Archives of Disease in Childhood, 1984, 59, 1020 -1026

Prostaglandin E1 in suspected ductus dependentcardiac malformationK A HALLIDIE-SMITH

Department of Cardiology, Royal Postgraduate Medical School, London

SUMMARY Fifty two sick neonates with major duct dependent cardiac defects were given shortterm intravenous infusions of prostaglandin E1 (alprostadil) in doses varying between 0-005 and0.1 ,ug/kg/minute. The object of the study was to try to achieve an effective but safe regimen thatcould be instituted as soon as such a diagnosis was suspected. Effective clinical improvement was

achieved at each dosage but the incidence of side effects seemed to be dose related, and no

serious side effects were noted at a dosage of 0-005 to 0-01 [tg/kg/minute. It is recommended thata low dosage regimen be started before transfer to a paediatric cardiac centre.

The role of prostaglandins in maintaining ductuspatency in the newborn infant is now well estab-lished and there are numerous reports of thesuccessful use of prostaglandin El and prostaglandinE2 in sick newborn infants with both cyanotic" andacyanotic-6 ductus dependent cardiac malforma-tions. These reports have mainly been concernedwith the administration of prostaglandins once anexact cardiac diagnosis has been established. Theobject of this study was to establish a safe andeffective regimen for prostaglandin El that could beinitiated on suspicion of a duct dependent cardiacdefect in a sick neonate, either shortly after arrivalat a paediatric cardiac centre or, perhaps moreimportantly, before transfer to such a centre. Therewould thus be the optimum chance of maintaining orimproving such an infant's general status beforeurgent cardiac investigations and surgery, contribut-ing to an improvement in morbidity and mortality inthis group of critically ill neonates.Our experience with prostaglandin El dates from

1978 when we started to use it in individual clinicaltreatment for sick infants with proved major ductdependent cardiac malformations. The currentseries covers a three year period from 1980 andutilises a standard regimen of administration basedon our earlier experience, the only variable factorbeing that of dosage.

Patients

The patients consisted of 52 consecutively admittedsick infants suspected of having major ductusdependent cardiac defects. Preterm infants, those

requiring assisted ventilation, and any in whomclinical and arterial blood gas data were inadequatewere excluded. Prostaglandin E1 was started afterclinical diagnosis of a major cardiac defect whoseclinical course would be adversely affected by ductusclosure. The cardiac diagnosis was subsequentlyconfirmed by two dimensional echocardiographyand by angiography (48 patients) or two dimensionalechocardiography alone (four patients). Thepatients were divided into three groups. Group 1consisted of 24 cyanotic infants with ductus depen-dent pulmonary blood flow (simple or complexpulmonary atresia (22 patients) and critical pulmon-ary stenosis (two patients)). Group 2 consisted of 18patients with ductus dependent systemic blood flow(severe coarctation of the aorta (six), interruptedaortic arch (three), and hypoplastic left heartsyndrome (nine)). Group 3 consisted of 10 infantswith ductus dependent systemic-venous mixing(simple transposition of the great arteries). Theinitial inclusion of infants in the third group wasbecause of unavoidable delay in access to thecatheter laboratory and hence of balloon atrialseptostomy.The infants were assessed clinically, and upper

and lower limb blood pressures were recorded. Achest radiograph and electrocardiogram were car-ried out on each infant. Observations of rectaltemperature, apex, and respiratory rate were made;radial artery blood gases were estimated within anhour of starting prostaglandin E1 and were repeatedone to four hours after the start of treatment. Anyside effects attributable to prostaglandin E1 wererecorded, and pyrexia was defined as a temperatureof above 3720C occurring more than once in 24 hours.

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Prostaglandin El in suspected ductus dependent cardiac malformation 1021

The ages of the infants on beginning prostaglan-din treatment ranged between 6 hours and 16 days.The older infants were in group 2. Twenty of theinfants were less than 24 hours of age. The group 1infants were all less than 8 days old and the group 3infants less than 4 days old. The decision to giveprostaglandin E1 was based on the clinical diagnosisof a duct dependent cardiac defect. The group 1and 3 infants had increasing cyanosis, with orwithout metabolic acidosis. The arterial Po2 variedfrom 2*0 to 4-6 kPa (15-0 to 34-6 mmHg) in group1 infants (Fig. 1) and 2-2 to 3-8 kPa (16-5 to28-6 mmHg) in group 3 infants (Fig. 2). Arterial pHvaried between 7-26 and 7-40 in group 1 and 7-18and 7*37 in group 3. Prostaglandin E1 was com-menced for clinical deterioration in group 2 infants.Many of them were shocked and in low cardiacoutput with signs of severe cardiac failure andoliguria. Some were profoundly metabolically acido-tic even after efforts at resuscitation and theirarterial pH varied between 6-8 and 7-22 (Fig. 3)before they were given prostaglandin E1.

