Feasibility of surgery for patent ductus arteriosus of premature babies in a neonatal intensive care unit.

Twenty-two premature neonates underwent surgical haemoclip closure of patent ductus arteriosus in a neonatal intensive care unit (NICU). Surgery was performed in the NICU in order to prevent hypothermia and interruption of care, and to avoid accidental vascular access removal and extubation. The results suggest that morbidity can be limited by performing the surgery in an NICU, and by switching from conventional to high-frequency mechanical ventilation in case of severe respiratory failure.     

Therapeutic management of patent ductus arteriosus

Management of patent ductus arteriosus (PDA) in premature neonates has always been a challenge to the neonatologist and continues to be a controversial topic. Indications for treatment are not clear. Approximately 40% of ductus arteriosus close spontaneously even in extremely-low-birth-weight neonates. Prophylactic or early pre-symptomatic treatment may unnecessarily expose these babies, in whom the ductus might close spontaneously, to pharmacologic agents and their adverse effects. On the other hand, with advancing postnatal age, delaying treatment could potentially decrease successful medical closure thereby increasing the rate of surgical ligation and the complications associated with surgery. We tried to develop some clinical guidelines for management of PDA in premature neonates based on evidence, or lack thereof, and experience.     

Phototherapy effect on the incidence of patent ductus arteriosus in premature infants: prevention with chest shielding

Patent ductus arteriosus is common among premature neonates, especially those with birth weights less than 1,500 g. In vitro, room light inhibits the contraction of immature piglet's ductal rings. Because phototherapy is used frequently from the first days of life to treat jaundice in preterm neonates, we compared the occurrence of patent ductus arteriosus among premature infants exposed to this intense light source with those whose chests were shielded. Seventy-four babies with respiratory distress syndrome were randomly assigned to either a treatment group (chest shielded with aluminum foil while on phototherapy, 36 babies) or control group (no shield, 38 babies). All were on radiant warmers, received mechanical ventilation for respiratory distress syndrome, and phototherapy (Air Shields model PTU 78-1) from day 1 of life. Irradiance was maintained at greater than 4.0 microW/cm2/nm in all cases. Although both groups had similar birth weights, gestational ages, severity of respiratory distress syndrome, intravenous fluid intake, and duration of phototherapy, the incidence of patent ductus arteriosus was significantly less in the shield group (shield 11/36 v No shield 23/38; P = .009). Patent ductus arteriosus murmurs developed in shielded patients at a later date, they required less vigorous treatment (ie, indomethacin), and they had shorter hospitalizations (74 v 85 days; P less than .05). The significant reduction of patent ductus arteriosus with shielding suggests that phototherapy may play a role in the occurrence of patent ductus arteriosus in premature infants. Shielding may be a practical method to decrease this common complication should this initial observation be confirmed.     

Does indomethacin for closure of patent ductus arteriosus affect cerebral function?

Objective: To study whether indomethacin used in conventional dose for closure of patent ductus arteriosus affects cerebral function measured by Electroencephalograms (EEG) evaluated by quantitative measures. Study design: Seven premature neonates with haemodynamically significant persistent ductus arteriosus were recruited. EEG were recorded before, during and after an intravenous infusion of 0.2 mg/kg indomethacin over 10 min. The EEG was analysed by two methods with different degrees of complexity for the amount of low‐activity periods (LAP, “suppressions”) as an indicator of affection of cerebral function. Results: Neither of the two methods identified any change in the amount of LAPs in the EEG as compared to before the indomethacin infusion. Conclusion: Indomethacin in conventional dose for closure of patent ductus arteriosus does not affect cerebral function as evaluated by quantitative EEG.     

Pathophysiology of patent ductus arteriosus in premature neonates

Failure of complete postnatal closure of the ductus arteriosus is associated with various neonatal morbidities. Functional closure resulting from smooth muscle constriction and permanent anatomic closure due to vascular remodeling are the results of a complex interaction of different mechanisms. Prostaglandins, oxygen, nitric oxide and various other factors play a key role in ductal closure. An understanding of the role of these factors, involved both in maintenance of vascular tone of the ductus in fetal life as well as stimulation of ductal closure in postnatal life, and the cardiovascular and respiratory consequences of a patent ductus arteriosus, is important for the clinician involved in management of premature neonates.     

