Stanley E. Kirkpatrick

Pharmacologic Closure of Patent Ductus Arteriosus in the Premature Infant

The prostaglandins affect smooth-muscle tone of the ductus arteriosus. Patent ductus often complicates the clinical course of prematurely born infants with respiratory-distress syndrome. In the present study, a single oral or rectal dose of a potent inhibitor of prostaglandin synthesis, indomethacin, was administered to six consecutive premature infants with the syndrome who would otherwise have undergone surgical ligation of the patent ductus. Within 24 hours all the clinical symptoms and physical, echocardiographic and radiographic signs attributable to substantial left-to-right shunting through a patent ductus arteriosus dramatically and permanently disappeared. A transient reduction in renal function was observed in two infants in whom sustained ill-effects did not occur. The observation that constriction and closure of the patent ductus arteriosus may be induced pharmacologically raises important possibilities for the improved treatment of the respiratory-distress syndrome.

Percutaneous closure of the small patent ductus arteriosus using occluding spring coils

OBJECTIVES This report summarizes our experience with the use of occluding spring coils to close the small patent ductus arteriosus. BACKGROUND Several patent ductus arteriosus occluders (most notably the Rashkind device) have been developed and studied. Occluding spring coils have been used to close abnormal vessels and vascular connections. We previously reported the use of occluding spring coils to close the small patent ductus arteriosus in a small group of patients. This report describes our series of patients having patent ductus arteriosus closure with occluding spring coils. METHODS Between June 1990 and June 1993, 30 patients underwent cardiac catheterization to have patent ductus arteriosus closure by occluding spring coils. Selection criteria were age > 6 months and narrowest patent ductus arteriosus internal dimension < or = 3.0 mm by color flow imaging. Definitive selection was based on review of aortograms performed at catheterization. A 5.2F coronary catheter was used to deliver one or two standard occluding spring coils. A loop was delivered in the main pulmonary artery, and the remainder of the coil was delivered across the patent ductus arteriosus and into the aortic diverticulum. Patent ductus arteriosus closure was confirmed by aortography or color flow imaging, or both. Follow-up after coil placement occurred at 6 weeks and 6 months and included two-view chest radiography, echocardiography and color flow imaging. RESULTS Of the 30 patients, 29 had successful implantation by one (27 patients) or two (2 patients) occluding spring coils. Of these 29 patients, 19 had a clinically apparent and 10 had a silent patent ductus arteriosus. Average ductus minimal internal dimension was 1.7 mm (range 1.0 to 3.0). Complete closure of the ductus was confirmed in 27 patients by aortography or color flow imaging or both (in 24 within 4 h, in 2 after 6 weeks and in 1 after 6 months). Six weeks after implantation, two patients had a tiny residual patent ductus arteriosus noted on color flow imaging. One patient did not have successful implantation. This patient had a 3.2-mm ductus, and two coils migrated to the distal left pulmonary artery and could not be retrieved. There were no deaths or any significant complications noted during early or late follow-up in these patients. CONCLUSIONS Occluding spring coils may have additional application in closing the small patent ductus arteriosus.

The Vasoactivity of the Fetal Lamb Ductus Arteriosus Studied in Utero

Summary: The ductus arteriosus of the undisturbed fetal lamb was studied chronically by techniques that allowed direct serial measurements of the calibre of the fetal channel. When the direct actions were studied of vasoactive agents on the ductus arteriosus, prostaglandins did not dilate the vessel beyond its resting dimensions. The cyclooxygenase inhibitor, indomethacin, was a potent vasoconstrictor with a plateau of the dose-effect relationship occurring at 0.2 mg/kg. Fetuses of 95–98 days gestational age were equally sensitive to indomethacin when compared to animals near term. Although the prostaglandins, PGE1, PGE2 PGF2α, PGH2, PGI2 and PGG2, had no direct effect on the ductus arteriosus, PGE1, PGE2, PGH2 and PGI2 reversed the vasoconstrictor action of indomethacin. Autonomic nervous system mediators and blockers, i.e., acetylcholine, atropine, norepinephrine, propranolol, phentolamine and methoxamine, had neither direct effects on the ductus arteriosus nor any influence on indomethacin-induced vasocon-striction. The same was true of angiotensin 1, angiotensin 2, blockade of conversion of angiotensin 1 to 2, serotonin, methysergide, aminophylline, adenosine, and dibutyryl cyclic AMP. Imidazole, a blocker of thromboxane synthase, had no direct effect on the ductus arteriosus, but reduced significantly the magnitude of the indomethacin constrictor action.The major finding of this investigation was the exquisite sensitivity of the ductus arteriosus to manipulations of the prostaglandin environment. The results suggest that both locally generated prostaglandins, as well as prostanoids in the circulation, may be involved in ductal patency and closure. A high degree of control is likely of the circulation of the ductus arteriosus and constriction of the fetal channel is probably the result of an active process.

