ductus. We found that alpha and beta adrenergic agonists (methoxamine and norepinephrine, respectively) and adrenergic (phentolamine and propranolol) and cholinergic (atropine) antagonists had no influence on ductal caliber. Acetylcholine infusions caused a mild reduction in ductal dimensions and internal cross sectional area, but concurrently lowered both pulmonary and systemic pressures. Therefore, it was difficult to distinguish between the hydrostatic influence of hypotension on ductal caliber and the direct effect of acetylcholine. Neither angiotensin 1 nor angiotensin 2 infusion, nor blockade of conversion of angiotensin 1 to 2 with the Squibb experimental compound SQ2088 1 influenced the dimensions of the ductus. A major finding of these studies was that inhibition of prostaglandin synthesis by a single intravenous dose of as little as 0.01 mg per kg of body weight of indomethacin caused significant PDA constriction. As anticipated, ductal constriction was accompanied by an elevation of main pulmonary arterial pressure with little change in systemic pressures. Infusions of prostaglandin E1 and E2 always reversed the constriction and returned ductal caliber to control dimensions. The responses to indomethacin were accompanied by striking reductions in circulating prostaglandin E2 levels measured by radioimmun'oassay. It has not yet been determined if ductal reactivity may be more importantly associated with alterations in prostaglandin synthetase activity within the ductus itself or with changes in circulating prostaglandin levels. Of major interest was the' finding of a direct correlation, after fetal administration of indomethacin, between fetal and maternal circulating levels of prostaglandins. These preliminary experimental findings suggest that the prostaglandins may directly influence ductal caliber, and suggest certainly that past theories concerning the mechanisms of spontaneous or delayed ductal constriction must be revised. The combination of clinical experience and the results of animal experimentation has led to our THE WESTERN JOURNAL OF MEDICINE
221
PREMATURE INFANTS
current approach to the nonsurgical treatment of preterm infants with threatening PDA. The pretreatment evaluation of infants in whom indomethacin is to be employed is to uncover problems related to bilirubin metabolism, coagulation and renal function. A single dose of indomethacin (0.2 mg per kg of body weight) is then administered intravenously. A meticulous serial assessment is undertaken of cardiopulmonary and clinical status, and laboratory measurements are done to detect bleeding, displacement of bilirubin from albumin, and renal function. Rapid changes in oxygen requirements and the theoretical possibility of retinal arterial vasoconstriction require analysis. If evidence exists that constriction of the ductus has been inadequate, the same dose' of indomethacin may be repeated at 12- to 24-hour intervals. If ductal left-to-right shunting remains uncontrolled after a total dose of 0.6 mg per kg of body weight has been administered, then the infant may be considered a candidate for operative ligation. In addition, if after initial closure, the subsequent clinical course indicates that the PDA has reopened and produces cardiopulmonary difficulties, the treatment regimen may be repeated. We currently employ an experimental intravenously given preparation of indomethacin in our clinical studies which insures delivery of the desired dose. It should be recognized that an orally given suspension or solution of uniform composition does not exist commercially and that potential problems in dosimetry and absorption have not been evaluated critically when the drug is delivered through a nasogastric tube to preterm infants. In our view, the high morbidity and mortality of premature infants with PDA provides abunda'nt justification for pursuing nonsurgical methods to alter the course of this common problem. One of the major aims of continued clinical studies in this area is to assess the potential complications
222
MARCH 1978 *
128 *
3
of the pharmacological approach to constriction and closure of the PDA. It is hoped to provide more appropriate guidelines for the optimal timing of therapeutic intervention. If results of clinical studies confirm our earlier observations, it will be appropriate to use these agents in infants early in the course of hyaline membrane disease with associated PDA. REFERENCES 1. Higgins CB, Rausch J, Friedman WF, et al: Patent ductus arteriosus in preterm infants with idiopathic respiratory distress syndrome-Radiographic and echo-cardiographic evaluation. Radiology (in press) 1977 2. Sahn DJ, Vaucher U, Williams DE, et al: Echocardiographic detection of large left-to-right shunts and cardiomyopathies in infants and children. Am J Cardiol 38:73-79, 1976 3. Powell ML: Patent ductus arteriosus in premature infants. Med J Australia 2:58-60, 1963 4. Barnard ED: A murmur that may arise from the ductus arteriosus in the human body. Proc R Soc Med 52:77-78, 1959 5. Moss AJ, Emmanouilides GC, Duffie ER: Closure of the ductus arteriosus in the newborn infant. Pediatrics 32:25-30, 1963 6. Rudolph AM, Drorbaugh JE, Auld PAM, et al: Studies on the circulation in the neonatal period: The circulation in the respiratory distress syndrome. Pediatrics 27:551-566, 1961 7. Kitterman JA, Edmunds LH, Gregory GA, et al: Patent ductus arteriosus in premature infants: Incidence, relation to pulmonary disease and management. N Engl J Med 287:473-477, 1972 8. Hall GS, Helmisworth JA, Schreiber JT, et al: Premature infants with patent ductus arteriosus and respiratory disease: Selection for ductal ligation. Ann Thorac Surg 22:146-150, 1976 9. Murphy DA, Outerbridge E, Stern L, et al: Management of premature infants with patent ductus arteriosus, J Thorac Cardiovasc Surg 67:221-228, 1974 10. Zachman RD, Steinmetz G, Botham R, et al: Incidence and treatment of the patent ductus arteriosus in the ill premature neonate. Am Heart J 87:6974699, 1974 11. Kilman JW, Kokos GS, Williams TE Jr, et al: Ligation of patent ductus arteriosus for persistent respiratory distress syndrome in premature infants. J Pediatr Surg 9:227-231, 1974 12. Thibeault DW, Emmanouilides GC, Nelson RJ, et al: Patent ductus arteriosus complicating the respiratory distress syndrome in preterm infants. J Pediat 86:120-126, 1975 13. Neal WA, Bessinger FB, Hunt CE, et al: Patent ductus arteriosus complicating respiratory distress syndrome. J Pediatr 86:127-131, 1975 14. Rittenhouse EA, Doty DB, Laurer RM, et al: Patent ductus arteriosus in premature infants: Indications for surgery. J Thorac Cardiovasc Surg 71:187-194, 1976 15. Nelson RJ, Thibeault DW, Emmanouilides GC, et al: Improving the results of ligation of patent ductus arteriosus in small preterm infants. J Thorac Cardiovasc Surg 71:169-178, 1976 16. Williams WH, Gelband H, Bancalari E, et al: The ductus debate: Ligation in prematurity? Ann Thorac Surg 22:151-156, 1976 17. Clarke D, Paton B, Way G, et al: Patent ductus arteriosus ligation and respiratory distress syndrome in premature infants. Ann Thorac Surg 22:138-145, 1976 18. Levitsky S, Fisher E, Vidyasagar D, et al: Interruption of patent ductus arteriosus in premature infants with respiratory distress syndrome. Ann Thorac Surg 22:131-137, 1976 19. Friedman WF, Hirschklau MJ, Printz MP, et al: Pharmacological closure of patent ductus arteriosus in the premature infant. N Eng J Med 295:526-533, 1976 20. Heymann MA, Rudolph AM, Silverman NH: Closure of the ductus arteriosus in premature infants by inhibition of progstaglandin synthesis. N Engl J Med 295:530-533, 1976
