6-ketoprostaglandin-f1-alpha and Ductus-Arteriosus--Patent

Prophylactic closure of the patent ductus arteriosus has been recommended as a means of decreasing the morbidity of the very low birth weight neonate. This study was undertaken in order to determine potential risk factors involved in the development of the silent ductus, its impact upon both the early cardiorespiratory symptomatology and the subsequent morbidity of the premature neonate, and finally the potential benefit to be derived from prophylactic closure in this presymptomatic stage. Infants with birth weights of 1000 g or less were studied on days 2-3 of life echocardiographically, clinically, and with determination of plasma dilator prostaglandin levels. On entry to the study, those infants with early evidence of silent left-to-right patent ductus arteriosus (PDA) shunting were randomized to receive either prophylactic indomethacin or placebo therapy. Those infants with no evidence of ductal shunting were not treated at all. Infants with silent PDAs had elevated levels of the dilator prostaglandin metabolite 6-keto PGF1 alpha on admission, although they had no echocardiographic abnormalities. No other risk factors for PDA development could be identified. Silent PDA infants had an increased incidence of subsequent symptomatic PDAs, and overall morbidity and mortality when compared with those with no evidence of PDA (silent or symptomatic). Prophylactic ductal closure decreased the incidence of subsequent PDA development, but had no effect on overall morbidity and/or mortality.

Topics: 6-Ketoprostaglandin F1 alpha; Bronchopulmonary Dysplasia; Dinoprostone; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Prognosis; Prostaglandins E; Risk

Indomethacin (0.2 mg/kg) or saline was given intravenously during the first 24 hours to 50 preterm infants in a double blind controlled trial. Eight of the control group later required treatment with indomethacin for clinical signs of left to right shunt, but only one in the treatment group (p = 0.03). Treatment with indomethacin prolonged bleeding time, raised serum creatinine concentrations, and was associated with gastrointestinal haemorrhage in seven infants. Five of these had a serum indomethacin concentration greater than 1.0 microgram/ml. There was a significant reduction of the stable metabolite of prostacyclin, 6-ketoprostaglandin F1 alpha, commencing six hours after treatment and lasting for four days. There was no significant difference in the incidence of intraventricular haemorrhage, days of treatment with oxygen or ventilation, or mortality between the two groups.

Topics: 6-Ketoprostaglandin F1 alpha; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Ductus Arteriosus, Patent; Female; Humans; Indomethacin; Infant, Newborn; Infant, Premature, Diseases; Male

We admitted 48 preterm neonates (600 to 1250 gm birth weight, normal 6-hour echoencephalograms) to a randomized prospective indomethacin or placebo trial for the prevention of neonatal intraventricular hemorrhage. Beginning at 6 postnatal hours, indomethacin or placebo was administered intravenously every 12 hours for a total of five doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, and renal and clotting functions were monitored. No differences in birth weight, gestational age, Apgar scores, or ventilatory needs were noted between the two groups. Six infants given indomethacin had intraventricular hemorrhage, compared to 14 control infants (P = 0.02). The indomethacin-treated group had significant decreases in serum prostaglandin values 30 hours after the initiation of therapy. The overall incidence of patent ductus arteriosus was 82% at 6 postnatal hours; 84% of the indomethacin-treated infants experienced closure of the ductus, compared to 60% of the placebo-treated patients. Closure of the ductus was not related to incidence of intraventricular hemorrhage. We speculate that indomethacin may provide some protection against neonatal intraventricular hemorrhage by acting on the cerebral microvasculature.