7-

6-

0~3-4-

. _c.-

3-

2-

7

00--W

P<O0OO1

BeforePGE1

AfterPGE1

Fig. 2 Arterial Po2 (kPa) before andfour hours or lessafter prostaglandin El (PGE,) in IO group 2 infants withtransposition ofthe great arteries.

7-5-

7-4-

7-3 -

-7-2-

t; 1

7 0 -

6.9 -

BeforePGE1

AfterPGE1

Fig. 1 Arterial Po2 (kPa) before andfour hours or lessafter prostaglandin El (PGE,) in 24 group I cyanoticinfants with duct dependent pulmonary bloodflow.

Conversion-SI to traditional units: Po2 kPa 7-5 mmHg.

6-8 -

P<o0oo1

Before AfterPGEI PGEi

Fig. 3 ArterialpH before andfour hours or less afterprostaglandin El (PGE1) in 18 group 2 infants with ductusdependent systemic bloodflow.

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The duration of treatment varied between fiveand 280 hours. (Group 1 mean 47 hours; group 2,mean 63 hours; group 3, mean 10 hours.) Prosta-glandin E1 was stopped after palliative or correctivesurgery, balloon atrial septostomy, or the diagnosisof an inoperable cardiac defect.The prostaglandin E1 was dissolved in 4-5%

dextrose saline or 5% dextrose infused into aperipheral vein using an IVAC or constant infusionpump. Each infant was initially given the maximumvolume of fluid calculated for age and weight. Theconcentration of prostaglandin E1 was electivelydecreased during this study to see whether sideeffects could be avoided while maintaining ductuspatency (Table 1). The first six infants were given aconcentration of prostaglandin El of 0-1 ug/kg/minute whereas the last six infants received 0-005ug/kg/minute. If major complications occurred theprostaglandin El was temporarily stopped andsubsequently restarted at a lower dosage.

Table 1 Dosage ofprostaglandin E, (PGE,) related tonumbers ofinfants in each clinical group

Dose PGEI Total Group I Group 2 Group 3(,g/kg/min)

0-1 6 3 3 00-05 15 6 4 50-03 9 4 5 00-02 6 3 2 10-01 10 4 3 30-005 6 4 1 1

Results

There were no failures of response to prostaglandinE1 in the 52 infants studied. The group 1 and 3infants became obviously less cyanosed within 30 to60 minutes of starting prostaglandin E1 and thearterial Po2 increased significantly within four hoursof starting treatment (Figs. 1 and 2), regardless ofdosage. There was an improvement in arterial pH in

Fig. 4 Right ventricular angio (lateral) ofinfant with simple transposition ofthegreat arteries illustrating posteriorpulmonary artery filling through widelypatent ductus arteriosus (infant receivingprostaglandin El 0.01 ug/kg minute).

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those infants in whom it had already been reduced.A widely patent ductus arteriosus was shown byright ventricular angiography or arteriography in thegroup 3 infants (Fig. 4) but it subsequently closedspontaneously in all these infants. The 10 infantscontinued to do well after balloon atrial septostomyand nine of them have already had successfulMustard procedures. There was a gradual butstriking improvement in the group 2 infants asjudged by muscle tone, clinical increase in cardiacoutput, and improvement in leg pulses in the infantswith coarctation of the aorta. Once a satisfactorycardiac output had been achieved renal flow couldusually be re-established with diuretics, though oneinfant required a short period of peritoneal dialysis.Clinical improvement was usually noticed in thisgroup one to two hours after starting prostaglandinEl and continued over many hours. Arterial pH,which responded significantly to prostaglandin El(Fig. 3), was unrelated to the concentration usedand continued after the four hour assessment. Thenumbers, however, are too small in the lowerdosages to be sure that the results would beconsistently satisfactory. After stopping prostaglan-din El in infants found to have the hypoplastic leftheart syndrome, some 36 to 48 hours elapsed beforethere was clinical evidence of reclosure of theductus.