A new technique for the continuous assessment of fetal and neonatal cardiac performance

A paucity of informaion exists concerning the intrinsic physiologic properties of the developing heart. Accordingly, new methods have been developed to evaluate fetal and neonatal cardiac performance in situ in the chronically instrumented fetal and newborn lamb. Sonocardiometry provides a continuous recording of internal left ventricular dimensions. Pressures are monitored from the carotid artery, superior vena cava, left atrium, and left ventricle. The heart may be paced with bipolar pacing wires sutured to the left atrium. A 14 day recovery period is allowed piror to hemodynamic study. The instrumentation does not prevent the spontaneous vaginal delivery of fetuses and their subsequent postnatal study. The recorded physiologic data allow the calculation of left ventricular volume, ejection fraction, velocity of circumferential fiber shortening, myocardial pressure-volume relations, force-velocity relations, peripheral resistance, and left ventricular cardiac output. Basal data are presented in this report. The percentage shortening of the left ventricle of the fetus was similar to adult values, whereas velocity of shortening and maximum rate of pressure rise were significantly less than in the adult. A striking finding in the immediate postnatal period was a doubling of the left ventricular output shortly after birth with an associated increase in cardiac dimensions.

Effects of Indomethacin on Fetal Rat Lungs: A Possible Cause of Persistent Fetal Circulation (PFC)

Summary: Indomethacin, because of its prostaglandin inhibition, may cause constriction of the ductus arteriosus and affect the pulmonary circulation. To study this possibility, we gave indomethacin daily by gavage to two groups of pregnant rats from the 17th day of pregnancy through delivery (group 1, 2 mg/kg/day; group 2, 4 mg/kg/day). Group 3, untreated control pregnant rats, received saline. The pups were killed 30 min after birth and heart-lung preparations were perfused with glutaraldehyde. Appropriate blocks were processed for quantitative morphometry of the pulmonary arteries and arterioles. For analysis, the vessels were grouped by external diameter, i.e., <30, 30 to 50, and 50 to 100 μm. Groups 1 and 2 showed an increased medial smooth muscle mass in both 30 to 50 and 50 to 100-μm vessels as indicated by medial thickness and medial areas (P < 0.05). Muscularized arterioles, <30 μm, were present in groups 1 and 2, but not in controls. The relative mass of lung parenchymal components were determined by point counting. Indomethacin-treated animals had an increased saccular wall mass, decreased airspace mass, and a decreased capillary to saccular wall ratio (P < 0.05). These results show that the fetal pulmonary circulations response to indomethacin comprises the appearance of medial hypertrophy and newly muscularized arterioles. When these changes occur in lungs with immature, thick saccular walls, there is a decreased surface for oxygen exchange and an increased pulmonary vascular resistance resulting in a persistent fetal circulation.Speculation: Indomethacin, during pregnancy, may cause constriction of the ductus arteriosus and induce a persistent fetal circulation in the newborn. Inasmuch as salicylates also may be causative agents of persistent fetal circulation, their use by pregnant women should be carefully examined.

Patent Ductus Arteriosus in Preterm Infants with Idiopathic Respiratory Distress Syndrome: Radiographic and Echocardiographic Evaluation

Clinical, radiographic, echocardiographic and operative findings were evaluated in 55 preterm infants with idiopathic respiratory distress syndrome (IRDS) complicated by patent ductus arteriosus (PDA). Pulmonary plethora was detected prior to age seven days in 52 infants, and prior to murmur detection in 42 infants. In those with large shunts, only 35% had cardiomegaly while 78% had a significant increase in cardiothoracic ratio (C/T) on sequential radiographs. Moreover, within 48 hours after ligation, 91% of infants had a significant decrease in C/T. Echocardiographic left atrial to aortic ratio (LA/Ao) was elevated in 71% with large shunts. In one patient with a large shunt there was neither a sequential increase in C/T nor an increased LA/Ao. Severity of left-to-right shunting across a PDA in the newborn was reliably gauged by combined radiographic and echocardiographic evaluation. Either modality alone failed to reflect the presence of a large volume shunt in a number of infants.

Renal responses of the fetal lamb to fetal or maternal volume expansion.