Topics: 6-Ketoprostaglandin F1 alpha; Cerebral Hemorrhage; Clinical Trials as Topic; Ductus Arteriosus, Patent; Echocardiography; Humans; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Prospective Studies; Random Allocation; Thromboxane B2

The use of indomethacin in preterm newborn infants with symptomatic patent ductus arteriosus is associated with compromised renal function. Ibuprofen has been shown to be as effective as indomethacin with fewer renal side effects. We examined the hypothesis that early postnatal ibuprofen has less adverse effects on neonatal rat renal prostanoids, COX-2 expression, and angiotensin II than indomethacin. Newborn rats received IP injections of human therapeutic doses of ibuprofen or indomethacin on the first 3 days of life. Control rats were treated with equivalent volume saline. Kidneys were assessed in suckling and weanling rats for prostanoids, COX-2 expression, and angiotensin II. In suckling rats, indomethacin suppressed PGE(2) and COX-2 expression, and increased PGF(2alpha), whereas ibuprofen increased COX-2 and angiotensin II. Although both NSAIDs suppressed 6-ketoPGF(1alpha) and TxB(2) levels in suckling rats, the effect was sustained in weanling rats with indomethacin. Our findings demonstrate that indomethacin exhibits more potent suppressive effects on renal COX-2 and vasodilator prostanoids which are important regulators of renal development and function. These long-term, sustained effects may explain in part, why indomethacin exerts more severe adverse renal effects than ibuprofen, when administered during early postnatal life.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Animals, Newborn; Animals, Suckling; Cyclooxygenase 2; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Ibuprofen; Indomethacin; Kidney; Prostaglandins; Rats; Rats, Sprague-Dawley; Stimulation, Chemical; Thromboxane B2

The ductus arteriosus (DA) of newborn infants exposed in utero to indomethacin is resistant to postnatal indomethacin; we hypothesized that this is due to ductus constriction in utero, with subsequent remodeling of the vessel.. Infusion of fetal lambs with indomethacin for 48 hours constricted the DA and increased the thickness of the avascular zone of the DA, which in turn induced the expression of vascular endothelial growth factor, endothelial nitric oxide synthase (due to ingrowth of vasa vasorum), neointima formation, and loss of smooth muscle cells; moderate degrees of DA constriction in utero increased NO production, which inhibited DA contractility. Marked degrees of DA constriction decreased tissue distensibility and contractile capacity.. DA patency is no longer controlled primarily by prostaglandins once it has been exposed to indomethacin in utero.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blotting, Western; Cell Death; Cell Division; Coronary Circulation; Dinoprostone; Ductus Arteriosus; Ductus Arteriosus, Patent; Endothelial Growth Factors; Fetus; In Vitro Techniques; Indomethacin; Lymphokines; Models, Biological; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroprusside; Pressure; Sheep; Tunica Intima; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To describe the association between early postnatal prostacyclin concentrations in preterm infants; echocardiographic measurements of ductal diameter and ventricular output and clinical outcomes of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA).. Forty nine preterm infants born before 30 weeks of gestational age (median birthweight 980 g, median gestational age 27 weeks) underwent echocardiographic studies at 5, 12, 24 and 48 hours of postnatal age. Measurements included ventricular outputs and the ductal shunt diameter as a measure of the shunt size. Simultaneous measurements of blood pressures, mean airway pressure and inspired fraction of oxygen (FIO2) were recorded. A blood sample for the prostacyclin metabolite 6-ketoprostaglandin F1-alpha (6KPGF1 alpha) was taken at the 5 and 24 hour echocardiogram.. The mean 6KPGF1 alpha concentrations were higher than adult concentrations at 5 (515 pg/ml) and 24 (255 pg/ml) hours. There was no association with gestational age. Raised 6KPGF1 alpha concentrations were related to increased need for mechanical ventilation and severity of respiratory disease. At 5 hours, increased 6KPGF1 alpha concentrations were associated with larger PDA and at 24 hours with larger PDA and higher left ventricular output. Infants with higher 6KPGF1 alpha concentrations were more likely to develop clinically significant PDA. There was no association between early measurements of 6KPGF1 alpha and IVH.. Early postnatal prostacyclin concentrations are markedly raised in preterm infants, particularly in those with more severe lung disease. Raised 6KPGF1 alpha concentrations were associated with an increased ductal diameter and subsequent PDA, but not IVH.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Cerebral Hemorrhage; Ductus Arteriosus, Patent; Echocardiography; Humans; Infant, Newborn; Infant, Premature; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Statistics, Nonparametric