Side effects

The side effects ascribed directly to prostaglandin Elare described in Table 2. Forty one episodes wererecorded in 19 infants, 12 of whom had more thanone side effect. The most serious side effect was ofsudden apnoea which occurred in four cyanoticinfants in group 1 within four hours of startingprostaglandin El. Hypoventilation and abnormalbreathing patterns were noted in six additionalinfants in whom respiration had been rapid butregular before starting the treatment. Nine infantsbecame 'jittery' within four hours of starting treat-ment and two developed generalised convulsions.Frequent loose stools were documented in at least

Table 2 Side effects ofprostaglandin E, (PGE,) related todosage (52 infants)

Side effect Total Dose PGE,occurrences (,g/kg/min)

Apnoea 4 0 05-01Hypoventilation 6 0-03-0-1Convulsions 2 0-05-0-1'Jitteriness' 9 0-02-0-1Diarrhoea 9 0-02-01Pyrexia 11 0-02-0 1

nine infants. Two infants in group 2 developednecrotising enterocolitis but they were so sick thatthis complication could not be definitely ascribed toprostaglandin El. Pyrexia occurred in 11 infants butwas not a worrying problem. The fever was usuallylow grade and sometimes resolved spontaneously,though in other infants it subsided after stoppingtreatment. There were no problems of hypotension,flushing, tachycardia, or arrhythmias in this series.Bradycardia occurred only in conjunction withrespiratory insufficiency.

Relating side effects to the dosage of prostaglan-din El we found that apnoea and convulsionsoccurred in the dose range 0-05 to 0 1 ug/kg/minute;hypoventilation in the range 0-02 to 0-1 ug/kg/minute; and 'jitteriness', diarrhoea, and pyrexia inthe range 0-02 to 0-1 ug/kg/minute. No side effectswere recorded in the 16 infants given a prostaglan-din El dosage of 0-005 to 0*01 ug/kg/minute.

Discussion

All infants in this series responded to prostaglandinEl, emphasising the potentially predictable responseof the newborn ductus.7 Twelve per cent, however,of a larger series of 301 infants with cyanoticcongenital heart disease failed to make a significantresponse,4 and non-responders have been reportedby others.2 3 5 6 It has been suggested that favour-able determinants of responsiveness are an initiallylow arterial Pao2 and an age of less than 96 hours,4while unfavourable determinants of responsivenessin retrospect are an irreversibly closed ductus3 4 6and severe acidaemia and collapse.5 There is noclear evidence that interarterial treatment is moreeffective than central or peripheral venous treat-ment and, indeed, oral administration of prostaglan-din E2 may be equally effective.8 Environmentaloxygen concentration was at one time thought to berelevant but more recent work has shown thatprostaglandin El is effective in relieving the ductusin both high and low oxygen concentrations.9

In the normal term infant functional closure ofthe ductus occurs within a few hours of birth andanatomical closure in 21 days,'0 when irreversibledegenerative changes in the medical musculaturehave occurred. From this time prostaglandins wouldclearly cease to dilate the ductus and it seems likelythat their effectiveness must decline in the precedingperiod. It has been suggested that increased flowthrough the ducts may delay anatomical closure"and it seems clear that the best chance of a goodresponse to prostaglandins lies in their early admin-istration while the circulatory and metabolic statusof the infant is relatively satisfactory. Most pub-lished reports refer to infants given prostaglandins

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after establishing a diagnosis but the infants in thepresent series were given prostaglandin El when aduct dependent cardiac defect was suspected, andthis approach would seem to have justifiable argu-ments in its favour. If the infant should subsequentlybe proved to have an unfavourable defect such asthe hypoplastic left heart syndrome, prostaglandinscan subsequently be stopped by agreement, as inthis series, though recent advances in palliativesurgical techniques have improved the potentialprognosis for some of these infants. If prostaglandinEl is given early, before definitive diagnosis, it mustsometimes be given outside its usual therapeuticindications. In the cyanotic group, persistence of thefetal circulation could be an important diagnosticerror. Prostaglandin El, however, may be helpful inthese infants because of its pulmonary vasodilatoreffect7 even though it will be stopped after a firmdiagnosis is made in order to encourage ductusclosure. An infant with obstructed total anomalouspulmonary venous drainage may deteriorate furtherif given prostaglandin El as a direct result ofincreasing ductal flow'2 but it is an uncommonanomaly with a characteristic clinical presentation.The precise diagnosis of an acyanotic collapsedinfant in gross cardiac failure may be extremelydifficult but if, for instance, an infant with myocar-ditis were given prostaglandin El based on theincorrect diagnosis of a duct dependent cardiacdefect, the infant should be helped by improvementof left ventricular myocardial oxygenation andfunction.14

