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Effect of patent ductus arteriosus on left ventricular output in premature infants.

A 5 MHz range-gated portable pulsed Doppler velocity meter was used to measure mean ascending aortic blood flow velocity noninvasively. Studies were performed from a suprasternal approach in 18 preterm infants with patent ductus arteriosus. Measurements were made in each patient before and after medical or surgical closure of the PDA. The internal ascending aortic diameter was determined echocardiographically and aortic cross-sectional area calculated according to the equation AAo = pi d2/4. Ascending aortic blood flow was computed as QAo (ml/min) = VAo (cm/sec) x AAo (cm2) x 60 (sec/min). Prior to PDA closure, QAo averaged 343 ml/min/kg, well above predicted normal values. After PDA closure, QAo fell to 252 ml/min/kg, significantly lower than the preclosure level (P less than 0.001), but slightly higher than the mean cardiac output of healthy newborn infants. The mean QAo after surgical ligation of the PDA was closer to the predicted normal value than after treatment with indomethacin alone. This study reflects the effect of left-to-right ductus shunting on left ventricular output and emphasizes the demands placed on the neonatal left ventricle by PDA.

Cardiac Output↗

Range-gated pulsed Doppler ultrasonographic evaluation of carotid arterial blood flow in small preterm infants with patent ductus arteriosus.

Range-gated pulsed Doppler (RGPD) ultrasonography was utilized to study the effect of a patent ductus arteriosus (PDA) on carotid arterial blood flow in small preterm infants. Carotid arterial flow velocity studies were performed on 23 preterm infants, sampling right and left carotid arteries. Studies on seven infants after PDA ligation and on seven who developed no evidence of PDA were used as controls. A strong relationship was demonstrated between diastolic reversal in the carotid arteries and PDA. The results of this study indicate that the RGPD flow velocity curve from the carotid artery is more sensitive than M-mode echocardiography or clinical examination in detecting PDA, and that PDA in small preterm infants is associated with a distinct abnormality in the carotid arterial flow pattern.

Blood Flow Velocity↗

Effect of prolonged indomethacin therapy on renal function and selected vasoactive hormones in very-low-birth-weight infants with symptomatic patent ductus arteriosus.

Renal function and changes in the activity of selected vasoactive hormones during prolonged indomethacin therapy (1 week) were studied in 11 very-low-birth-weight infants with symptomatic patent ductus arteriosus. The initiation of indomethacin therapy was associated with a reduction in diuresis, a transient decrease in creatinine clearance, and an increase in body weight (P less than 0.01). Furthermore, there was a transient trend toward hyponatremia and hyperkalemia. This acute renal dysfunction was compatible with a complex picture of renal hypoperfusion associated with a fall of plasma renin activity from high levels prior to indomethacin treatment, with a transient rise in the plasma level of arginine vasopressin and with suppressed renal and systemic prostaglandin synthesis. During treatment, an effective circulatory volume was restored by closing the ductus. In parallel, PRA and AVP plasma concentrations returned to nearly normal values. Subsequently, kidney function was not further impaired despite continued indomethacin therapy. These observations suggest that prolonged indomethacin therapy for prevention of sPDA relapse probably constitutes no further risk to kidney function after successful pharmacologically induced ductal constriction.

Arginine Vasopressin↗

Clinical course to 1 year of age in premature infants with patent ductus arteriosus: results of a multicenter randomized trial of indomethacin.

Reported are 1-year follow-up results of a randomized clinical trial comparing three strategies of managing clinically significant patent ductus arteriosus at the time of diagnosis in premature infants: (1) immediate administration of a three-dose course of intravenously administered indomethacin in addition to usual medical therapy (fluid restriction and use of diuretics or digitalis or both), with surgery as a backup measure, (2) usual medical therapy alone initially, with indomethacin as the first and surgery as the final backup measure, and (3) usual medical therapy alone initially, with surgery alone as backup. Of primary concern were the relative merits of these three managements strategies in the terms of the long-term occurrence of a wide range of health problems. Although at the time of neonatal hospitalization there was a significant excess of bleeding episodes in infants receiving indomethacin as part of initial treatment, and a significantly higher rate of retrolental fibroplasia in the those given usual medical therapy with surgery as backup, there were no statistically significant differences at 1 year of age related to these intermediate outcomes. In other regards, too, the treatment strategies appeared interchangeable in terms of the 1-year outcome.