The presence of prostacyclin synthase (PGI2 synthase), 6-keto-prostaglandin F1 alpha (6k-PGF1 alpha), and the stable hydrolysis product of prostacyclin (PGI2), prostaglandin E2 (PGE2), as well as the activity of 15-hydroxy-prostaglandin dehydrogenase (PGDH) were studied in the aorta, pulmonary artery, the normal ductus arteriosus (DA), and persistent DA (PDA) of the dog using histochemical and immunohistochemical techniques. The normal DA is characterized by the development of intimal thickening, a process that does not occur in the persistent DA. Distribution of PGI2 synthase was identical in the aorta, pulmonary artery, and persistent DA. In these vessels endothelial cells contained higher levels of PGI2 synthase as compared with medial smooth muscle cells. In the normal DA, levels of PGI2 synthase were clearly higher in smooth muscle cells at the sites of intimal thickening than at other sites. Distribution of 6-keto-PGF1 alpha resembled the localization of PGI2 synthase. Presence of PGE2 and activity of PGDH could not be demonstrated. The results demonstrated existence of a clear relationship between ductal morphology and the presence of PGI2 synthase. This finding suggests a more important role for PGI2 in regulating ductal patency than has heretofore been appreciated. It was assumed that the role of PGI2 in regulating ductal patency is, at birth, at least overruled by the constrictive effect of the cytochrome P450 mono-oxygenase mechanism. It is still possible to attribute a role to PGI2 in the regulation of cushion formation. Once smooth muscle cell activity has been enhanced by the presence of a glycosaminoglycan rich environment, increase in PGI2 may produce a concurrent inhibition of smooth muscle cell growth.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Cytochrome P-450 Enzyme System; Dinoprostone; Dogs; Ductus Arteriosus; Ductus Arteriosus, Patent; Endothelium, Vascular; Histocytochemistry; Hydroxyprostaglandin Dehydrogenases; Immunohistochemistry; Intramolecular Oxidoreductases; Isomerases; Muscle, Smooth, Vascular; Pulmonary Artery

Maintaining patency of the ductus arteriosus pending surgical intervention can be critical to the survival of the neonate with ductal dependent congenital heart disease. Spontaneously delayed ductal closure has been observed clinically and experimentally in newborns with critical pulmonic stenosis. Infants with ductal dependent congenital heart lesions were therefore studied to ascertain whether there was an endogenous increase in dilator prostaglandins prolonging ductal patency. Six neonates with cyanotic lesions (group 1) and six with left ventricular obstructive lesions (group 2) were studied. Circulating PGE2 was not increased in either group. The levels of plasma 6 keto PGF1 alpha, a stable hydrolysis product of prostacyclin, were found to be elevated, but only in the cyanotic group (3143 +/- 1844 vs 404 +/- 250 pg/ml; p less than 0.05; normal less than 500 pg/ml). As expected, PaO2's were also different (36 +/- 15 vs 72 +/- 34 mmHg; p less than 0.05). It is speculated, therefore, that increased synthesis and/or release of prostacyclin, possibly mediated by the hypoxia of the cyanotic ductal dependent lesion, contributes to persistent patency of the ductus arteriosus.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprostone; Ductus Arteriosus, Patent; Epoprostenol; Heart Defects, Congenital; Humans; Infant, Newborn; Oxygen; Partial Pressure; Prostaglandins E