Although there are numerous reports of the roleof prostaglandin in neonates with cardiac malforma-tion, as were those designated to our groups 1 and 2,there are few references to their use in group 3infants with simple transposition of the great arteriesbefore balloon atrial septostomy. Both prostaglan-din El and E2, however, seem to raise successfullythe arterial Pao2 in this group of cyanosed infants. l5Presumably the mechanism of the improved arterialPao2 is due to increased ductus flow resulting inincreased blood flow to pulmonary artery and leftatrium, increased left atrial pressure, and henceincreased arterial venous mixing through a stretchedforamen ovale. A decrease in pulmonary vascularresistance may also be a favourable factor. Theinfants we have reported and those of Beitzke andSuppan15 responded to prostaglandin treatment butthis response implies the capability of adequatearterial-venous mixing at atrial level. We haverecently had experience of an infant with simpletransposition of the great arteries who failed torespond to prostaglandin El infusion and, indeed,developed pulmonary oedema. Subsequentcatheterisation confirmed the diagnosis but the

catheter could not be passed to the left atrium so itwas supposed that the infant had premature closureof the foramen ovale and emergency surgical septec-tomy was carried out. Despite the possibility of thisproblem, our policy is to utilise prostaglandin El forsick infants suspected of having transposition of thegreat arteries, particularly if there is a predicteddelay in access to laboratory facilities for balloonatrial septostomy. It is also our current practice toarrange for prostaglandin El treatment to be startedbefore transfer in any infant judged to have a majorduct dependent cardiac defect after telephone dis-cussion with the referring paediatrician.

Despite awareness of the possibility of sideeffects, it may be difficult to decide whether aparticular complication results directly from pros-taglandin treatment or whether it could have beencoincidental in the clinical course of a sickneonate, 16 and reports on the incidence of knownside effects are few. In a large multicentre study of481 infants, however, 21-5% had one or moredocumented side effect,'6 compared with 36-5% inour own series.The most important reported short term side

effects of prostaglandin El treatment in sick neo-nates are those affecting the cardiovascular system(hypotension, vasodilatation, flushing, rhythm andconduction disturbances); the respiratory system(apnoea and hypoventilation); the gastrointestinalsystem (frequent stools and diarrhoea); the centralnervous system (twitching and convulsions); andgeneralised systemic (pyrexia). The sideeffects of prostaglandin E2 seem to be similar tothose of E1.'8 Pyrexia is thought to be due to acentral effect of prostaglandins on the mid brain andthe re-setting of the thermoregulation centres athigher body temperature. 19 Diarrhoea has beenspecifically reported in infants receiving prostaglan-din E1, and colicky pain and diarrhoea have beencomplained of by human volunteers given oralprostaglandins.2' It is possible that abdominal dis-comfort may have accounted for the restlessness ofsome of our infants. 'Jitteriness', tremors, andconvulsions, however, are probably due to thecentral action of prostaglandins.22 Hypoventilationand apnoea are thought to be central in origin'9 butthis well documented and serious side effect is ofinterest because studies in conscious adults23 andanaesthetised dogs and cats24 25 have shown thatprostaglandin El stimulates ventilation. Prostaglan-dins E1 and E2 have been shown to cause apnoea innewborn swine,26 and, recently, institution of res-piratory movements in fetal lambs, within an hourof starting prostaglandin E2 has been reported.27 Itis possible that there may be a critical concentrationof prostaglandin E2 in the newborn infant above

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which inhibition of respiration occurs, but thisremains speculative.