Clinical aspects of very‐low‐birthweight infants showing reopening of ductus arteriosus

Background: Indomethacin is used to treat the hemodynamically significant patent ductus arteriosus in premature infants. Some infants show ductus arteriosus reopening after effective constriction by the drug. The purpose of this study was to examine the clinical characteristics of such infants. Methods: We studied 57 very‐low‐birthweight infants with effective constriction of patent ductus arteriosus by the initial course of indomethacin. They were classified into the reopened group if they developed hemodynamically significant patent ductus arteriosus again or into the closed group if they showed complete closure. Clinical characteristics were compared between the two groups. Results: Ductus arteriosus reopening was shown in 15 (26%) of the 57 infants. These 15 infants had successful clinical ductal closure after a subsequent course of indomethacin or oral mefenamic acid treatment or surgical ligation without any severe complications. Infants in the reopened group showed significantly higher rates of developing chronic lung disease at 36 weeks of gestation than those in the closed group (53% vs 18%; P= 0.009). Furthermore, multivariate logistic regression analysis revealed ductus arteriosus reopening was the only independent risk factor for developing chronic lung disease at 36 postconceptional weeks in this population (adjusted odds ratio, 6.1; 95% confidence interval, 1.4–31.2; P= 0.02). Conclusions: Incomplete closure of the ductus arteriosus is associated with recurrence of a clinically significant patent ductus arteriosus and reopening of the ductus after initial closure with indomethacin is associated with chronic lung disease.     

Treatment of patent ductus arteriosus with bidirectional flow in neonates

Background

Patent ductus arteriosus is a common occurrence among prematurely born neonates and is believed to play a role in the development of other complications of prematurity including intraventricular hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. The clinical decision to treat the patent ductus arteriosus is complicated by the lack of evidence available regarding clinical conditions under which closure should be attempted.

Study aims

To compare clinical outcomes for neonates who underwent treatment of patent ductus arteriosus exhibiting bidirectional blood flow versus those with flow that was left to right.

Study design

Cohort study of all neonates with patent ductus arteriosus in which medical closure was attempted at the Duke University between January 2002 and October 2007.

Outcome measures

Death and other important clinical conditions.

Results

We identified 20 neonates with bidirectional flow out of 317 cases in which medical closure of patent ductus arteriosus was attempted. There was no significant increase in overall complications due to closure of a bidirectional patent ductus arteriosus [40% (8/20)] versus ones with left to right shunting [38% (111/297) p = 0.82]. Death occurred in 15% (3/20) with bidirectional PDA compared to 11% (34/297) in the left to right group, p = 0.72.

Conclusion

The trend in mortality is worrisome but does not contraindicate an aggressive approach to the clinically significant PDA that has bidirectional flow at the time of the echocardiogram.     

Ductal Left-to-Right Flow and Pulmonary Circulation in Normal Neonates: Pulsed Doppler Echocardiographic Evaluation

To determine whether ductal left-to-right flow affects pulmonary circulation in the neonatal period, ductal patency and flow patterns of the right ventricular outflow tract were studied using Doppler echocardiography in 40 normal neonates. The ductus arteriosus was defined as being patent when diastolic or continuous flow could be detected at the pulmonary end of the ductus. Evaluation of pulmonary circulation was carried out by examining the flow velocity pattern of the right ventricular outflow tract; pulmonary hypertension was considered to be present when the Doppler echocardiogram pattern was triangular with peak velocity in early systole. Neonates were initially examined within nine hours (mean 5.3 hrs) after birth, and two to three times daily thereafter, until no ductal flow could be detected. In all the neonates, the ductus arteriosus was patent at the initial examination. The predicted time of closure of the ductus arteriosus was within seven hours after birth in 5% of the neonates, within 21 hours in 50%, and within 65 hours in 95%. The flow velocity pattern of the right ventricular outflow tract changed from a triangular shape with peak velocity in early systole soon after birth to a domelike contour with peak velocity in mid-systole: thus the mean ratio of acceleration time to right ventricular ejection time increased with age. In neonates with patent ductus arteriosus at age 13.6–20.7 hours, the mean ratio of acceleration time to right ventricular ejection time was less than in age-matched neonates with closed ductus arteriosus. These results indicate that the ductal left-to-right flow affects the pulmonary circulation.     

Patency of the ductus arteriosus in the premature infant: is it pathologic? Should it be treated?

