The effects of prostacyclin (PGI2) on haematological and haemodynamic parameters, and lung histology in puppies undergoing cardiopulmonary bypass surgery with profound hypothermia.

Puppies 6-12 kg underwent cardiopulmonary bypass with profound hypothermia. Thirteen animals received 200 ng kg-1 min-1 of PGI2 during bypass whilst 11 control animals received equivalent volumes of glycine buffer (placebo) over a similar period. Results indicated preservation of platelets, leukocytes and fibrinogen levels, together with shortened activated partial thromboplastin times and fewer fibrinogen degradation products post-bypass in PGI2-treated animals. There was an initial fall in blood pressure and systemic vascular resistance in PGI2 treated animals, but pulmonary pressures and resistances, cardiac outputs, and heart rates showed no significant differences from controls. Higher and more satisfactory end of bypass and post-bypass blood pressure levels, together with a lesser fall-off in mean total pulmonary compliance, and shortened bypass times were achieved in treated animals. PGI2 appeared to afford some protection against lung damage as observed by histological studies. All beneficial effects appeared to be significantly greater amongst smaller animals. The results indicate possible benefits from the use of PGI2 in infant open heart surgery.

Pathology of the ductus arteriosus treated with prostaglandins: comparisons with untreated cases.

Our histological study of the ductus arteriosus compared 12 infants who were treated with E-type prostaglandins with 12 control infants matched as closely as possible for age and diagnosis. Distinguishing histological features were seen in five of the treated cases and in none of the untreated cases. These features were intimal tears in two and hemorrhage into the media in five. Medial edema, mural thrombosis, and interruption of the internal elastic lamina at sites not beneath intimal cushions occurred both in treated and untreated infants and therefore were not distinguishing features. The gross anatomical features of the ductus arteriosus were assessed in these 24 and in another 85 cases. Significant differences in the ductus arteriosus were noted between cases with pulmonary atresia or aortic atresia and normals, but not between those treated with E-type prostaglandins and controls.

Comparative studies on the hemodynamic effects of prostaglandin E1 prostacyclin, and tolazoline upon elevated pulmonary vascular resistance in neonatal swine.

Forty-eight hour old anesthetised and ventilated neonatal piglets were cannulated in order to measure pressure, blood gases and cardiac outputs (CO) from which pulmonary (PVR) and systemic (SVR) vascular resistances were calculated. After baseline measurements had been made inspired gases were altered to produce hypoxemia and hypercapnia, to raise PVR. Animals then received Prostaglandin E1 (PGE1), Tolazoline (TOL), and Prostacyclin (PGI2) in varying dosages until PVR was reduced or the dosage no longer tolerated. With "hypoxia" CO, PVR and pulmonary artery (PA) pressures rose; aortic pressure also rose although SVR tended to fall. PGE1 (5microgram/kg/min) and PGI2 (1.0 microgram/kg/min) both produced a significant fall in PVR. The decrease in PVR with TOL (1 mg/kg/10 minutes and 2 mg/kg/1 hour) was less consistent and in surviving animals did not achieve statistical significance by multivariate analysis. SVR fell with all drugs although the change with TOL was again non-significant. With both PGI2 and TOL there was a trend for CO to rise and, although this did not reach significant levels, it restricted the drop in arterial pressure to approximately control levels. The fall in arterial pressure with PGE1 was greater. The death rate with treatment with TOL was much higher than that seen with the other two drugs. Circulatory changes in a group of animals with normal blood gases treated with PGI2 (1 microgram/kg/min) were similar to those seen with the hypoxic group.

Control of elevated pulmonary vascular resistance in neonatal swine with prostacyclin (PGI2).

Three groups of neonatal piglets were anesthetised and base-line hemodynamic measurements were made. The piglets were then subjected to hypoxia and hypercapnea to raise pulmonary vascular resistance (PVR) and further hemodynamic measurements were made over a period of at least 100 minutes. During the last 80 minutes of this period the control group received an infusion of 0.05M Tris buffer [the vehicle for prostacyclin (PGI2)], the second group received an infusion of 0.5 microgram/kg/min PGI2, and the third group received an infusion of 1.0 microgram/kg/min PGI2.