Whereas Lewis et al'6 found cardiovascular com-plications to be their most common group sideeffect, we did not record any such complicationother than bradycardia associated with hypoventila-tion or apnoea, while pyrexia, though not constitut-ing a clinical problem, was our most frequent sideeffect. The most, dramatic and worrying complica-tion was that of apnoea which occurred in 7-7% ofour 52 infants, in 16-5% of a series of 78 infants,'7and in 12% of 481 infants.'6 Although these attacksmay be terminated by stopping prostaglandin'7 thesudden and unsuspected onset of apnoea, oftenearly in treatment, implies standby facilities forintubation and ventilation during prostaglandin Eltreatment'6 28 and could add to the hazards ofinterhospital transfer. Cyanotic congenital heartdisease and a birthweight of less than 2 kg have beenshown to be predisposing features. 16 It has also beensuggested that apnoea may occur more readily ininfants receiving prostaglandin E2 rather than El3and serious apnoeic attacks have been reported withboth its short term use28 and long term oraltreatment.29 This suggestion remains unsubstan-tiated; in our series, apnoea occurred only incyanotic infants with duct dependent pulmonaryblood flow but our patients were all term infants.The site of prostaglandin infusion is not now

thought to be related to side effects other than thatinterarterial administration may favour vasodilata-tion and oedema. In our own experience peripheralvenous administration has proved entirely satisfac-tory, although a central line may be preferred.While oral prostaglandins have their protagonistsboth in the short and the long term,8 neverthelessthe intravenous route offers dosage confidence andsome practical advantages in the early stages oftreatment.We strongly support the view that apnoeic attacks

and other major side effects are dose related,whether using prostaglandin El or E2.'8 We did notrecord any serious side effects in infants given lessthan 0-02 ug/kg/minute and, conversely, our fourinfants who became apnoeic were receiving 0-05 to0*1 ug/kg/minute. Review of the reports confirmsdosage of prostaglandin El varying between 0-02ug/kg/minute and 05 ug/kg/minute, with 0-1 ug/kg/minute being the most frequently documentedconcentration. An initial dose of 0 1 ug/kg/minute isstill recommended by the manufacturers (Upjohn)supplying alprostadil.

Side effects were not directly related to dosage inthe report of the United States multicentre trial,'6although it is clear that the infusion rate was reducedbelow 0O1 ug/kg/minute in some of the infants

studied and was stopped in others because of sideeffects. Recently a review article has recommended0-05 ug/kg/minute as initial dosage30 with subse-quent reduction in dosage. We feel, however, thateven this regimen may be unsafe for transportingsick infants, particularly since apnoeic attacks mayoccur early in treatment, and would reiterate thatdosages of 0-005 ug/kg/minute to 0-01 ug/kg/minutehave so far been found both effective and free fromserious side effects, while recognising the potentialfallacies of small numbers and individual tolerance.Although our lowest dose of 0005 ug/kg/minute wastherapeutically successful in the six infants wetreated, we need further experience before unre-servedly supporting this as a recommended dosage.We suggest, however, that a logical and safeapproach to treatment would be to begin with asmall concentration of prostaglandin E1, of 0-001to 0-01 ug/kg/minute, with the option of a later smallincrease in dosage in the unexpected event of therebeing an inadequate response in an infant known tohave a duct dependent cardiac defect once thatinfant has been assessed at a paediatric cardiaccentre.

Messrs Upjohn Ltd supplied the prostaglandin E,.

References

l Olley PM, Coceani F, Bodach E. E type prostaglandins. A newemergency therapy for certain cyanotic congenital heart mal-formations. Circulation 1976;53:728-31.

2 Neutze JM, Starling MB, Elliott RB, Barratt-Boyes B. Pallia-tion of cyanotic congenital heart disease in infancy with E typeprostaglandins. Circulation 1977;55:238-41.

3Lewis AB, Takahashi M, Lurie PR. Administration of prosta-glandin El in neonates with critical congenital cardiac defects.J Pediatr 1978;93:481-5.

4Freed MD, Heymann MA, Lewis AB, Roehl SL, Kensey RC.Prostaglandin El in infants with ductus arteriosus dependentcongenital heart disease. Circulation 1981;64:899-904.

5Hastreiter AR, Van der Horst RL, Sepehri B, Du Brow IW,Fisher EA, Levitsky S. Prostaglandin El infusion in newbornswith hypoplastic left ventricle and aortic atresia. Pediatr Cardiol1982;2:95-8.

6 Heymann MA, Berman W, Rudolph AM, Whitham V. Dilata-tion of the ductus arteriosus by prostaglandin E, in aortic archabnormalities. Circulation 1979;59:169-73.

7Coceani F, Olley PM, Lock JF. Prostaglandins, ductus arter-iosus, pulmonary circulation: current concepts and clinicalpotential. Eur J Clin Pharmacol 1981;18:75-81.

