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Original Articles

Indian Pediatrics 1998; 35:1063-1069 

Prostaglandin E1 in Infants with Congenital Heart Disease: Indian Experience


 

Anita Saxena, M. Sharma, S.S. Kothari, R. Juneja, S.c.B. Reddy, R. Sharma,
A. Bhan and P. Venugopal


From the Cardiothoracic Center, All India Institute of Medical Sciences, New Delhi
110 029, India.

Reprint requests: Dr. Anita Saxena, Professor, Department of Cardiology, Cardiothoracic Center,
All India Institute of Medical Sciences, New Delhi
110 029, India.

Manuscript received: April 22, 1998; Initial review completed: July 11, 1998;
 Revision accepted: July 14, 1998.


 

Abstract:

Background: E-type prostaglandins (PGE1) can effectively maintain the patency of the ductus arteriosus in neonates. Its use, therefore can be life saving in infants born with ductus dependent congenital heart disease. Although PGE1 is available for over two decades in western world, it has been introduced in India only since April, 1995. Objective: To assess the efficacy of PGE1 at our center. Setting: Hospital based. Method: 65 infants with ductus dependent congenital heart disease were included. Age at time of starting PGE1 infusion ranged from 18 hours to 39 days. Forty two of these were more than a week of age, 19 were more than 14 days, and two were above one month. PGE1 was started in an initial dose of 0.05 g/kg/min, decreased to 0.005-0.01 g/kg/ min for maintenance. The indications for use of PGE1 were to increase pulmonary blood flow in 33 cases with pulmonary atresia, tricuspid atresia or critical pulmoriic stenosis (Group 1); to increase systemic blood flow in 15 cases with coarctation of aorta, hypoplastic left heart and interruption of aortic arch (Group II); to improve mixing in 13 cases of transposition of great arteries (Group III) and for improving the left ventricular volumes by keeping the duct open in 4 cases of transposition of great arteries with intact ventricular septum (Group IV). The efficacy of the drug was assessed by a rise in PaO2 and SaO2 % determined for Groups I & III, and by appearance of lower limbs pulses in Group II. Left ventricular volumes were serially measured by echocardiography in Group IV cases. Results: The drug was successful in 62 of the 65 cases. There were two failures. One was a 39 days old baby with Ebstein's anomaly of tricuspid valve and pulmonary atresia and other was an eight days old baby with coarctation of aorta and renal failure. In addition, PGE1 could not be continued in another baby due to development of a linear skin rash locally. Side effects included apnea in 5 (9%) of 56 spontaneously breathing patients. Necrotizing enterocolitis, hyperpyrexia and jitteriness was seen in one case each. Six patients died. Two were related to PGE1, one due to failure, another due to its side effects. Definitive. procedure were performed in 51 cases electively. PGE1 was used upto 13 days with sustained benefit. Conclusion: PGE1 is an effective drug for keeping the ductus open in infants with ductus dependent congenital heart disease. It can be used for neonates beyond the first week of life with efficacy. Apnea is a major side effect and close monitoring is essential.

Key words: Congenital heart disease, Patent ductus arteriosus, Prostaglandin E1.

COCEANI and Olley in 1973 demonstrated that E type prostaglandins can markedly relax the isolated ductus arteriosus in fetal lambs(1). This report along with several other animal experiments led to the clinical use of prostaglandin E1 (PGE1) to maintain patency of the ductus arteriosus in infants born with cyanotic congenital heart disease or with reduced systemic blood flow(2-5). The drug may be life saving in these ductus dependent cardiac malformations. Although PGE1 is available for over two decades in the western world, it has been introduced in India only in April, 1995. Most of the reported data is in very young neonates and the drug is most useful if given within 96 hours of life(6). In a country like ours, where late referral pattern is common, a large number of infants with ductus dependent heart disease are 'referred beyond one week of life. We have used this drug in 65 infants at our center and describe our experience.

Subjects and Methods

Patients presenting with a ductus dependent congenital heart disease in the first month of life were included in the study if their parents were willing for subsequent definitive intervention. In addition PGE1 was used in two more babies above one month of age as a life saving medicine since they presented in a moribund state and were too sick for any intervention. The drug was thus used in a total of 65 infants. Cyanosis was present in 58 patients and 3 patients presented with shock. Sixty one of these infants had an echocardiographically confirmed ductus arteriosus dependent congenital heart defect. In rest of 4 infants, PGE1 infusion was given on clinical suspicion of such a lesion, confirmation by echocardiography was done later. Preinfusion echocardiography demonstrated a very thin jet of restrictive ductus in 45 babies and a closed ductus in 11 cases, in the rest 5 cases, ductus was open. The age of patients ranged from 18 hours to 39 days, 42 were beyond seven days of age. As mentioned earlier only two infants were more than one month of age (Table 1). There were 51 male infants and 14 were female. Nine infants were acutely ill at the time of presentation and had severe hypoxemia with metabolic acidosis necessitating ventilatory support prior to institution of PGE1 therapy.

