"Silent" patent ductus arteriosus and bronchopulmonary dysplasia in low birth weight infants

We conducted a clinical study on the antecedents of bronchopulmonary dysplasia (BPD) in 290 premature RDS infants with < or = 1.75 kg birth weight (BW). They were enrolled in a prospective trial of indomethacin treatment for "silent" patent ductus arteriosus (PDA), screened by 2-D echocardiographic and pulsed Doppler evaluation on the third day of life. The trial took place at the NICU of the Pediatric Department of Padua University between January 1987 and December 1991. Out of 290 infants screened, 96 had evidence of "silent" PDA (33%) and 77 responded to indomethacin treatment (80%). Comprehensively 79 (27%) developed BPD, and from these the incidence of BPD was statistically increased in infants with "silent" PDA, 47 out of 96 (49 +/- 9%), with respect to 32 out of 194 (16 +/- 3%) preterm infants without PDA. Statistical analysis showed that in preterm infants with "silent" PDA the development of BPD was correlated at 99% C.L. to their low BWs (mean BW = 1.13 kg): in fact the mean and the mode of BW distributions were statistically lower in the presence of BPD, 1.03 kg versus 1.24 kg, and 0.88 kg versus 1.65 kg respectively. Moreover, the preterm infants with "silent" PDA unresponsive to the first course of indomethacin and/or submitted later to surgical closure, presented a statistically lower BW with respect to the early responders, 1.06 kg versus 1.18 kg, and at the same time a statistically higher incidence of BPD (63 +/- 20% versus 43 +/- 9%). From these data we conclude that, although "silent", PDA increase per se the incidence of BPD, even if benefits from an early induced closure. Furthermore, a lower BW of infants affected by "silent" PDA represents a contributing factor to the development of BPD.     

Surgical ligation of patent ductus arteriosus in very low birth weight infants: is it safe?

We evaluated the outcome of a combined medical and surgical treatment of patent ductus arteriosus (PDA) in newborns weighing less than 1500 g. Charts were retrospectively reviewed for 76 newborns with a PDA between 1993 and 1997. Thirteen infants had pre-existing conditions prohibiting the use of indomethacin; eight were managed surgically, five medically. The remaining 63 infants received indomethacin therapy. Thirty-two medical failures occurred, requiring surgical ligation of the PDA. Those requiring surgery had a lower average birth weight (847 versus 997 g) and gestational age (26 versus 28 weeks; P < 0.05). Indomethacin treatment was successful in 27 infants. There were only three operative complications: a small pneumothorax, wound bleeding, and a small aortic tear. All recovered uneventfully and no deaths were attributable to the surgical procedure itself. There was no difference in the incidence of respiratory distress syndrome, duration of intubation, sepsis, neonatal enterocolitis, renal dysfunction, bleeding disorders, or intraventricular hemorrhage among both groups. Surgical ligation of a PDA is associated with a high success rate, a low incidence of complications, and no additional morbidity than indomethacin alone. We propose that surgical ligation should be regarded as a first line therapy for very small premature infants who are at higher risk of medical failure.     

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.     

Percutaneous closure of patent ductus arteriosus using special screwing detachable coils

Jackson screwing detachable coils, developed for arterial and venous embolization, have been successfully employed recently for the percutaneous occlusion of patent ductus arteriosus (PDA). Special screwing detachable coils were designed for closure of the PDA, and the experience gained by their use is described in this report. Occlusion was attempted in 29 patients with a minimal ductal diameter of 0.9-4.2 mm. Coils were successfully placed in all 29 patients. One coil, which embolized 10 min after detachment, was retrieved. In 26 patients (89%), complete closure was achieved. Only 35 coils were placed in 29 patients. Residual shunts in three patients are minimal, detectable only on color-flow mapping. Screwing detachable coils for closure of PDA are safe and effective for occlusion of PDA with a minimal diameter < 4.2 mm. Embolization of the coil is very rare. A high closure rate is achieved with a low number of placed coils.     

Surgical indications and results for congenital cardiac anomalies associated with left to right shunt and severe pulmonary hypertension

Prior to 1970, 35 patients of VSD with Pp/Ps of 0.8 or more were subjected to primary closure of the defect, resulting in 11 operative deaths. Since 1971, however, the surgical results have been much improved and 29 such patients were operated on without death. It has been considered the optimal time of elective closure of VSD with severe pulmonary hypertension is at the age of 1 to 3 years, however, if decrease in apical diastolic rumble and heart size are found, earlier operation less than one year of age is to be scheduled. Surgical indications and results of PDA, PDA with VSD, and ASD associated with severe pulmonary hypertension were also discussed.     

Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis

Inhibition of prostaglandin synthesis constricts the ductus arteriosus in fetal lambs in utero. We administered the inhibitors, aspirin or indomethacin to 18 premature infants with patent ductus arteriosus, and assessed the effects clinically and by echocardiography (left atrial/aortic-root ratio). After aspirin (20 mg per kilogram, every six hours for four doses) the ductus closed permanently in one infant within 24 hours; in another, constriction occurred with clinical improvement, and the third did not respond. In five infants given 0.3 mg per kilogram of indomethacin, complete closure occurred within one day; two of them, who received three doses had an elevated serum creatinine for one week. In one infant the ductus reopened, requiring a second dose of indomethacin 11 days after the first. Ten infants received 0.1 mg per kilogram of indomethacin, and closure occurred within 24 to 30 hours in eight. One had a soft murmur for four days, and one did not respond to two doses of indomethacin. A murmur reappeared after three to seven days in three infants but only one required further treatment. In infants receiving a single dose of 0.3 mg per kilogram, or one or more doses of 0.1 mg per kilogram, renal function was unaltered.     

Patch testing in children

Indomethacin is a very effective tocolytic agent. However, concern about its possible constrictive effect on fetal ductus arteriosus has limited the use of this medication in pregnancy. A 29-year-old woman was treated with indomethacin at 27 weeks of gestation for preterm labor and polyhydramnios. She received a dose of 75 mg/day for 5 weeks. At 35 weeks of gestation, she had a cesarean delivery due to fetal distress, and a hydropic baby was delivered. The infant died shortly after. Nonimmune hydrops fetalis and closed ductus arteriosus were the only pathological findings at autopsy. In utero, irreversible, complete closure of the ductus arteriosus is very rare. In the case presented, prolonged use of indomethacin during pregnancy was associated with complete closure of the ductus arteriosus that developed most probably after discontinuation of therapy. This case emphasizes the need for frequent fetal echocardiography examinations during as well as after maternal indomethacin treatment.     

Ligation of medically refracted patent ductus arteriosus (PDA) in an extremely low body weight premature infant

Medically refracted patent ductus arteriosus (PDA) in an extremely low birth weight (ELBW) preterm (gestation 24 weeks 2 days) infant was successfully ligated under general anesthesia in the neonatal intensive care unit (NICU). Pharmacological agents are more effective to close PDA in preterm infants than in full-term infants, although within 48 h three doses of indomethacin were not sufficient to close PDA in this case. At the age of 69 h the infant developed severe symptoms including bradycardia, systemic hypotension, pulmonary hypertension, diastolic steal (reverse distal aorta flow velocity), and anuria. A PDA ligation was thus performed surgically at 72 h of age. General anesthesia and surgical stress were tolerated by this 531 g infant. Postoperatively all symptoms improved dramatically and the general conditions were stable. On the 38th day the endotracheal tube was extubated and on the 50th day nasogastric milk feeding was started. The oxygen supply was weaned on the 78th day. Growth and development until 6 months were within the normal range of very low birth weight infants. A surgical ligation as early as possible in medically refracted PDA in an ELBW infant is thus considered to be a safe and effective treatment. It prevents the development of further complications of cardiopulmonary vascular problems. Color Doppler echocardiography can reliably measure the PDA size, flow velocity, and hemodynamic changes of persistent PDA, even in tiny infants.     

