surgical closure of the ductus arteriosus in premature infants

Surgical Closure of the Ductus Arteriosusin Premature Infants

By L. HENRY EDMUNDS, JR., M.D., GEORGE A. GREGORY, M.D., MICHAEL A. HEYMANN, M.B.,B.CH., JOSEPH A. KITTERMAN, M.D., ABRAHAM M. RUDOLPH, M.D.,

AND WILLIAM H. TOOLEY, M.D.

SUMMARYDuring a 62-month period patent ductus arteriosus (PDA) was diagnosed in 88 premature in-

fants with birth weights less than 1750 g. Twenty-one of these infants required operative closureof the PDA. Six infants had uncontrolled heart failure without associated pulmonary disease.Fifteen infants had severe idiopathic respiratory distress syndrome (IRDS) and required operationfor deteriorating pulmonary function when heart failure developed. Twelve of these 15 infantsweighed less than 1250 g at birth. The ductus arteriosus was ligated in 19 patients and was dividedin two patients. The six infants without IRDS survived, and four are completely normal. Of 15infants with IRDS eight had steady improvement in pulmonary function after operation. Three ofthese eight patients eventually died. In three infants pulmonary function improved slowly and intwo patients pulmonary function did not improve after operation; all of these patients eventuallydied. Two patients died of peritonitis secondary to bowel ischemia. Of the five infants with IRDSwho are alive, one is two months of age, two are moderately retarded in psychomotor develop-ment, and two, who developed hydrocephalus, are severely retarded. Although operation success-fully controls heart failure in premature infants with PDA and IRDS, progressive pulmonary diseaseand the complications of extreme prematurity pre-empt good results in most of these infants.

Additional Indexing Words:Idiopathic respiratory distress syndrome Respiratory assistanceCardiac catheterization Cineangiography

Heart failure

APPROXIMATELY 15% of premature infantswith birth weights less than 1750 g have

patent ductus arteriosus (PDA), and approximately60% of these infants also have the idiopathicrespiratory distress syndrome (IRDS). Usually, theductus arteriosus closes spontaneously in thesepatients;1-5 occasionally, the combination of prema-

turity and severe heart failure from PDA threatenslife. When IRDS is also present, the onset of heart

From the Departments of Surgery, Anesthesia, andPediatrics, and the Cardiovascular Research Institute,University of California, San Francisco, California.

Supported by NHLI Grants HL-15300 and HL-06285.Presented at the 45th Scientific Sessions of the American

Heart Association, Dallas, Texas, 1972.Dr. Heymann is the recipient of Research Career

Development Award HD 35398 from the National Instituteof Child Health and Human Development.

Address for reprints: L. Henry Edmunds, Jr., M.D.,Department of Surgery, Hospital of the University ofPennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania19104.

Received March 14, 1973; revision accepted for publica-tion June 6, 1973.

856

failure often causes deterioration of pulmonaryfunction. We have closed the ductus arteriosus byoperation in premature infants when the onset ofsevere heart failure threatens life or causes a

pronounced deterioration in pulmonary function.In the 62 months between January, 1968, and

February, 1973, patent ductus arteriosus was

diagnosed in 88 premature infants (birth weightless than 1750 g) during their neonatal hospitaliza-tion at the University of California, San Francisco.The ductus arteriosus closed spontaneously in 50patients (57%), and 17 (19%) infants who were notoperated upon died from intracranial hemorrhage(nine patients), infection (four patients), peritoni-tis (three patients), or renal failure (one patient).Twelve of these 17 infants had IRDS. Twenty-one(24%) infants had surgical closure of the patentductus. This report describes our experience withthe 21 infants who had this operation.*

* Eight of these infants are included in the previousreport.1

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CLOSURE OF DUCTUS IN PREMATURE INFANTS

Patient DataClinical FindingsEleven infants were born at the University of

California Medical Center and ten were transferredfrom other hospitals 0 to 33 days after birth. The 21infants were divided into two groups on the basis ofthe presence or absence of the idiopathic respira-tory distress syndrome.

