In 1930, Raphael Kurzrok and Charles Lieh of Department of Gynecology and Obstetrics of the university of Columbia in New York noted that the uterus of women undergoing artificial insemination sometimes had either violent contractions or relaxation. Five years later, Ulf Von Euler in the Karolinska Institute in Stockholm discovered an acid in extracts of seminal vesicles of monkeys, sheep, and goats which decreased the blood pressure and caused contraction of the smooth muscle. He named this substance “prostaglandin” as it was thought that the extract came from the prostate gland. ^{Reference Von Euler1} However, further investigation was not performed until one of his disciples, Sune Karl Bergström, began to purify the extract and, in 1957, isolated crystals of alprostadil. ^{Reference Bergström, Carson and Weeks2,Reference Bergström and Sjovall3} In 1981, alprostadil was approved for medical use in the United States. ^{Reference Freed, Heyman and Lewis4,Reference Lewis, Freed and Heynman5} The Nobel Prize in medicine 1982 was awarded jointly to Sune Karl Bergström, John Robert Vane, and Bengt Samuelsson for their discoveries concerning prostaglandins.

Porstaglandins are a group of lipid compounds enzymatically derived from 20 carbon fatty acids (eicosanoids), which contain a cyclopentane ring and constitute a family of cellular mediators, with various conflicting effects. Prostaglandin E1 (PGE1) or alprostadil is a by-product of dihomo-γ-linoleic acid (an omega-6 fatty acid), has a half-life of 5–10 minutes, and is physiologically synthesised in humans. Prostaglandins affect and act on different systems of the body, including the nervous and reproductive systems, smooth muscle, and platelets; they play a major role in regulating diverse functions such as blood pressure, blood clotting, allergic inflammatory responses, and the digestive system motility. ^{Reference Palomares and Vera6}

Alprostadil is a natural prostaglandin which is widely used in ductus-dependent CHD, usually in the first weeks of postnatal life, either to maintain the pulmonary flow (Qp) or systemic flow (Qs) or in patients with severe pulmonary arterial hypertension. The usual intravenous loading dose is 0.05–0.4 mcg/kg/min followed by a well-established intravenous maintenance dose of 0.01–0.05 mcg/kg/min. ^{Reference Dice7} The expected response is to either increase ductal size or reach patency after physiological closure, with an onset of action that varies from 30 minutes to up to 2 hours or even more.

Adverse reactions reported during intravenous infusion are decreased work of breathing, apnoea, fever, hypotension, flushing, irritability, disturbances in platelet aggregation, oedema, diarrhoea, friability of the ductal tissue and pulmonary branches, cortical hyperostosis, and antral hyperplasia.

Intravenous prostaglandin bolus has not been reported; therefore, the aim of this manuscript is to share the experience of its use in patients with pulmonary atresia with hypercyanotic episodes that do not respond to conventional management.

Materials and methods

Case series

Case 1

Four-month-old male infant presented with cyanosis. Echocardiography and cardiac angiotomography revealed right atrial isomerism, levocardia, balanced atrioventricular septal defect, dextroposed anterior aorta with pulmonary atresia, and confluent pulmonary branches. He was taken to the catheterisation laboratory to determine venous pulmonary return. During induction of anaesthesia, oxygen saturation dropped from 78 to 57% with further desaturation as low as 29%. Due to severe metabolic acidosis, we administered intravenous boluses of normal saline, sodium bicarbonate, and adrenaline. Percutaneous access through left common carotid artery was obtained, and aortic arch angiography demonstrated poor contrast material pass in the pulmonary branches (Fig. 1a and b). Selective angiography in the ductus revealed severe spasm in its pulmonary end with a filiform lumen of approximately 0.15 mm (Fig. 2a). We decided to administer a single-dose PGE1 bolus at 8 mcg/kg by peripheral vein in less than 5 seconds immediately followed by a 10-ml normal saline bolus (resembling adenosine administration). After 2 to 3 minutes, we observed improvement of oximetry, reaching 69% in about 4 minutes, with a drop in arterial blood pressure from 93/42 (61) mmHg to 79/34 (50) mmHg. Six minutes after PGE1 bolus, ductal angiography showed increase in the diameter of the pulmonary end measuring 1.2 mm (Fig. 2b) allowing for safe placement of a non-medicated coronary stent (4.5 mm x 24 mm). During catheterisation, single-dose heparin at 110 UIkg was administered followed by 48-hour infusion and replaced by oral acetylsalicylic acid. He required 6 days of mechanical ventilatory support, and bidirectional cavopulmonary shunt was performed 16 days later; however, a tear of the lower lobar branch of the right pulmonary artery caused severe haemorrhage and patient died 24 hours after surgery.

Figure 1.

a ) and b ): Aortic arch angiography with poor contrast pass in the pulmonary branches.

Figure 2.

Ductal angiography showing a : critical stenosis in the pulmonary end measuring 0.15 mm (arrow) and b : 6 minutes after PGE1 bolus, pulmonary end diameter has increased to 1.2 mm (arrow).