Bronchopulmonary Dysplasia↗

Recurrence of symptomatic patent ductus arteriosus in extremely premature infants, treated with indomethacin.

The administration of a single intravenous injection of indomethacin was followed by a major constrictive effect on the ductus in 36 of 42 very-low-birth-weight (less than or equal to 1000 gm) infants with symptomatic patent ductus arteriosus (PDA). In 26 of the 36 responders, the effect was sustained; symptomatic PDA recurred in the remaining 10. Infants who experienced a recurrence of symptomatic PDA had lower birth weights and had received indomethacin at an earlier postnatal age than did infants with a sustained effect. These results may be explained by differences in the production and clearance of prostaglandins or in the sensitivity of the ductus to prostaglandin effects between infants with a recurrence and infants with sustained constriction of PDA.

Ductus Arteriosus, Patent↗

Patent ductus arteriosus in neonates with severe respiratory disease.

Daily aortic contrast echo studies were carried out in 200 neonates with severe respiratory disease to determine the natural history of the ductus arteriosus during the first days of life and the effect of patency on subsequent morbidity and mortality. Decisions related to surgical or pharmacologic closure of a PDA were not based on the results of the contrast echo studies. The risk that intervention would be required was greater in infants weighing less than 1500 gm (P less than 0.005) and in patients in whom the ductus had not closed spontaneously by day 3 (P less than 0.001) regardless of birth weight. The clinical course in infants with a PDA on the third day of life revealed a lower survival rate (P less than 0.005), a greater requirement for prolonged respiratory support (P less than 0.005), and a higher incidence of bronchopulmonary dysplasia (P less than 0.005) in all birth weight categories. Ductal patency often was not associated with early clinical manifestations. No infant who had a negative echo study on the third day of life subsequently developed signs or symptoms of patent ductus arteriosus. We conclude that patency of the ductus arteriosus is a negative prognostic factor in the severely ill neonate with respiratory distress.

Aorta↗

Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin.

To determine the efficacy of indomethacin to prevent the occurrence of symptomatic patent ductus arteriosus (PDA), a randomized clinical trial was conducted involving 32 preterm infants weighing 750 to 1500 g at birth who had hyaline membrane disease. By random assignment, 15 infants were given a single dose of indomethacin, 0.2 mg/kg intravenously, 24 hours after birth. Seventeen infants composed a control group for which indomethacin was reserved as treatment for symptomatic PDA. Birth weight, gestational age, male/female ratio, black/white ratio, and severity of disease were similar for both groups. Only one of the 14 survivors who received prophylactic indomethacin had symptomatic PDA, compared with nine of the 16 survivors in the control group (P = 0.007). There was no difference between the groups in development of bronchopulmonary dysplasia, duration of time endotracheal intubation, was required, duration in oxygen, duration to reach full feedings and regain birth weight, and duration of hospital stay. There was no difference between the two groups in incidence of intraventricular hemorrhage, and none developed necrotizing enterocolitis. These results indicate that the use of prophylactic indomethacin is beneficial in prevention of symptomatic PDA; the lack of differences in pulmonary sequelae or other complications may have been related to a population sample size not large enough to impart sufficient statistical power.

Birth Weight↗

Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation.

OBJECTIVE: To identify early echocardiographic markers allowing prediction of subsequent symptomatic patent ductus arteriosus (PDA). METHODS: One hundred sixteen preterm infants ( < 1500 gm) requiring mechanical ventilation underwent echocardiography at a mean postnatal age of 19 hours (range, 7 to 31 hours). Four potential markers were studied: the left atrial to aortic root ratio, pulsed Doppler signal within the course of the duct (ductal diameter), and the direction of postductal aortic diastolic flow. Subsequent ductal closure or significant patency (if suspected clinically) was confirmed echocardiographically. RESULTS: A significant PDA developed in 42 infants (36%). Ductal diameter was the most accurate echocardiographic marker in predicting subsequent significant most accurate echocardiographic marker in predicting subsequent significant PDA. With a ductal diameter of 1.5 mm or greater there were 34 true-positive, 11 false-positive, 63 true-negative, and 8 false-negative results, giving a positive likelihood ratio of 5.5 and a negative likelihood ratio of 0.22 for prediction of development of a PDA requiring treatment. The sensitivity was 81% and the specificity was 85%. Only one infant older than 28 weeks of gestational age had a significant PDA, and limiting the analysis to infants younger than 29 weeks of gestation further improved the predictive accuracy of ductal diameter. The positive likelihood ratio was 8.1 and the negative likelihood ratio was 0.19, with a sensitivity of 83% and a specificity of 90%. CONCLUSION: Color Doppler measurement of the internal ductal diameter allows early prediction of significant PDA in preterm infants.