Six infants did not have IRDS. Initially, thesebabies had normal chest roentgenograms and didnot have clinical signs of respiratory difficulty. Oneinfant who was born at an outside hospital hadintubation of the trachea at birth for resuscitation;however, within a few hours the tube was removed.The other infants did not have tracheal intubationat any time before operation. Gestational agesranged from 28 to 35 weeks (mean 31) (fig. 1).Birth weights ranged from 880-1650 g (mean 1260)(fig. 2). All were single births. Three werefemales.

Fifteen infants with IRDS developed respiratory

GESTATIONAL AGE

NO IRDS

35

IRDS

0

difficulty and had abnormal chest roentgenogramssoon after birth. Thirteen were intubated at birth,all required some form of respiratory assistancewith high concentrations of inspired oxygen (con-tinuous positive airway pressure [CPAP] or maskand bag ventilation), and 13 required mechanicalventilation. Gestational ages ranged from 27 to 35weeks (mean 29.7) (fig. 1). Birth weights rangedfrom 850-1600 g (mean 1149) (fig. 2). Five wereproducts of multiple births (three sets of twins andtwo sets of triplets). Eleven were females.The diagnosis of patent ductus arteriosus was first

suspected by 1) the appearance of a coarse systolicmurmur over the left anterior chest; 2) an increasein arterial pulse pressure, or 3) increasing respira-tory difficulty associated with a rise in arterialcarbon dioxide tension. All of the 21 patientsdeveloped a murmur at 3 to 13 (mean 5.7) days ofage, and in 14 the murmur eventually extended pastthe second sound into diastole or became continu-ous.

The most important clinical signs that indicatedthe onset of severe heart failure are presented intable 1. All 21 of the infants had at least one of the

WEIGHT

NO IRDS IRDS

2000

0

Grams*)

0)

to)

0

5)

(5))

.

0

0

1600_

0

1

1200[

800_

BIRTH OPERATIONFigure 2

BIRTH OPERATION

Figure 1

Gestational ages at birth for six infants without IRDS and

15 infants with IRDS are indicated by circles. Horizontalbars represent the mean gestational ages. The difference inmean gestational ages is not significant (P> 0.05).

Circulation, Volume XLVIIJ, October 1973

Weights of both groups of infants at birth and at operationare illustrated. The circle indicates one infant whose birthweight was not recorded. Horizontal bars indicate meanweights. The difference in mean birth weights is not sig-nificant (P > 0.05), but the difference in mean weights atoperation is significant (P < 0.05).

33K_

Weeks0

31_

29_

27

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Table 1Clinical Features in 21 Premature Infants with PatentDuctus Arteriosus

No IRDS IRDS

Systolic murmur 100 100Increased arterial pulse pressure 100 100Episodic apnea 100 73Episodic bradyeardia 83 93

Tachypnea > 60/min 83 67Hyperactive precordium 83 87Gallop rhythm 67 47Pulmonary rales 67 73Hepatomegaly 67 80

CO2 retention > 60 torr 33 100

Cardiomegaly 100 33Increased pulmonary vascularity 100 80

physical signs of severe heart failure. All infantswith IRDS developed CO2 retention (>60 torr),but only two infants without IRDS did. Conversely,all of the infants without IRDS had roentgeno-graphic evidence of cardiomegaly and increasedpulmonary vascularity, but only a third of the groupof infants with IRDS had enlarged hearts.The electrocardiogram was normal in three

infants without IRDS and showed a pattern of leftventricular hypertrophy in three others. In infantswith IRDS the electrocardiogram was usuallynormal, but occasionally indicated increased (abovenormal) right ventricular forces. One infant withIRDS had left ventricular hypertrophy.At the time the ductal murmur appeared,

hematocrit averaged 41 (range 36-48) in infantswithout IRDS, and averaged 39 (range 35-44) ininfants with IRDS. At the time of operation, themean hematocrit was 37 (range 33-45) in bothgroups of infants.Ophthalmic examinations for retrolental fibro-

plasia were made on one or more occasions in allexcept three patients who died. Retinas werenormal in the five infants without IRDS and in teninfants with IRDS. Three infants with gestationalages of 28 weeks at birth developed ophthalmicevidence of retrolental fibroplasia.