Underlying Diagnosis

The patients were divided into four groups according to the underlying diagnosis and the indication for use of PGE
1: (i) Group I - 33 cyanotic infants with ductus dependent pulmonary blood flow (pulmonary atresia, critical pulmonic stenosis); (ii) Group II - 15 patients with ductus dependent systemic blood flow. These were cases of coarctation of aorta, interruption of aortic arch and hypoplastic left ventricle; (iii) Group III - 13 infants with transposition of great arteries and intact ventricular septum. PGE1 was used to improve systemic venous mixing by keeping the ductus arteriosus open; and (iv) Group IV - 4 infants with transposition of great arteries with intact ventricular septum who presented beyond 12 days of age. Indication for PGE1 was to prepare the left ventricle by keeping the duct open prior to arterial switch operation.

PGE
1 was initiated as a continuous intravenous infusion through a pump in a dose of 0.05 ~g/kg/min by dissolving 250
g of Prostin VR (Upjohn Ltd.) in 50 ml of 5% dextrose. The dose was increased in increments of 0.05 g/kg/min to a maximum of 0.4 g/kg/min if the desired response (see below) was not obtained. Once the beneficial effect of PGE1 was seen, the infusion rate was rapidly decreased to as low as 0.005 g/kg/min for maintenance.


TABLE I

Age of Infants at Start
of PGE1 Infusion

Age (Days) No.
0-7 23
8-14 23
15-30 17
> 30 2


All the infants were assessed clinically before starting the infusion and careful monitoring of blood pressure, respiratory rate, skin color, temperature, peripheral pulses was done during the PGE1 infusion. Any complication or side effect of the drug was noted. The response to PGE1 infusion was assessed differently for the various groups. For Groups I and III a rise in PaO2 (measured by blood estimation) or SaO2 % (measured noninvasively by pulse oximeter) along with clinical improvement of cyanosis was taken as indicator of response. Appearance of lower limb pulses with equalization of upper limb and lower limb blood pressure along with improvement in color of the baby was taken as indicator of response to PGE1 for Group II infants. Infants in Group IV were assessed by serial echocardiography to look for left ventricular loading. The duration of PGE1 infusion varied from two hours to 13 days with a mean duration of 27 hours, depending upon the time of subsequent definitive/palliative procedure. The end point for analysis was surgery for Group I, surgery or balloon dilation for Group II, balloon atrial septostomy for Group III and surgery for Group IV cases.

Results

Intravenous infusion of PGE1 was considered successful in 62 of 65 infants studied. Clinical evaluation revealed a reduction in cyanosis in Groups I and III patients and this response was seen in less than 15 minutes in all successful cases (45/46). Estimation of arterial saturation by pulse oximetry also revealed increase in Sa02%' In 26 infants where arterial blood gases were taken after starting PGE1 infusion, a rise in PaO2 and pH was demonstrable in successful cases. The clinical response was sustained on PGE1 infusion. The patency of ductus arteriosus was also demonstrable on echocardiography with color flow imaging. Subsequent follow up of infants in each group is shown in Table II. Out of 25 patients in Group I operated, 21 underwent a systemic to pulmonary artery shunt procedure and in four. who had pulmonary atresia and intact ventricular septum, patch repair of right ventricular outflow tract was done. All eleven patients in Group III underwent a primary arterial switch operation.

Infants in Group III showed a relatively slow response to PGE1 infusion. Successful results were obtained in 14 of 15 cases. There was improvement in color, urine output with appearance of good volume lower limb pulses after 30 minutes but within one hour in all responders except one, where an adequate response was seen at two hours, only after the PGE1 infusion rate was in- creased to 0.3
g/kg/min. This baby had septicemia, developed necrotizing enterocolitis and died four days after starting PGE1 infusion. A Norwood state I procedure was performed on two patients with hypoplastic left heart syndrome. Arch interruption correction with ventricular septal defect closure was done in two patients and five infants underwent surgery for coarctation of aorta. Three infants with coarctation of aorta had balloon angioplasty.

Left ventricle was adequately prepared in less than 24 hours on PGE
1 infusion for an arterial switch operation in three of four infants with transposition of great arteries (Group IV). In one patient, however, PGE1 infusion could not be continued after 10 minutes due to local linear skin rash. This rash was seen repeatedly even after using drug from a new ampoule and changing the infusion system.