Prostaglandin (PG) levels and M-mode echocardiography were used to evaluate the severity of patent ductus arteriosus (PDA) in 19 premature infants. Mean 6-keto-PGF1 alpha levels in infants with more severe left-to-right shunting were significantly higher than those in infants with a moderate level of shunting (1335 +/- 763 vs. 504 +/- 348 pg/ml, respectively). Furthermore, there was a significant correlation between this elevation and a decrease in the left ventricular systolic time interval, suggesting that both reflect the severity of ductal shunting. Although other echocardiographic measurements of cardiovascular function generally showed some tendency to vary with 6-keto-PGF1 alpha levels, none was as closely correlated with the extent of PG elevation. Levels of PGE2 also seemed to vary with PDA severity; however, this correlation was not as significant.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprostone; Ductus Arteriosus, Patent; Echocardiography; Electrocardiography; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Prostaglandins E; Respiratory Distress Syndrome, Newborn; Stroke Volume; Time Factors

Pretreatment plasma dilator prostaglandin levels were measured in 16 premature infants with patent ductus arteriosus in an attempt to correlate abnormally elevated levels with clinical responsiveness to indomethacin therapy. Nine of the 16 infants responded well to indomethacin, with complete disappearance of their murmurs by 48 h. Eight of these nine infants had elevated baseline 6 keto PGF1 alpha levels (greater than 500 pg/ml). In contrast, seven of the 16 infants did not respond to indomethacin, and six of these had 6 keto PGF1 alpha within the normal range (less than 500 pg/ml). PGE2 levels varied in the same general direction, but lacked the specificity and sensitivity of the 6 keto PGF1 alpha levels. Thus, 6 keto PGF1 alpha levels seem to correlate with, and may eventually be helpful in predicting, clinical indomethacin responsiveness in the premature neonate with patency of the ductus arteriosus.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprostone; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Prostaglandins E

Urinary excretion of prostacyclin and thromboxane metabolites (2,3-dinor-6-ketoprostaglandin F1 alpha, thromboxane B2, and 2,3-dinor-thromboxane B2) as indices of systemic biosynthesis was prospectively determined in nine premature infants during the first 10 days of life, by gas chromatography-mass spectrometry. The patients ranged in gestational age from 27 to 29 weeks and in birth weight from 720 to 980 gm. Four infants developed symptomatic patent ductus arteriosus (PDA). Excretion of all metabolites exceeded adult values on the basis of body surface area at birth, reached a maximum on the fourth day of life, was related to urine output, and did not distinguish patients with and without symptomatic PDA. We conclude that neither circulating prostacyclin nor thromboxane A2 contribute significantly to the pathophysiology of symptomatic PDA in very low birth weight infants.

Topics: 6-Ketoprostaglandin F1 alpha; Ductus Arteriosus, Patent; Epoprostenol; Gas Chromatography-Mass Spectrometry; Gestational Age; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Prospective Studies; Thromboxane B2

It is generally accepted that vasodilator prostaglandins are involved in the pathogenesis of persistent ductus arteriosus (PDA) in preterm infants suffering from respiratory distress syndrome (RDS). When studying the prostaglandin metabolism it became apparent that in about 80% of these infants the activity of PGI2 and/or PGE2 was increased. In parallel to weaning infants from the respirator a decrease in prostaglandin activity was observed which was associated with ductal closure. The inhibition of prostaglandin synthesis with indomethacin had the same effect. Considering the various lines of evidence that an artificially ventilated lung is releasing vasodilatory prostaglandins into the circulation we postulated the following sequence of events in the pathogenesis of PDA in preterm infants: development of RDS or other pulmonary lesions which require artificial ventilation; this mechanical intervention causes permanent shear stress and barotrauma on the pulmonary tissue; this stress causes release of arachidonic acid from phospholipids; subsequently vasodilatory prostanoids, such as PGI2 and PGE2 are released and reach the pulmonary circulation and the ductus arteriosus. As a consequence the left-to-right shunt causes pulmonary hypercirculation with further need to continue artificial ventilation. A vicious circle is established. This circle can be broken by ductus ligation, by indomethacin treatment, by less traumatic artificial ventilation or by early weaning from the respirator with theophylline.