Indications for OperationThe indication for operation in the infants

without IRDS was heart failure that could not bemanaged by digoxin, diuretics, and other medicalmeasures. One of these infants had three cardiacarrests prior to operation.The indication for operation in the 15 patients

with associated IRDS was marked deterioration in

pulmonary function coincident with the onset of thesigns of severe heart failure. Signs of pulmonaryfunctional deterioration included 1) need for moreoxygen to maintain arterial oxygen tension withinnormal limits (12 patients); 2) arterial carbondioxide tension above 85 torr (ten patients); 3)need for a mechanical ventilator in infants whowere receiving continuous positive airway pressure(five patients); 4) severe apnea when off therespirator (seven patients); and 5) more frequentand severe episodes of bradyeardia on and off therespirator (14 patients). All except one infantreceived digoxin and diuretics.

Catheterization and CineangiogramsA large left-to-right shunt through the patent

ductus arteriosus was demonstrated by angiographyin 20 infants (fig. 3). The six infants without IRDShad right and left cardiac catheterization to rule outassociated heart lesions; except for patent foramenovale, none were found. Systolic pressure differ-ences between the descending thoracic aorta andpulmonary arteries varied between 3 and 33 mmHg (mean 18). Mean pressure differences rangedbetween 4 and 12 mm Hg (mean 6).Only four of 15 infants with IRDS had full

cardiac catheterization; ten had retrograde aorticcatheterization through the umbilical or femoralarteries. Aortic and pulmonary arterial pressureswere obtained in nine patients. Systolic pressuredifferences between the descending thoracic aortaand pulmonary artery ranged between 10 and 28mm Hg (mean 21). Mean pressure differencevaried between 0 and 21 mm Hg (mean 9).Because of difficulties in obtaining well mixedsamples, calculations of shunts were unreliable.

OperationAge at operation ranged between 16 and 44 days

(mean 29) for infants without IRDS and betweenfive and 35 days (mean 15) for infants with IRDS.All patients had intravenous catheters, and 15infants had umbilical, femoral, or radial arterialcatheters during operation. Operation was per-formed with halothane anesthesia in ten infants,with fluroxene in nine, and with ketamine in two.The ductus arteriosus was exposed through aposterolateral thoracotomy and was equal to orlarger than the diameter of the aortic arch in allpatients. The ductus arteriosus was doubly ligatedwith zero or number 1 gauge silk in 19 patients. Inone patient the ductus was divided electively; inanother the ductus was divided after the ligature

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Figure 3

Lateral cineangiogram of an infant without IRDS illustrating the nearly equal size of the patent ductusarteriosus (PDA) and aortic arch (AA).

cut the vessel. Aside from atelectasis and onepatient with transient paresis of the left vocal cordno operative complications occurred in the 21patients.

Results of OperationPostoperative CourseThe six patients without IRDS improved dramat-

ically after operation. In all patients heart failurewas controlled, and heart size and pulmonaryvascularity decreased in postoperative roentgeno-grams (fig. 4). All patients were extubated withinthree days and breathed room air three to 25 days(mean 10) after operation. Atelectasis occurred infour infants but involved lobes of both right andleft lungs. In five patients a faint systolic murmurwas heard after operation, but all murmurs haddisappeared at the time of discharge from thehospital ( 18 to 51 days after operation).

Postoperative pulmonary function improvedCirculation, Volume XLVIII, October 1973

steadily in eight of the 15 patients with IRDS.These infants were extubated two to 33 days (mean13) after operation.One patient died of intracranial hemorrhage nine

days after operation, and one who was extubatedand breathing room air died of fluid overload aftertransfer to another hospital (table 2). The other sixpatients were discharged home 49 to 109 days afteroperative closure of the ductus arteriosus.