8 Silove ED, Cox JY, Shiu MF, et al. Oral prostaglandin E2 inductus dependent pulmonary circulation. Circulation 1981;63:682-8.

9Clyman RI, Heymann MA, Rudolph AM. Ductus arteriosusresponses to prostaglandin E, at high and low oxygen concentra-tions. Prostaglandins 1977;13:219-22.

10 Rudolph AM. Congenital disease of the heart. Chicago: YearBook Medical Publishers, 1974:172.Clyman RI, Mauray F, Roman C, Heymann MA, Payne B.Factors determining the loss of ductus responsiveness toprostaglandin E. Circulation 1983;68:433-6.

2 Freedom RM, Olley PM, Coceani F, Rowe RD. The prostaglan-din challenge. Test to unmask obstructed total anomalous

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13 Hallidie-Smith KA. The short term use of prostaglandin El inthe newborn infant with duct dependent congenital heartdisease. Arch Dis Child 1983;58:649.

14 Awan NA, Evenson MK, Needham KE, Beatlie M, AmsterdamEA, Mason DT. Cardiocirculatory and myocardial energeticeffects of prostaglandin El in severe left ventricular failure dueto chronic coronary heart disease. Am Heart J 1981;102:703-8.

15 Beitzke A, Suppan CH. Use of prostaglandin E2 in managementof transposition of great arteries before balloon atrial septos-tomy. Br Heart J 1983;49:341-4.

16 Lewis AB, Freed MD, Heymann MA, Roehl SK, Kensey RC.Side effects of therapy with prostaglandin El in infants withcritical congenital heart disease. Circulation 1981;64:893-8.

17 Schober JG, Kelner M, Mocellini R. Indications and pharmaco-logical effects of therapy with prostaglandin El in the newborn.Adv Prostaglandin Thromboxane Res 1980;7:905-11.

18 Silove E. Administration of E type prostaglandins in congenitalheart disease. Pediatr Cardiol 1982;2:303-5.Coceani F. Prostaglandins and the central nervous system. ArchIntern Med 1974;133:122-9.

20 Sankaran K, Conly J, Boyle CAJ, Tyrrell M. Intestinal colic anddiarrhoea as side effects of intravenous alprostadil administra-tion. Am J Dis Child 1981;135:664-5.

21 Horton DCO, Macia IKM, Thompaon CJ. Effects of orallyadministered PGE1 on gastric secretion and gastrointestinalmotility in man. Gut 1969;9:655-8.

22 Fariello R, Olley PM, Coceani F. Neurological and elec-troencephalographic changes in newborns treated with prostag-landins El and E2. Prostaglandins 1977;13:901-7.

23 Carlson LA, Ekelund L-G, Oro L. Circulatory and respiratoryeffects of different doses of prostaglandin E1 in man. ActaPhysiol Scand 1969;75:161-9.

24 McQueen DS. The effect of some prostaglandins on respirationin rats and cats. Br J Pharmacol 1972;45:147-8.

25 McQueen DS, Ungar A. The modification by prostaglandin E1of central nervous interaction between respiratory and cardio-inhibitor pathways. tn: Mantegazza P, Horton EW, eds.Prostaglandins, peptides and amines. London: Academic Press,1969:123-4.

26 Starling MB, Neutze JM, Elliott RL, Elliott RB. Studies on theeffects of prostaglandins E1, E2, A1 and A2 on the ductusarteriosus of swine in vivo using cineangiography. Prostaglan-dins 1976;12:355-67.

27 Kitterman JA, Liggins GC, Fewell JE, Todey WH. Inhibition ofbreathing movements in fetal sheep by prostaglandins. J ApplPhysiol 1983;54:687-92.

28 Jones ODH, Rigby ML, Lincoln C, Shinebourne EA. Severeapnoea and prolonged duct patency after use of prostaglandinE2. Br Heart J 1980;43:727.

29 Morrell P, Sutherland GR, Bain HH, Hunter S. Complicationsof long term prostaglandin E2 therapy in infants with complexheart disease. Br Heart J 1982;4:895.

30 Heyman MA. Progress in cardiology. St Louis, Missouri: CVMosby Co, 1982:837-43.

Correspondence to Dr K A Hallidie-Smith, Royal PostgraduateMedical School, Hammersmith Hospital, London W12 OHS.

Received 17 July 1984

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