A total of 19 infants underwent cardiac catheterization on PGE1 infusion in 16 an interventional procedure was performed. No complications were seen at catheterization related to PGE1 infusion. Of the 7 patients who died, one death was probably related to PGE
1 induced necrotizing enterocolitis. One more infant died due to failure to respond to PGE1 infusion. This baby had Ebstein's anomaly of tricuspid valve with pulmonary atresia and presented with sudden increase in cyanosis at 39 days of age. He did not respond to PGE1 infusion and died before any. definitive procedure could be contemplated. Five deaths were unrelated to PGE1 infusion and occurred due to noncardiac causes like septicemia and meningitis.

Failures

There Were two nonresponders (4.6%). One was the baby who presented at 39 days of age and details have been given above. The other patient was an eight day old baby with severe coarctation of aorta and renal failure. The cause of lack of response of PGE1 infusion is not clear in this neonate. PGE1 could not be continued in the third infant belonging to Group IV due to linear skin rash at the local site.

Side Effects

The most serious side effect was apnea, observed in 5 of 56 spontaneously breathing infants. All these babies were intubated and given respiratory assistance. Four of these belonged to Group I and the fifth was from Group II. Apnea occurred in the initial one hour of starting PGE1 infusion in all 5 of these. However, the dose of PGE1 was not increased in any of these after one hour. Necrotizing enterocolitis developed in one case, probably related to high concentration of PGE1 infusion (0.3
g/kg/min). Hyperpyrexia developed in one case, the infusion rate was maintained at 0.2 g/kg/ min in this baby for optimal. response. Jitteriness was seen in one case however, no baby developed seizures. Linear Skill rash starting at local site of infusion developed repeatedly in one infant.

Discussion

There are several reports in the literature confirming the efficacy of PGE
1 in infants with ductus dependent congenital heart disease(2-8). We had three failures out of a total of 65 cases (95.4% success), nonresponders have also been described in several articles before (4-6,9). An initial low arterial PaO2 and age below 96 hours are favourable determinants of success(6). An irreversibly closed ductus and severe acidemia and collapse are usually associated with a low success rate of PGE1 infusion (5,6,9,10). In our study, however, 42 of 65 infants were beyond one week of age, although both failures occurred in this group. All 23 infants less than one week of age responded to PGE1 infusion. The lack of response in older infants may be due to near complete and irreversible closure of ductus in some of these patients along with lack of responsiveness of prostaglandin receptors by this age(6). In the normal term infant, functional closure of ductus occurs within a few hours of birth and anatomic closure in 21 days(11).


 

TABLE II

Fallow-up of Infants Given PGE
1 Infusion (n = 65)

Groups Total No. No. Responded No. intervend Mortality LAMA *
Group I 33            32                25             4(1)**   4
Group II 15 14 12 2 (1 )** 1
Group III 13 13 11 1 1
Group IV 4 3 3

*LAMA-Left against medical advise.
**Numbers in parenthesis indicate mortality related to PGE1 infusion.


PGE1 infusion is indicated for all infants born with ductus dependent cardiac malformations. These include ductus dependent pulmonary blood flow in cyanotic infants, e.g., pulmonary atresia with or without ventricular septal defect, critical pulmonic stenosis, etc. PGE1 is indicated in all these conditions and therefore its use is justified in any infant born with cyanosis and suspected cardiac malformation. In fact the infusion can be strated if the infant is sick even before a diagnostic echocardiography is carried out. The only condition where PGEl is not indicated and in fact may worsen the baby is uncommonly encoun- tered obstructed total anomalous pulmonary venous drainage(12) which has a characteristic clinical and X-ray chest picture. Of the acyanotic group, again PGE1 should be given even before confirming the diagnosis in a baby presenting in a sudden state of shock with cardiac failure and acidosis as majority of these cases will have a ductus dependent systemic blood flow lesions like hypoplastic left ventricle syndrome, critical aortic stenosis, coarctation of aorta, etc.

The role of PGE1 infusion in transposition of great arteries with intact ventricular septum has been well established in several reports, it helps by allowing systemic venous mixing through the ductus(7,8) in cases with restrictive interatrial communication. PGEl infusion has been used in patients with transposition of great arteries and intact ventricular septum presenting between 10 and 20 days of life to prepare the left ventricle for an arterial switch operation(13). In these neonates, the left ventricle becomes incapable of sustaining the systemic circulation shortly after birth because of rapid dimunition in left ventricular mass. secondary to fall in left ventricular pressure, making them unsuitable for arterial switch operation. PGE1 infusion helps to load the left ventricle by keeping the duct open thereby preventing the fall in left ventricular mass and make them suitable for an arterial switch operation(13). This is especially useful if immediate surgery cannot be undertaken for some associated complication like septicemia. We used PGE1 infusion for preparation of left ventricle prior. to arterial switch operation on four babies of complete transposition of great arterias and intact ventricular septum (Group IV), in three of these, PGE1 infusion could be continued. Left ventricle appeared volume loaded on echocardiography in all three of these so as to make them suitable for arterial switch operation within 24 hours of starting the infusion.