PURPOSE OF REVIEW: The ductus arteriosus is a vessel that connects the pulmonary artery to the aorta and provides a pulmonary-to-systemic diversion during fetal life. In the vast majority of infants, the ductus arteriosus closes by 3 days of life. In some infants, especially preterm infants with lung disease, there is delayed closure of the ductus arteriosus. There has been controversy as to whether or when the ductus arteriosus should be closed by either pharmacologic or surgical methods. RECENT FINDINGS: There have been several epidemiologic studies describing an association between a patent ductus arteriosus and the development of morbidities, such as chronic lung disease. These associations have suggested to some that a causal relationship exists between patency of the ductus arteriosus and chronic lung disease and other morbidities. However, recent metaanalyses of randomized, controlled trials of the use of indomethacin for the prevention and treatment of the patent ductus arteriosus have not documented a decrease in the incidence of these morbidities after treatment, despite success in closure of the patent ductus arteriosus. SUMMARY: In preterm infants, patency of the ductus arteriosus may represent a normal physiologic adaptation to allow shunting from either systemic-to-pulmonary circulation (eg, in the first day of life) or from pulmonary-to-systemic circulation (eg, in the presence of severe lung disease). Therapies designed to close the ductus arteriosus are contraindicated in some settings and should not be considered a standard of care at any time until these therapies are proven to decrease long-term clinical morbidities in randomized, placebo-controlled trials.     

Value of continuous Doppler velocimetry for the diagnosis of patent ductus arteriosus

A study of the curve of wave Doppler ultrasonography of 3 arterial axes (carotid, subclavian and femoral) was performed in 32 children in whom the diagnosis of patent ductus arteriosus was suspected. A continuous 8 MHz wave directional ultrasonic Doppler apparatus was used. At the level of subclavian and femoral arteries, patent ductus arteriosus is associated with a negative holodiastolic wave on the curve. At the carotid level, disappearance of the physiologic diastolic elevation may be the only change observed. Three groups were studied (1) 15 premature neonates with isolated murmur, (2) 15 premature neonates with respiratory distress and (3) 2 older children. In group 2, diagnosis of patent ductus arteriosus relies on clinical signs. A good correlation between Doppler and clinical data and/or TM ultrasonography was observed in 93% of cases.     

Cytomegalovirus infection and bronchopulmonary dysplasia in premature infants

During a five-year period, 32 preterm infants weighing less than 2000 g were diagnosed as having postnatally acquired cytomegalovirus (CMV) infection in a neonatal intensive care unit. These CMV-infected infants were matched with 32 uninfected controls for gestational age, birth weight, and birth date; the two groups did not differ in Apgar scores or the incidence of respiratory distress syndrome and patent ductus arteriosus. Roentgenographic evidence of bronchopulmonary dysplasia (BPD) developed in 24 (75%) of 32 CMV-infected infants, an incidence significantly greater than that observed in control infants (12/32; 38%). Infants with acquired CMV infection required more respiratory support and longer hospitalization than uninfected controls. This association between acquired CMV infection in premature infants and the development of chronic lung disease provides further evidence that vigorous efforts to prevent CMV infection in hospitalized neonates is warranted.     

Clinical and echocardiographic diagnosis of patent ductus arteriosus in premature neonates

The ductus arteriosus frequently fails to close in premature neonates. Considerable difference in opinion exists around what signifies a hemodynamically significant patent ductus arteriosus (PDA) and how reliable clinical signs are in determining the degree of the left-to-right shunting. Although reliance on clinical signs alone could delay the diagnosis of a PDA, there is insufficient evidence to suggest that early treatment improves outcome. Echocardiography is often used as the gold standard for diagnosing a PDA. A combination of echocardiographic measurements may assist in the early diagnosis of a PDA with a hemodynamically significant degree of left-to-right shunting, especially in extremely premature babies, where closure can be significantly delayed. Decision to treat PDA should be based on a combination of clinical signs and echocardiographic parameters. Monitoring B-type natriuretic peptide may be useful in the diagnosing neonates with symptomatic PDA.     

Late Morbidity During Childhood and Adolescence in Previously Premature Neonates After Patent Ductus Arteriosus Closure

The health status of previously premature neonates after closure of a patent ductus arteriosus (PDA) was analyzed in childhood and adolescence. Physician questionnaires were used to study 180 hospital survivors among 210 consecutive premature neonates who underwent PDA closure between 1985 and 2005. Complete follow-up data were obtained for 129 patients (72%). During a median follow-up period of 7 years (range, 2–22 years), three late deaths (2.3%) had occurred. Only 45% of the patients were considered healthy. Morbidity included developmental delay (41.1%), pulmonary illness (12.4%), neurologic impairment (14.7%), hearing impairment (3.9%), gastrointestinal disease (3.1%), and thoracic deformity (1.2%). None of the adverse variables during the neonatal period (intraventricular hemorrhage, bradycardia apnea syndrome, bronchopulmonary dysplasia, pulmonary bleeding, hyaline membrane disease, artificial respiration time [continuous positive airway pressure + intubation], or necrotizing enterocolitis) statistically predicted respective system morbidity at the follow-up evaluation. Hyaline membrane disease (odds ratio, 2.5; p = 0.026) and longer hospitalization time (odds ratio, 1.2 days per 10 hospitalization days; p = 0.032) in the newborn period were significant predictors of an unhealthy outcome at the last follow-up evaluation. Survival until childhood after closure of a hemodynamically significant PDA in premature neonates is satisfactory. However, physical and neurodevelopmental co-morbidity persist for half of the patients, perhaps as a sequela of prematurity unrelated to ductus closure.     

