Indian Pediatrics 1998; 35:1063-1069 

Prostaglandin E₁ in Infants with Congenital Heart Disease: Indian Experience

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 PGE₁: (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.

PGE₁ was initiated as a continuous intravenous infusion through a pump in a dose of 0.05 ~g/kg/min by dissolving 250 µg of Prostin VR (Upjohn Ltd.) in 50 ml of 5% dextrose. The dose was increased in increments of 0.05 µg/kg/min to a maximum of 0.4 µg/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 µg/kg/min for maintenance.

TABLE I

Age of Infants at Start of PGE₁ Infusion

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 µg/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 PGE₁ 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 PGE₁ 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 µg/kg/min). Hyperpyrexia developed in one case, the infusion rate was maintained at 0.2 µg/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 PGE₁ 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 PGE₁ Infusion (n = 65)

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 µg/ 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 PGE₁ 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.