Side Effects

Most of these infants are sick prior to start of PGE1 therapy, therefore it may be difficult to decide whether a given complication is due to the drug or due to the clinical course of the baby. In several large series, the incidence of side effects has been reported to vary from 21.5% to 53% (14-16). We observed side effects in 9/65 cases (13.8%). The most important side effects are hypotension and respiratory depression including apnea. It is observed in several re- ports that incidence of side effects is related to the dose of PGE1 infusion(14,15,17), We did not specifically address this issue in our study. However, both the patients who received a maintenance infusion of > 0.1
g/ kg/min developed complications due to the drug. In another study(16), the incidence of complications was similar with both low and high dose of PGE1 infusion. It is perhaps logical to start with a small dose which can be increased in small increments if there is inadequate response.

To conclude, the drug PGE
1 is a major asset to the medical treatment of infants with ductus dependent congenital heart disease prior to palliative/ corrective procedure. The benefit of the drug is seen even in babies presenting beyond one week of age. However, a careful and cautious approach is necessary while giving the PGE1 infusion as serious side effects may occur. Apnea is a major side effect and babies of PGE1 infusion must be monitored closely.

 

References

1. Coceani F, Olley PM. The response of the ductus arteriosus to prostaglandins. Can J Physiol Pharmcol1973; 51: 220-225.

2. Elliot RB, Starling MB, Neutze JM. Medical manipulation of the ductus arteriosus. Lancet 1975; 1: 140-142.

3. Olley PM, Coceani F, Bodach E. E type prostaglandins. A new emergency therapy for certain cyanotic congenital heart malformations. Circulation 1976; 53: 728-731.

4. Neutz JM, Starling MB, Elliot RB, Barrett- Boyes BG. Palliation of cyanotic congenital heart disease in infants with E type prostaglandins. Circulation 1977; 55: 238- 241.

5. Heymann MA, Berman W Jr, Rudolph AM, Whitman V. Dilatation of the ductus arteriosus by prostaglandin E1 in aortic arch abnormalities. Circulation 1979; 59: 169-173.

6. Freed MD, Heymann MA, Lewis AB, Roehl SL, Kensey RC. Prostaglandin E1
in infants with ductus arteriosus dependent congenital heart disease. Circulation 1981; 64: 899-904.

7. Lang PL, Freed MD, Bierman FZ, Norwood WI, Nadas AS. Use of prostaglanding E1
in infants with d-transposition of the great arteries and an intact ventricular septum. Am J Cardiol 1979; 44: 76-81.

8. Benson LN, Olley PM, Patel RG, Coceani P, Rowe RD. Role of prostaglandin E1
infusion in the management of transposition of great arteries. Am J Cardiol 1979; 44: 691-696.

9. Lewis AB, Takahashi, M, Lurie PR. Administration of prostaglandin E1
in neonates with critical congenital cardiac defects. J Pediatr 1978; 93: 481-485.

10. Hastreiter AR, Van der Horst RL, Sepheri B, Du Brow IW, Fisher EA, Levitsky S. Prostaglandin E1
infusion in newborns with hypoplastic left ventricle and aortic atresia. Pediatr Cardiol1982; 2: 95-98.

11. Rudolph AM. The ductus arteriosus and persistent" patency of ductus arteriosus. Ill: Congenital Disease of the Heart. Chicago, Year Book Medical Publishers, 1974; p 172.

12. Freedom RM, Olley PM, Coceani P, Rowe RD. The prostaglandin challenge. Test to unmask obstructed total anomalous pulmonary venous connections in asplenic syndrome. Br Heart J 1978; 40: 91-94.

13. Yasui H, Kado H, Yonenaga K, Hisahara M, Ando H, Iwao H, et al. Arterial switch operation for transposition of the great arteries, with special reference to left ventricular function. J Thorac Cardiovasc Surg 1989; 98: 601-610.

14. Lewis AB, Freed MD, Heymann MA, Roehl SK, Kensey RC. Side effects of therapy with prostaglandin E1
in infants with critical congenital heart disease. Circulation 1981; 64: 893-898.

15. Hallidie-Smith KA. Prsotaglandin
E1 suspected ductus dependent cardiac malformation. Arch Dis Child 1984; 59: 1020- 1026.

16. Singh GK, Fong LV, Salmon AP, Keeton BR. Study of low dosage prostaglandinusages and complications. Europ Heart J 1994; 15: 377-381.

17. Silove E. Administration of E type prostaglandins in congenital heart disease. Pediatr Cardiol 1982; 2: 303-305.

 

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