Effects of prolonged versus acute indomethacin therapy in very low birth-weight infants with patent ductus arteriosus

Indomethacin has proven effective in closing the patent ductus arteriosus (PDA) in most low birth weight (LBW) neonates with this disorder. Early reopening of the ductus is a problem and often leads to the need for surgery. Prolonged use of indomethacin for several days has been suggested as a means to alleviate this problem. The present study was designed to determine if prolonged therapy over 5 days is more effective than a two-dose regimen in preventing reopening of the PDA. Seventy neonates were randomized for either prolonged therapy over 1 week or to receive two doses of indomethacin. All infants were given two doses of indomethacin 0.15 mg per kg, 12 h apart. The maintenance group received an additional 0.1 mg per kg daily for 5 days. Ten days after the infants' initial dose of indomethacin, 6 of 22 in the nonmaintenance group as compared to 0 of 22 in the maintenance group had reopening of their ductus arteriosus. Ten infants in the maintenance group eventually had the ductus reopen at a median of 29, range 11–66 days compared to a median of 3, range 2–44 days in the nonmaintenance group. Significantly fewer babies in the maintenance group had a grade II–IV intraventricular hemorrhage compared to the nonmaintenance group. There was no other significant difference in the two groups in the incidence of necrotizing enterocolitis, retrolental fibroplasia or death. Indomethacin given over 5 days is effective for closure of the ductus arteriosus and will prevent reopening until after the acute clinical course in babies under 1500 g; however, the overall incidence of reopening was not different.Abbreviations HMD hyaline membrane disease - IVH intraventricular hemorrhage - NICU neonatal intensive care unit - NIH National Institutes of Health - PDA patent ductus arteriosus - LBW low birht weight - VLBW very low birth weight (less than 1500 g)     

Use of combination therapy with acetaminophen and ibuprofen for closure of the patent ductus arteriosus in preterm neonates

ObjectiveTo compare effectiveness and safety of combination therapy (acetaminophen and ibuprofen) to monotherapy (ibuprofen, indomethacin, or acetaminophen alone) in treatment of the patent ductus arteriosus (PDA) in premature neonates.MethodsThis was a retrospective cohort study of neonates admitted to a tertiary-level neonatal intensive care unit. Included neonates were born at <32 weeks gestation and received pharmacotherapy for PDA closure. Based on the primary therapy received, our cohort was divided into the following four groups: indomethacin alone, ibuprofen alone, acetaminophen alone, and ibuprofen and acetaminophen (in combination). Baseline characteristics, effectiveness, safety, neonatal mortality, and morbidities rates between these groups were compared.ResultsOne hundred and forty neonates were analyzed; 17 received combination therapy, and 123 neonates received monotherapy: 22 (17.9%) ibuprofen, 29 (23.6%) acetaminophen, and 72 (58.5%) indomethacin. The PDA closure rates were 41.7% for indomethacin, 41.2% for combination therapy, 37.9% for acetaminophen, and 31.8% for ibuprofen (P=0.100). Rates of adverse effects were comparable between the groups.ConclusionThe rate of ductal closure was not different between combination therapy and monotherapy. The study did not demonstrate any increased adverse effects in the combination group. Future well-designed prospective clinical trials are needed to guide clinical practice.     