Topics: 6-Ketoprostaglandin F1 alpha; Combined Modality Therapy; Dinoprostone; Ductus Arteriosus, Patent; Epoprostenol; Humans; Indomethacin; Infant, Newborn; Prostaglandins; Prostaglandins E; Pulmonary Circulation; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Theophylline

To determine if vascular abnormalities in preterm neonates might be related to vasoactive prostaglandins, stable prostacyclin (6-KPGF1 alpha) and thromboxane A2 (T X B2) metabolites in arterial blood were measured at less than or equal to 6 hours after birth and at 24, 48, and 72 hours using a radioimmunoassay. Neonates of less than 32 weeks gestation (N = 26) were diagnosed as having either the idiopathic respiratory distress syndrome (IRDS, N = 15) or pulmonary edema (PE, N = 11), and were also grouped according to the presence or absence of intracranial hemorrhage (ICH, N = 11) or patent ductus arteriosus (PDA, N = 10). Initial plasma 6-KPGF1 alpha was greater in neonates with ICH (0.23 +/- 0.04 ng/ml, mean +/- SE) than without ICH (0.11 +/- 0.04, p less than 0.05). Neonates with both ICH and IRDS (N = 8) had significantly elevated T X B2 at all sampling times compared to neonates with IRDS and no ICH (N = 7). Both T X B2 and 6-KPGF1 alpha increased with time in those with major ICH. Among neonates without ICH, 7 with IRDS had higher initial 6-KPGF1 alpha (0.19 +/- 0.07 ng/ml) and lower T X B2 (0.15 +/- 0.04 ng/ml) than 8 with PE (0.04 +/- 0.01 and 0.37 +/- 0.09 ng/ml, respectively). The initial 6-KPGF1 alpha (0.024 + 0.003 ng/ml), measured in neonates with PE and without PDA or ICH (N = 6), was significantly less than the corresponding value in the other neonates (0.201 +/- 0.036 ng/ml) (N = 20).

Topics: 6-Ketoprostaglandin F1 alpha; Cerebral Hemorrhage; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Infant, Premature, Diseases; Pulmonary Edema; Respiratory Distress Syndrome, Newborn; Thromboxane B2; Thromboxanes

Patency of the ductus arteriosus in preterm infants is mediated by vasodilating prostanoids; however, reliable methods to monitor prostanoid activity or production in preterm infants are lacking. We measured the excretion rates of major and characteristic urinary metabolites of prostacyclin (PGI2), PGE1, and PGE2, 6-keto-PGF1 alpha, and 7 alpha-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid (PGE-M), respectively. Besides these parameters which reflect total body prostanoid turnover and production, the urinary levels of PGE2 and PGF2 alpha, the primary prostaglandins, were measured as an index of renal prostanoid synthesis. There were four study groups. One contained 11 thriving preterm infants; a second, six preterm infants with respiratory distress syndrome (RDS); a third, 30 preterm infants with RDS and patent ductus arteriosus (PDA); and a fourth, nine fullterm infants. All infants with RDS required artificial ventilation. There were no significant differences in PGE-M, PGE2, and PGF2 alpha excretion rates among the various groups; however, a significant increase of the 6-keto-PGF1 alpha excretion rates was observed in the groups of infants with RDS and with and without PDA (P less than 0.01 and P less than 0.02, respectively). Spontaneous (n = 2) or indomethacin-induced (n = 6) closure of PDA was associated with weaning from the respirator and a concomitant drop into the normal and subnormal range of the excretion rates of 6-keto-PGF1 alpha (P less than 0.01) and PGE-M (P less than 0.02).

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Dinoprost; Dinoprostone; Ductus Arteriosus, Patent; Female; Humans; Indomethacin; Infant, Newborn; Male; Prostaglandins E; Prostaglandins F; Prostanoic Acids; Respiration, Artificial; Respiratory Distress Syndrome, Newborn