Respiratory function of three patients improvedslowly after operation, but each died during asudden hypoxic episode 20, 30, and 160 dayspostoperatively. Two were receiving respiratoryassistance at the time of death.Two patients with IRDS did not improve and

died of progressive respiratory insufficiency one and24 days after operation. Two infants died one andfour days after operation from peritonitis secondaryto ischemic bowel disease7 which was probablypresent preoperatively.

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Figure 4

Anteroposterior chest films one day before (A) and one day after (B) ligation of the patent ductus ar-teriosus in an infant without IRDS. Postoperatively both heart size and pulmonary vascularity decreasedmarkedly.

Of 11 patients with IRDS who hpulmonary function postoperatively,tinued to have brief episodes of bradysize decreased in six of the 11 patiEheart size had appeared normal prnand pulmonary vascularity decreasedinfants had postoperative atelectasis, ointerstitial emphysema of the right 1irequired right thoracotomy for recurnthorax which was present preoperinfants developed hydrocephalus: cDandy-Walker malformation and oihydrocephalus, apparently secondary t

Table 2

Postoperative Change in IRDS in Patients

Numrberof

Patients

Hospital DeathsImprovement in IRDSSlow improvement in IRDSNo improvement in IRDSPeritonitis (Change in IRDS

not determined)Total

Late DeathsRespiratory infection

2*32

2

9

1

* One patient died of fluid overload and thintracranial hemorrhage

iad improvedseven con-

'cardia. Heart

hemorrhage. Both received ventricular-peritonealshunts.

c-,nts (in two, Follow-Up

woperatively), At present, six operative patients without neona-in ten. Seven tal IRDS are ten to 60 months of age. Four childrenme developed are normal and do not have evidence of mental,ung, and one auditory, or visual losses. Two children are notrent pneumo- normal. One of these was born at 28 weeksatively. Two gestation, weighed 880 g, has mild hemiplegia,:ne had the grade 1 retrolental fibroplasia, and a developmentalwc developed quotient of 64 (normal 90 to 110) at 35 mouths ofo intracranial age. The other child was born at 35 weeks

gestation, weighed 1580 g, and has a developmentalquotient of 65 at 26 months of age. Environmentalinfluences may be important in the slow develop-

Who Died ment of this child.One of the six infants who recovered from IRDS

Postoperative and severe heart failure died at home of respiratorynay infection seven weeks after discharge from the

hospital. At autopsy the lungs were found to be9,080 160 fibrotic and grade 5 retrolental fibroplasia was1, 24 present. The other five patients are two to 23

months of age. The two infants with hydrocephalus1, 4 are severely retarded, and one of these patients is

blind from retrolental fibroplasia. One 23-month-oldinfant has no speech yet and has psychomotor

130 development appropriate for a 16-month-old infant.e second died of One infant nine months of age has development

appropriate for the age of five months.Circulation, Volume XLVIII, October 1973

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Autopsy FindingsAutopsies were performed in eight of the nine

patients who died in hospital. In seven patients,areas of atelectasis, proliferated alveolar septal cellsand macrophages, and moderate or severe intersti-tial fibrosis were present in the lungs. In one ofthese infants cuboidal cells lined primitive alveoli,and the lungs of two infants had areas thatcontained hyaline membranes. None of the lungshad congested alveolar capillaries or evidence ofsquamous metaplasia in the bronchi. The micro-scopic appearance of the lung of the extubated in-fant who died of fluid overload did not differ fromthat observed in infants who had only slow or noimprovement in pulmonary function after operation(fig. 5). In contrast, the lung of the infant who diedof intracranial hemorrhage nine days after opera-tion was normal.

DiscussionAfter the twentieth week of gestation the human

ductus arteriosus constricts in response to oxygen,acetylcholine, alpha receptor catecholamines, his-tamine, 5-hydroxytryptamine, and bradykinin.6' 8-12In vitro the response to high oxygen concentrationscan be blocked by atropine and acetylcholinester-ase,11 2 but is not blocked by dibenamine. In fetallambs, the degree of ductal constriction by oxygenis proportional to blood oxygen tension and togestational age.7' 1' This relationship may be relatedto the growth of cholinergic nerves in the ductusbetween the twentieth week and term.9 Althoughthe exact mechanisms that cause closure of theductus arteriosus of term infants at birth are notclearly understood, the reduced cholinergic innerva-tion and reduced response to oxygen partiallyexplain the high incidence of patent ductus

$!