Thoracic sequelae after surgical closure of the patent ductus arteriosus in premature infants

Thirty-six children (median chronological age 6 years 1 month) who had undergone surgical closure of a patent ductus arteriosus through a left posterolateral thoracotomy in the neonatal period (median gestational age 32 weeks) were investigated prospectively with respect to anatomical and functional changes of the chest. At follow-up examination, residual or recurrent patent ductus arteriosus was not observed. Three patients had chronic bronchial obstruction. Two patients showed pathological musculoskeletal thoracic sequelae that did not require any treatment at the time of follow-up: persistence of immediate postoperative left phrenic palsy ( n = 1) and thoracic scoliosis ( n = 1). Twenty of the 27 patients in whom chest X-ray was performed had minor radiological skeletal anomalies in the form of rib deformation or fusion related to die thoracotomy, lesions which have a potential to induce thoracic scoliosis. Left shoulder elevation at chest X-ray and isolated left arm dysfunction at clinical examination were not observed. Despite the low incidence of scoliosis and the absence of left arm dysfunction observed at mid-term follow-up in our series, the incidence of minor rib deformations with a potential to induce severe anomalies such as scoliosis should motivate late follow-up examination at adolescence to definitively assess the prevalence of thoracic sequelae after surgical closure of the patent ductus arteriosus in premature infants.     

Minimal effective dose of indomethacin for the treatment of patent ductus arteriosus in preterm infants

The aim of this study was to determine if it was possible to decrease the number of boluses of indomethacin for the treatment of patent ductus arteriosus. This retrospective study included 46 preterm neonates (<34 weeks' GA) who had had an ultrasound diagnosis predictive of subsequent symptomatic patent ductus arteriosus. All patients had received a daily intravenous doses of indomethacin, 0.1 mg/kg. Mean age at initiation of treatment was 4.5 +/- 3.1 days. Patency of the ductus arteriosus was controlled echocardiographically each day and treatment was discontinued as soon as the ductus arteriosus was closed. The initial success rate was 84.7%, of which 6.5% reopened. The mean cumulative dose of indomethacin was 0.35 mg/kg. There was no correlation between gestational age or birth weight and total cumulative dose. Overall tolerance was satisfactory with only one case of transient acute renal failure. A weak correlation between the cumulative dose of indomethacin and natremia (r = -0.43) or weight gain (r = 0.35) was noted, and none with serum creatinine or blood urea nitrogen levels. We confirm that lower indomethacin treatment of patent ductus arteriosus in premature neonates are as effective as standard protocols.     

Open Heart Surgery for a Very-Low-Weight (660 g) Premature Infant

An intracardiac calcified thrombus in a premature infant weighing only 660 was successfully removed using normothermic caval inflow occlusion. This technique avoids the use of a heart–lung machine with its deleterious effects for this specific group of patients. In addition, closure of the persistent ductus arteriosus by ligation was accomplished. Because the authors see increasing numbers of preterm neonates who need intensive care management, their experience may be helpful for those dealing with this group of patients.     

Effect of indomethacin on closure of ductus arteriosus in very-low-birthweight neonates

Aim: To identify factors related to indomethacin non-responsiveness for patent ductus arteriosus (PDA) closure in very-low-birthweight (VLBW) neonates. Methods: A chart review of 107 VLBW neonates with a clinical diagnosis of PDA who received indomethacin, admitted to a tertiary neonatal intensive care unit in Toronto, Canada, was conducted (study period November 2001 to October 2003). Positive responders were those with no clinical evidence of PDA for 72 h after indomethacin. Results: Response to the first course of indomethacin was 75%, and to the second course 67% among initial responders. Higher CRIB score (OR 1.15, 95% CI 1.02-1.31) and early surfactant administration (OR 3.74, 95% CI 1.04-13.47) were associated with non-responsiveness to indomethacin.

Conclusion: Indomethacin is effective for PDA closure. The response rate diminished with subsequent courses. Early surfactant and severity of illness at admission were associated with non-responsiveness to indomethacin.     

Transcatheter closure of patent ductus arteriosus in pediatric patients

A "double disk" occlusion device (Rashkind PDA occluder system) has been designed to allow transcatheter closure of patent ductus arteriosus (PDA). During a 3-year period, we examined 37 infants and children (not premature neonates) with PDA as their only significant cardiovascular defect. Seventy-eight percent of these patients were considered potential candidates for the use of the PDA occlusion device, and it was successfully placed in all but 2 of 27 patients who underwent cardiac catheterization (PDA too small in one and too large in one). Only one of the remaining 25 patients had a significant residual shunt after placement of the device, which therefore was removed in the catheterization laboratory before surgical ligation of the PDA. There was no clinical evidence of a residual PDA in any patient. The duration of hospitalization was less than 24 hours for each of the last 20 procedures. Echocardiography demonstrated return to normal chamber dimensions in all patients, but a tiny, clinically undetectable residual leak around the device was found in three patients by Doppler evaluation. The transcatheter procedure was preferred over surgery by more than 90% of families and can be completed with a much shorter hospitalization than surgical ligation. We conclude that transcatheter closure of patent ductus arteriosus is feasible in the majority of children with PDA.