Ductus Arteriosus↗

Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less.

OBJECTIVES: To test the hypotheses that (1) infection increases ductal dilatory prostaglandins and inflammatory mediators that may influence the closure of a patent ductus arteriosus (PDA), increasing the incidence of late episodes of PDA (after 7 days) and the rate of closure failures, and (2) the concurrence of PDA and infection increases the risk of chronic lung disease (CLD). METHODS: One hundred fourteen premature infants (birth weight, 500 to 1000 gm) were prospectively assessed for PDA and infection. Serum levels of 6-ketoprostaglandin F1 alpha and tumor necrosis factor alpha were measured routinely in all infants and when PDA or infection was present. Multivariate assessment of risk factors for PDA closure failure and for CLD was done by logistic regression, and expressed as an odds ratio and as 95% confidence intervals. RESULTS: Late PDA episodes were more frequent in infants with infection than in those without infection. A temporally related infection (<5 days between both diagnoses) was associated with an increased risk of PDA closure failure (odds ratio, 19.1 (confidence interval, 4 to 90)). In addition to birth weight and the severity of initial respiratory failure, PDA and infection increased the risk of CLD (odds ratio, 11.7 (confidence interval, 1.7 to 81) for PDA; odds ration, 3.1 (confidence interval, 1 to 11) for infection). Furthermore, when both factors were temporally related, they further increased the risk of CLD (odds ratio, 29.6 (confidence interval, 4.5 to >100)). Infants with infection and those with PDA had higher levels of 6-ketoprostaglandin F1 alpha than did control subjects. Levels of tumor necrosis factor alpha were also elevated in infants with infection and in those with late PDA. CONCLUSIONS: Infection adversely influences PDA outcome by increasing the risk of late ductal reopening and PDA closure failures. Increased levels of prostaglandins and tumor necrosis factor alpha in infants with infection may explain the poor PDA outcome. The concurrence of PDA and infection potentiates their negative effects on the risk of CLD.

Chronic Disease↗

Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room.

OBJECTIVE: To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room. DESIGN: Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation. RESULTS: Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis. CONCLUSION: The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus.

Birth Weight↗

Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus.

OBJECTIVE: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on mesenteric and renal blood flow velocity in preterm infants. STUDY DESIGN: Seventeen mechanically ventilated preterm infants (<33 weeks' gestation) with PDA received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 9), infused over 15 minutes. Mesenteric and renal blood flow velocity were measured by using Doppler ultrasonography. RESULTS: Indomethacin caused a significant reduction in mesenteric and renal blood flow velocity 30 minutes after drug administration; mesenteric and renal blood flow velocity did not return to the pretreatment values by 120 minutes. Ibuprofen did not alter blood flow 30 minutes after treatment, and blood flow increased 120 minutes after treatment. Mesenteric and renal blood flow velocity changes were significantly different between the 2 treatment groups. CONCLUSIONS: Compared with indomethacin, ibuprofen did not significantly reduce mesenteric and renal blood flow velocity.

Anti-Inflammatory Agents, Non-Steroidal↗

Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants.