Figure 5Photomicrograph of the lung of the extubated infant who died of fluid overload 18 days after operation.There is marked interstitial fibrosis, septal cell hyperplisia and proliferation of macrophages without cap-illary congestion or evidence of squamous cell metaplasia in the bronchi.


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EDMUNDS ET AL.

arteriosus in premature infants. This hypothesis issupported by the finding that in many cases theductus arteriosus does not close spontaneously untilthe premature infant reaches its full gestationalage.2,3, 5

Injections of acetylcholine at the origin of theductus arteriosus from the aorta have shown thatthe patent ductus in premature infants is capable ofconstriction.'4 Although the ductus has remainedclosed in some infants, the effectiveness of thismethod of therapy has not been completelyinvestigated. Our experience, and that ofothers,'5-'7 indicates that ligation of the ductus canbe performed in premature infants without neona-tal IRDS with low operative mortality and morbidi-ty. Since most patent ducti eventually closespontaneously, operation is usually not necessary inpremature infants.'-3 5

Operation is clearly indicated for infants withoutIRDS who have heart failure that cannot becontrolled by medical means. Cardiac catheteriza-tion confirms the presence of a large ductusarteriosus and rules out other cardiac lesions.Because the ductus is often friable, ligation is morerapid and safer than division. In this selected groupof patients, both early and late results aresatisfactory. The certain retardation in one infantprobably resulted from an exceptionally shortgestation. The slow development of a second infantis not explained by past medical events and stillmay prove to be temporary.

In each of our 15 patients with prematurity,IRDS, and PDA, definite deterioration in pulmo-nary function occurred when signs of severe heartfailure developed. As pulmonary vascular resistancedecreased after birth,18 the left-to-right ductal shuntpresumably caused pulmonary congestion intersti-tial edema, and elevated pulmonary venous pres-sure. Although we do not know that heart failureincreases pulmonary damage in patients with IRDS,we do know that the advent of heart failureincreases pulmonary dysfunction in some infants.When medically uncontrollable heart failure occursand respiratory status worsens, operation is the onlypotentially effective therapeutic course available.Our results in premature infants with severe

IRDS and heart failure from PDA are disappoint-ing. Although operation controls heart failure, mostof the infants die from progressive and irreversiblelung disease or from complications of extremeprematurity. With the exception of one infant whois only two months of age, all of the survivingpatients have brain damage or are retarded in

psychomotor development. Premature infants withbirth weights less than 1250 g have an increasedincidence of brain damage and retrolental fibropla-sia,19 and in these extremely premature infants,IRDS increases the likelihood of intellectual im-pairment.20 Of our 15 infants with IRDS and PDA,12 had birth weights less than 1250 g. Operationsuccessfully controlled heart failure in these pa-tients; however, progressive and irreversible lungdisease in some, and complications of prematurityin others, precluded satisfactory results.

Brain damage, retrolental fibroplasia, bowelischemia, and progressive, irreversible lung diseaseare not inevitable consequences of prematurity andsevere IRDS without heart failure. As far as we candetermine, operation does not induce these compli-cations. Early control of heart failure, by operationif necessary, removes the immediate threat to life,prevents additional pulmonary dysfunction due topulmonary congestion and edema and shouldproduce some healthy survivors. Unfortunately, ourexperience shows that progressive lung disease andthe complications of extreme prematurity still pre-empt a successful outcome in the majority of thesetiny patients.

AcknowledgmentThe authors thank Dr. Benson B. Roe who operated on

two of these infants, and Dr. Noel Fishman who operated onone infant. The authors also thank the surgical, anesthesia,and pediatric house officers and the nurses who participatedin the intensive care of these infants.