The effects of some methyl prostaglandin derivatives on the ductus arteriosus of swine in vivo.

Three methylated analogues of prostaglandin E1 and E2 were examined for their ability to open the ductus arterious of neonatal piglets in vivo. Fifteen (S) 15 methyl prostaglandin E1 (15-Me PGE1), 15 (S) 1K methyl prostaglandin E2 (15-Me PGE2), and 16' 16' dimethyl prostaglandin E1 (16-diMe PGE1) all opened the ductus when given intravenously, intramuscularly or orally. The effects on ductal patency lasted four hours or more in many instances. Side-effects included apnea with intravenous and intramuscular dosages, and with high oral dosages of 15-Me PGE1. A transient drop in heart rate and blood pressure occurred with each dose. In one animal the ductus was kept open for 19 days with six-hourly intramuscular injections of 3 microgram/kg 15-Me PGE1. Transient sedation occurred with each dose. Death occurred on the 19th day and histological studies showed that the morphology of the ductus wall was similar to that seen in a two day old animal. These studies suggest that maintenance od ductal patency in the infant may be possible with oral administration of methyl prostaglandin derivatives.

Effect of prostaglandins and some methyl derivatives on the ductus arteriosus.

In vitro studies showed that PGF2a constricted the ductus arteriosus of newborn animals, whereas PGEs produced dilatation. The finding that constriction could also be produced by c-GMP and dilatation by c-AMP raised the possibility that the PGs might produce their effects by altering the relative proportions of cyclic nucleotides in the ductus wall. Results of experiments with inhibitors of PG synthesis and with drugs which are known to interfere with the degradation of c-GMP and c-AMP accorded with this hypothesis. Angiographic studies in neonatal piglets showed that PGEs and PGAs were potent dilators of the ductus. Prostaglandin action was confirmed in infants with congenital heart disease who were dependent on ductus patency for survival. In those patients, PGs proved to be an extremely useful tool. Experimental studies are in progress in the hope of finding a PGE analog, active by the oral route, which may be suitable for the long-term treatment of patients.

Palliation of cyanotic congenital heart disease in infancy with E-type prostaglandins.

Prostaglandin-E (PGE) infusions have been used in an attempt to increase ductal patency in 11 infants aged one to 99 days with cyanotic heart disease. PGE1 was used in nine infants and PGE2 in two. Five patients had pulmonary atresia, four extreme pulmonary stenosis, one Ebstein's anomaly and one simple transposition of the great arteries. All but the oldest infant showed a satisfactory increase in oxygen saturation (average 36%) attributed to dilatation of the ductus. The failure in one infant may have been due largely to hypoplasia of the left pulmonary artery. The only important side effect was apnea in one infant receiving PGE2. The efficacy of this form of treatment is confirmed in infants dependent on ductal patency for survival. PGE is an important asset in saving the lives of neonates requiring an aorticopulmonary shunt operation. The recommended starting dose is 0.1 mug/kg/min of PGE1 given by constant infusion.

Studies on the effects of prostaglandins E1, E2, A1, and A2 on the dustus arteriosus of swine in vivo using cineangiography.

Prostaglandins E1, E2, A1, and A2 have been shown by cineaortography to open and dilate the ductus arteriosus in anesthetised piglets 3 to 6 hours of age. The dosage of PGEs required was 1 to 4 mug/kg/min. and of PGAs 20 to 40 mug/kg/min. The effect of PGEs faded within 20 minutes of stopping infusion but the effect of PGAs was still evident up to 45 minutes after stopping the infusion. Little effect was noted from hypoxia or from the addition of indomethacin to prostaglandin infusion. Side effects were not troublesome with the dosage employed but hypotension and apnea sometimes occurred at the onset of PGE infusions.

Medical manipulation of the ductus arteriosus.

Prostaglandin E-1 was infused into two children with cyanotic congenital heart-disease where patency of the ductus arteriosus was necessary to maintain arterial oxygen saturation. With each infusion oxygen saturation rose, probably as a result of dilatation of the ductus. Administration of the non-specific antagonist of prostaglandin synthesis, indomethacin, to one patient was associated with a fall in arterial saturation. The prevention of ductus closure by p.g.E-1 infusions over the first few weeks of life is a possiblility.