OBJECTIVE: To evaluate whether a prolonged low-dose course of indomethacin would produce an improved closure rate and have fewer side effects compared with a short standard dosage schedule in the management of patent ductus arteriosus (PDA) in preterm infants. STUDY DESIGN: Sixty-one infants of gestational ages 24 to 32 weeks with a PDA confirmed with echocardiography were randomized to receive 0.2 to 0.1 to 0.1 mg/kg indomethacin in 24 hours (short course, n = 31) or 0.1 mg/kg every 24 hours 7 times (long course, n = 30). Echocardiography was done 3, 9, and 14 days after the treatment was started, and side effects were monitored. RESULTS: Primary PDA closure occurred more often in the short course group (94% vs 67%, P =.011), but the sustained closure rates were not different (74% vs 60%). Surgical PDA ligations were less frequent in the short course group than in the long course group. The short course group had a shorter duration of oxygen supplementation, less frequent symptoms of necrotizing enterocolitis, and a lower rate of urea retention. Mortality and other neonatal morbidity rates were similar. CONCLUSION: A prolonged low-dosage indomethacin regimen offers no advantage compared with a standard-dosage short course in the management of a hemodynamically significant PDA in preterm infants.

Cyclooxygenase Inhibitors↗

Management of the premature infant with a patent ductus arteriosus.

The maturation of the lung is one of the greatest challenges the premature infant must face after birth. Premature infants have been observed to have a higher prevalence of patency of the ductus arterious, presenting the physician with a dilemma and a challenge. This article discusses the clinical and pathophysiologic manifestations and the management of patent ductus arteriosus in the premature infant.

Blood Transfusion↗

Transcatheter occlusion of the patent ductus arteriosus with a single device technique: comparison between the Cook detachable coil and the Rashkind umbrella device.

UNLABELLED: Transcatheter coil occlusion of the patent ductus arteriosus (PDA) has become the interventional treatment option of choice. Immediate occlusion of any residual shunting results in excellent closure rates, but frequently requires multiple coil deployment. AIMS: To assess the efficacy and limitations of single Cook detachable coil PDA closure compared to a preceding series of Rashkind umbrella procedures. METHODS AND RESULTS: Between 1990 and 1999, transcatheter occlusion of a small (<2 mm; n=45) or moderate-sized (2-4 mm; n=47) PDA was successfully attempted in 90/92 consecutive patients (mean age 6+/-4.8 years) with a coil (39/41) or Rashkind device (51/51). Immediate angiographic closure rates for both devices were low, although better for small (54-68%) than moderate ducts (7-22%, P<0.01). A 2-year echocardiographic closure rate of small ducts increased to 92% for the coil group versus 95% for the Rashkind group. By that time, moderate-sized ducts were only occluded in 64% with the coil and 54% with the Rashkind device. A visible residual shunt at post-implant angiography in moderate ducts was associated with a high incidence (59%) of long-term echocardiographic shunt patency and a need for repeat interventions for audible residual shunts (32%). CONCLUSIONS: Single coil transcatheter occlusion is the treatment of choice for the small duct as most residual shunts will resolve spontaneously. However, long-term shunt persistence after single coil deployment in moderate sized ducts is as frequent as with the Rashkind device. A primary multiple coil approach is advocated if the postcoil aortogram shows residual ductal shunting and if there is persistence of a ductal murmur on auscultation.

Cardiac Catheterization↗

Closure of residual leak after umbrella occlusion of the patent arterial duct, using Gianturco coils.

Residual leak after transcatheter occlusion of the patent arterial duct (PDA) using the Rashkind double umbrella technique is a well documented problem. At our institution, there is a 15% incidence of persistent residual leak after 12 months. Since September 1994, 15 patients have undergone successful occlusion of the residual leak using single or multiple Gianturco coils. The median age of the patients was 48 months (range: 12-354 months). The median fluoroscopy time was 11 min (range: 4-14). There were no complications and no embolization of the coils. Eleven patients had total occlusion demonstrated on angiography 5-10 min after coil occlusion. A further three patients were demonstrated on colour Doppler echocardiography to have no residual leak before discharge the same day-despite a small leak on angiography. Only one of 15 patients had a small residual leak at the time of hospital discharge and this was finally occluded 1 year later with another coil. Coil occlusion of a residual leak on the umbrella device is effective and a safe and reliable procedure which appears to be an improvement on using a second umbrella device.

Cardiac Catheterization↗

Transarterial occlusion of patent ductus arteriosus with Gianturco coils in pediatric patients: a preliminary result in central Taiwan.