Fetal and maternal glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, sodium excretion, and fractional sodium reabsorption were measured in a chronically instrumented sheep preparation. Fetal GFR was essentially stable between 110 and 135 days of gestation (term = 147 days). There was a significant increase in GFR after 135 days. After the infusion of 50 ml of normal saline over a 30-minute period, fetal GFR and sodium excretion increased significantly. Fractional sodium reabsorption was significantly decreased. Thus, the fetus is capable of responding to volume expansion with saline with an increase in GFR and a decrease in fractional sodium reabsorption. After the infusion of 1000 ml of normal saline into the ewe in 1 hour, maternal GFR and RPF rose significantly. Sodium excretion rose 6-fold and fractional sodium reabsorption fell significantly. After the infusion of saline into the ewe, there was no change in fetal GFR, RPF, sodium excretion, urine volume, or fractional sodium reabsorption. Since there were no changes in fetal renal function after maternal volume expansion with saline there was no evidence for the transplacental passage of a natriuretic factor from ewe to fetus.

Influence of indomethacin on renal function in conscious newborn lambs.

Transient renal dysfunction has been observed in some premature infants who received indomethacin to constrict patent ductus arteriosi, and it has been suggested that this complication may be dose related. Accordingly, the present study was designed to investigate the influence of high (7.5 mg/kg) and low (0.2 mg/kg) doses of indomethacin on effective renal blood flow, glomerular filtration rate, urine flow, sodium and potassium excretion and plasma levels of indomethacin in conscious newborn lambs studied continously over a 24-hour period. When compared to control lambs, both indomethacin doses reduced effective renal blood flow significantly at 2--4 h, but only high doses significantly reduced renal blood flow at 22--24 h (6.5 +/- 0.9 vs. 13.4 +/- 1.4 ml/min/kg, respectively; p less than 0.001). At 8-16 and 16-24 h after drug administration, urine flow was significantly lower than in the control group only in high-dose lambs (p less than 0.05). During the 16 to 24-hour period, urine flow for control, low- and high-dose animals was 0.15 +/- 0.01, 0.14 +/- 0.01, and 0.08 +/- 0.02 ml/min/kg, respectively. Glomerular filtration rate and sodium and potassium excretion rates were not affected by either indomethacin dose.

Acute effects of maternal ethanol infusion on fetal cardiac performance

In adult animals and man, both acute and chronic ethanol intake is associated with depression of myocardial performance. Accordingly, the cardiac effects of maternal ethanol infusions, in a manner comparable to common obstetric practice of inhibition of premature labor with ethano mighte for inhibition of premature labor, were evaluated in six chronically instrumented fetal sheep. Fetal and ewe arterial PO2, PCO2, and pH values remained within normal limits with infusion rates of 15 c.c. per kilogram of 10 per cent ethanol over two hours (blood ethanol = 110 mg. per cent) and 15 c.c. per kilogram over one hour (blood ethanol = 210 mg. per cent). Fetal instrument evaluation (for 14 to 30 days after operation) provided data concerning pressures and cardiac dimensions which allowed analysis of left ventricular performance. Ethanol produced a significant depression of the extent (p less than 0.01) and velocity (p less than 0.001) of left ventricular myocardial fiber shortening as well as in the mean rate of left ventricular myocardial fiber shortening as well as in the mean rate of left ventricular circumferential fiber shortening (p less than 0.01). These indices of cardiac contractility were depressed in the absence of changes in end diastolic diameter, left atrial pressure, and systemic arterial pressure. Thus, the practice of inhibition of premature labor with ethano6 might contribute to depressed myocardial performance in the neonatal period.

THE INFLUENCE OF INDOMETHACIN ON NEONATAL RENAL FUNCTION

Transient renal dysfunction has been observed in premature infants receiving indomethacin (indo) to inhibit prostaglandin (PG) synthesis and hence constrict their patent ductus arteriosus. The present study was designed to evaluate in 14 newborn lambs the influence of high (7.5 mg/kg) and low (0.2 mg/kg) doses of indo. on renal blood flow (RBF), glomerular filtration rate (GFR), and urine flow (V). The latter indices of renal function were studied by 1311-hippuran and 14C-inulin clearances in conscious, chronically instrumented lambs over a 24-hour period. Both indo. doses reduced RBF significantly at 4 hours (high 12.4 ± 1.2 (SE), low-12.8 ± 1.0 ml/kg/min) but only high-dose animals were significantly lower than the control group at 12 (8.2 ± 0.8, p < 0.025) and 24 hours (6.5 ± 0.9, p < 0.001). PGE levels, determined by radioimmunoassay, Correlated directly with alterations in RBF. GFR was unaltered in all groups. Urine flow was significantly lower than in the control group at 24 hrs. only in the high-dose indo. group (0.08 ± 0.2 vs 0.15 ± 0.1 cc/kg/min, p < 0.025). Filtration fraction rose significantly at 12 hrs. in both indo. groups. Thus, these data suggest that the renal dysfunction observed transiently in some human prematures may be dose-related and support the need to carefully monitor renal function in continued clinical applications of a pharmacological approach to constriction of the ductus arteriosus.