Case 2

Eight-month-old female presented with a diagnosis of pulmonary atresia with intact ventricular septum. Catheterisation was performed to determine the status of ventricle–coronary connections. She had a hypercyanotic episode with a drop of oxygen saturation as low as 19%, and urgent catheterisation was performed which revealed a tortuous ductus with severe stenosis at its pulmonary end measuring 0.45 mm (Fig. 3a). Prior to ductal cannulation with a coronary angioplasty guide, PGE1 bolus at 15 mcgkg was administered through peripheral venous line which achieved a response in 1–2 minutes with an oxygen saturation increase of 91%. After 4 minutes selective angiography demonstrated an increase in the pulmonary end ductal diameter up to 3.5 mm (Fig. 3b), arterial blood pressure dropped form 96/48 (64) to 74/36 (47) mmHg. A non-medicated coronary stent (4.5 mm x 32 mm) was placed and allowed reaching a final stent diameter of 5 mm. Single-dose heparin at 110 UIkg was administered followed by a 48-hour infusion and oral acetylsalicylic acid. The patient was extubated on the same day and discharged within 48 hours. At 1 year 2 months age, a bidirectional cavopulmonary shunt was performed with stent removal and ductal ligation. She was discharged 8 days later without complications.

Figure 3.

a : Aortic arch angiography showing ductal spasm (arrow); pulmonary end measuring 0.45 mm, b : four minutes after prostaglandin bolus, angiography demonstrating an increase of lumen diameter measuring 3.5 mm (arrow).

Case 3

Three-day-old term male neonate was diagnosed with situs inversus, dextrocardia, single-ventricle physiology, and pulmonary atresia. Eight hours prior to catheterisation alprostadil was suspended as an attempt of reducing the diameter of the ductus to allow for safe placement of a coronary stent. At the beginning of catheterisation, oximetry was 55%. During femoral artery cannulation, he presented a hypercyanotic episode with desaturation as low as 9%. Aortic arch angiography in postero-anterior view (Fig. 4) showed absence of contrast material in the pulmonary branches and bradycardia of 68 beats per minute ensued. We administered a PGE1 bolus at 30 mcgkg through peripheral venous catheter, nearly immediate increase in saturation was achieved with heart rate normalisation. Two minutes after bolus administration oxygen saturation was 88%, arterial blood pressure decreased from 77/40 (53) to 41/24 (31), which required increase in adrenaline infusion rate. A new angiography was performed which allowed visualisation of both pulmonary branches (Fig. 5a and b) and the ductus (Fig. 6a). A non-medicated coronary stent (4 mm x 24 mm) was safely placed (Fig 6b) followed by heparin 110 UIkgdose plus acetylsalicylic acid. Four days later the patient was successfully extubated and discharged on the 7th day. Patient is currently awaiting bidirectional cavopulmonary surgery.

Figure 4.

a and b : Aortic arch angiography; absence of contrast material in pulmonary branches.

Figure 5.

Aortic arch angiography 4 minutes after PGE1 bolus. a : Contrast material can be seen in both pulmonary branches, and b : few milliseconds after with improved visualisation of both pulmonary branches.

Figure 6.

a : Aortic arch angiography 6 minutes after PGE1 bolus (left lateral projection); pulmonary trunk and pulmonary branches, ductus at the pulmonary end measuring 1.2 mm (arrow). b : Ductal stent adequately positioned.

Discussion

Guidelines and recommendations for the use of alprostadil in newborns and infants have clearly established both loading infusion and maintenance doses, ^{Reference Dice7} the goal being to use the minimum dose necessary to achieve the desired effect, expecting to avoid adverse reactions, complications, and even sequelae. However, there are no recommendations for bolus use in cases of hypercyanotic episodes due to severe ductal spasm which can ensue anytime anywhere, especially during the induction of anaesthesia, administration of contrast material, or ductus cannulation. The latter is a very dangerous scenario since not being able to cross the ductus with the guide wire entails a high risk of total ductal closure, imminent deterioration, and death.

In patients with pulmonary atresia with image confirmation of severe ductal spasm, with or without bradycardia, as ductal cannulation is a life-threatening procedure, we suggest keeping in mind the use of alprostadil bolus, provided continued monitoring can be carried out with an arterial line, orotracheal intubation, and secure venous access.

In our case series, the only adverse reaction was hypotension, varying from mild to severe. Medical treatment alone solved hypotension without sequelae. In all three patients, we used heparin infusion during catheterisation and 48 hours afterwards, followed by oral acetylsalicylic acid without presenting haemorrhagic complications. Neither fever nor neurological complications were reported. In our second and third case follow-up at 6 months revealed normal neurological development according to age (Table 1).

Table 1.

Case series.

This case series suggests that this drug can be life-saving for those patients with ductus-dependent CHD with confirmed ductal spasm; however, more information is required to make a wider recommendation on the use of PGE1 bolus. It is unknown whether PGE1 bolus might hold implications as a rescue therapy in resuscitation algorithms when conventional approaches fail in neonates and infants.

Worthy of remark is the fact that prostaglandin achieved an increase in ductal diameter in 4-month and 8-month infants. This discredits the belief that PGE1 no longer holds effect in ductal tissue after 2–3 months of postnatal life. We conducted a literature search without finding any evidence of inefficacy of prostaglandin beyond the neonatal period; therefore, we suggest dismissing this concept until proven otherwise.