OBJECTIVE: We wish to present the preliminary result of transarterial occlusion of patent ductus arteriosus (PDA) with Gianturco coils in pediatric patients in central Taiwan. MATERIALS AND METHODS: We attempted occlusion of PDA with Gianturco coils in a total of 26 consecutive patients, 13 infants and 13 children, 23 female and three male, between July 1 1997 to September 30 1998. Median patient age was 2.57 years (from 0.25 to 14.02 years old). Median patient weight was 10.8 kg (4.0 to 36.0 kg). Premature babies with PDA, full-term babies who were less than three months old and patients who had other congenital heart disease were not included in this study. All PDAs were approached transarterially from the femoral artery. Coils were selected to provide a helical diameter that was twice or more the minimum ductus diameter and a length approximating five loops. In five patients who had a PDA diameter > or =3.5 mm, we used a snare technique to assist coil delivery beforehand, and to test coil stability, or to retrieve coil that had migrated to the pulmonary artery afterwards. Physical auscultation, chest radiographs and echocardiography with color Doppler were done in all patients within 24 h, and one, two, three, six and 12 months after coil occlusion. RESULTS: The median ductus minimum diameter was 2.3 mm (range, 1.0 to 4.7 mm). Fifteen patients had the megaphone type (type A), four had the window type (type B), five had the tubular type (type C), one had the aneurysmal type (type D) and one had the elongated conical type (type E). Twenty-one patients underwent single coil occlusion and five had multiple coils occlusion. Twenty-one patients had immediate angiographic closure of the ductus and disappearance of heart murmur at 15 min after the procedure. Dark-brown urine (hemoglobinuria) was found in one patient, 10 h after the first procedure, due to a mild residual ductal shunt. Two more coils were implanted in a second procedure that was performed within 24 h, and the ductus was completely occluded. The dark-brown urine regressed. At one month follow-up, four patients had mild residual ductal shunts, which were completely occluded by one more coil in three patients and by two more coils in the other patient. Malpositioned coils were deployed in five patients immediately after the procedure. In total, the closure rate at 15 min, within 24 h, and at one, two, three, six and 12 months were 81, 85, 85, 100, 100, 100 and 100%, respectively. In one year of follow-up, there was no instance of coil migration, ductus reopening or stenosis of the left pulmonary artery. CONCLUSIONS: Transarterial occlusion of PDA, with a Gianturco coil having approximately five loops, can be effectively achieved in patients with a minimum ductus diameter up to 4.7 mm. In patients with a ductus of more than 3.5 mm, the snare-assisted technique was employed advantageously to control coil delivery with accuracy and stability. Coil malposition or migration can be easily retrieved using a 10-mm Nitnol snare catheter. Hemoglobinuria, due to intravascular hemolysis, may regress within 24 h after the second attempt at coil implantation.

Adolescent↗

Hybridoma technology: a view from the patent arena.

The patenting of biological molecules, such as hybridomas and monoclonal antibodies, has become an important issue in biology. While challenging cherished beliefs and practices of many biologists, it has been a central issue for hybridoma and monoclonal antibody research.

Antibodies, Monoclonal↗

Clinical utility of two-dimensional doppler echocardiographic techniques for estimating pulmonary to systemic blood flow ratios in children with left to right shunting atrial septal defect, ventricular septal defect or patent ductus arteriosus.

Range gated two-dimensional Doppler echocardiographic methods were evaluated for quantifying pulmonary (QP) to systemic (QS) blood flow ratios. Twenty-one patients were studied, 4 with patent ductus arteriosus, 6 with atrial septal defect and 11 with ventricular septal defect. The Doppler pulmonary to systemic flow (QP:QS) estimation method involved calculating volume flow (liters/min) at a variety of intracardiac sites by using imaging information for flow area and Doppler outputs to calculate mean flow velocity as a function of time. Area volume flows were combined to yield QP:QS ratios. The sites sampled were main pulmonary artery, ascending aorta, mitral valve orifice and subpulmonary right ventricular outflow tract. The overall correlation between Doppler QP:QS estimates and those obtained at cardiac catheterization (n = 18) or radionuclide angiography (n = 3) was r = 0.85 (standard error of the estimate = 0.48:1). These preliminary results suggest that clinical application of this Doppler echocardiographic method should allow noninvasive estimation of the magnitude of cardiac shunts.

Adolescent↗