References1. KITTERMAN JA, EDMUNDS LH JR, GREGORY GA,

HEYMANN MA, TOOLEY WH, RUDOLPH AM: Patentductus arteriosus in premature infants. Incidence,relation to pulmonary disease and management. NEngl J Med 287: 473, 1972

2. AULD PAM: Delayed closure of the ductus arteriosus. JPediatr 69: 61, 1966

3. DANILOwICZ D, RUDOLPH AM, HOFFMAN JIE: Delayedclosure of the ductus arteriosus in premature infants.Pediatrics 37(1): 74, 1966

4. GIRLING DJ, HALLIDIE-SMITH KA: Persistent ductusarteriosus in ill and premature babies. Arch Dis Child46: 177, 1971

5. POWELL ML: Patent ductus arteriosus in prematureinfants. Med J Aust 2: 58, 1963

6. KENNEDY JA, CLARK SL: Observations on thephysiological reactions of the ductus arteriosus. Am JPhysiol 136: 140, 1942

7. BORN GVR, DAWES GS, MOTT JC, RENNiICK BR: Theconstriction of the ductus arteriosus caused by oxygenand by asphyxia in newborn lambs. J Physiol 132:304, 1956


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8. KOVALCIK V: The response of the isolated ductusarteriosus to oxygen and anoxia. J Physiol 169: 185,1963

9. ARONSON S, GENNSER G, OWMAN CH, SJOBERG NO:Innervation and contractile response of the humanductus arteriosus. Eur J Pharmacol 11: 178, 1970

10. BOREUS LO, MALMFORS T, MCMURPHY DM, OLSON L:Demonstration of adrenergic receptor function andinnervation in the ductus arteriosus of the humanfetus. Acta Physiol Scand 77: 316, 1969

11. MCMURPHY DM, BoREus LO: Studies on the pharma-cology of the perfused human fetal ductus arteriosus.Am J Obstet Gynecol 109: 937, 1971

12. OBEnm4NSLI-WEISS I, HEYMANN MA, RUDOLPH AM,MELMON KL: The pattern and mechanisms of'response to oxygen by the ductus arteriosus andumbilical artery Pediatr Res 6: 693, 1972

13. McMURPHY DM, HEYMANN MA, RUDOLPH AM,MELMON KL: Developmental changes in constrictionof the ductus arteriosus: Responses to oxygen andvasoactive agents in the isolated ductus arteriosus ofthe fetal lamb. Pediatr Res 6: 231, 1972

14. HEYMANN MA, RUDOLPH AM: Constriction of theductus arteriosus by acetylcholine in prematureinfants. Circulation 44 (suppl II): II-177, 1971

15. DECONCQ HG JR: Repair of patent ductus arteriosus ina 1,417 gm infant. Am J Dis Child 106: 402, 1963

16. CLEVELAND RJ, NELSON RJ, EMMANOULIIES CC,LIPPMANN M, BLOOMER WE: Surgical managementof patent ductus arteriosus in infancy. Arch Surg 99:516, 1969

17. GUPTA JM, VAN VLIET PKJ, FISK GC, WRIGHT JS:Ductus ligation in respiratory distress syndrome. JThorac Cardiovase Surg 63: 642, 1972

18. WAGENVOORT CA, NEUFELD HN, EDWARDS JE: Thestructure of the pulmonary arterial tree in fetal andearly postnatal life. Lab Invest 10: 751, 1961

19. LUBCHENcO LO, DELIVORIA PAPADOPOULOS M, SEARLSD: Long term follow-up studies of prematurely borninfants II. Influence of birth weight anl gestationalage on sequelae. J Pediatr 80: 509, 1972

20. TOOLEY WH: Neonatal Intensive Care and Longitudi-nal Development, 64th Ross Conference on PediatricResearch, edited by M. T. Stahlman (in press)

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KITTERMAN, ABRAHAM M. RUDOLPH and WILLIAM H. TOOLEYL. HENRY EDMUNDS, JR., GEORGE A. GREGORY, MICHAEL A. HEYMANN, JOSEPH A.

Surgical Closure of the Ductus Arteriosus in Premature Infants

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surgical closure of the ductus arteriosus in premature infants

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