Transcatheter closure of patent ductus arteriosus using controlled-release coils

Controlled-release coils have become available recently for the closure of patent ductus arteriosus (PDA). Transcatheter closure of patent arterial ducts was attempted in 13 patients, ranging in age from 5 months to 15 years, mean 4.1 years. Implantation of controlled-release PDA coils was attempted via the femoral artery through 5 Fr catheters in all cases except one, in whom both the femoral arterial and venous routes were used. The procedure was successful in 10 of the 13 patients. In these, the pulmonary artery systolic pressure ranged between 25 and 42 mmHg and the duct diameter varied from 1.5 to 6 mm at its narrowest point. Six of the patients received a single coil. Two coils were inserted in three patients and three coils in one patient. In three patients the ducts were too large for safe release of the coils, despite attempted implantation of up to three coils simultaneously. These coils were easily withdrawn into the catheter. Immediately at the end of the procedure, the duct was completely occluded in nine of the 10 patients, and in one patient there was a small residual flow. The procedure time varied between 35 min and 2.5 h, mean 81 min and the fluoroscopy time varied from 5 to 78 min, mean 25 min. None of the patients experienced hemorrhage, diminished lower extremity pulse, hemolysis or infection. In one patient, a 5 mm coil embolized into the right pulmonary artery soon after release. It was retrieved with a snare, then 8 mm and a 5 mm coil were implanted satisfactorily in the arterial duct. At follow-up by color Doppler echocardiography, the duct was completely occluded in all patients. Transcatheter closure of patent arterial ducts by controlled-release PDA coils is effective and safe. Even when more than one coil is inserted, it is still cheaper than transcatheter umbrella closure. This method is therefore of great value, particularly in less affluent countries.     

Controllable graded cerebral ischaemia in the gerbil: studies of cerebral blood flow and energy metabolism by hydrogen clearance and 31P NMR spectroscopy

Patent ductus arteriosus is an uncommon anomaly in adult patients. Surgical closure of patent ductus arteriosus in this age group presents difficult problems to the surgeon. We report our experience of 21 adult patients (19-62 years of age, mean 40 years) who underwent closure of the ductus by transfemoral implantation of a Rashkind double umbrella device. The patients came to light because of atrial fibrillation, congestive heart failure, residual flow after surgical ligation of the duct or because of incidental diagnosis made during physical examination or chest X-ray. In ten patients the pulmonary arterial pressure was normal (systolic pressure < 30 mmHg), in eleven it was elevated (systolic pressure from 30 to 100 mmHg, mean 50 mmHg). In seven patients the duct was clearly calcified and the size of the duct varied from 3 to 9 mm (mean 4.3 mm). In 16 patients the ductus resulted perfectly closed after implantation of the first double umbrella device, two patients had minimal residual aortopulmonary flow, whereas in three patients the residual shunt was significant; two of these also developed haemolysis and went to surgery, in the latter the shunt was completely abolished after implantation of a second 17-mm device 16 months later. In conclusion transcatheter closure of patent ductus arteriosus in adults is feasible, even in the presence of calcifications and/or pulmonary hypertension; taking into account the significant surgical risk, PDA umbrella closure should be considered the first choice procedure in this group of patients.     

Natural history of innocent heart murmurs in newborn babies: controlled echocardiographic study

AIM: To define the origin and the natural history of innocent heart murmurs in newborn infants. METHODS: Fifty healthy babies born at term with the clinical diagnosis of an innocent heart murmur and 50 controls without a murmur were studied. Each baby had a complete two dimensional and pulsed Doppler echocardiogram and those with any abnormality were followed up at 6 weeks, 3 months, and 6 months until the murmur had disappeared or the heart was totally normal. Babies with congenital heart disease were excluded from the study. RESULTS: Pulmonary branch stenosis (PBS) was found in 25 (50%) of the study group and in six (12%) controls; patent ductus arteriosus (PDA) in 30 (60%) subjects and in six (12%) controls; and a patent foramen ovale (PFO) in 50 (100%) subjects and in 41 (82%) controls. At 6 weeks the murmur had disappeared in 64% of babies. PBS was still present in eight of 22 (36%) babies at 6 weeks, in 12% at 3 months, but in none at 6 months. At 6 weeks, seven of the eight with PBS still had a murmur compared with two of 14 (14%) babies in which the PBS had resolved (P < 0.005). At 6 weeks the PDA had closed in all patients but the foramen ovale was still patent in 29 of 44 (66%) subjects and nine of 33 (27%) controls. The closure of the PFO was not influenced by its size at birth. CONCLUSIONS: An innocent heart murmur in a baby born at term is often related to PBS, particularly if the murmur is still present after 24 hours of age, when most PDA have closed. At 6 weeks the murmur had disappeared and the PBS had resolved in 64% of the babies. PBS had resolved in all babies at 6 months.     

Effects of clonidine in a primed rat model of acute hepatic porphyria

The hypothesis that local release of prostanoids may contribute to the pharmacologic effect of nitroglycerin (NTG) has long been debated. Results of prostanoid blockade by indomethacin on NTG-induced effects, to date, have been inconclusive. To quantitate the effects of intravenous indomethacin on NTG-induced myocardial blood flow by using positron-emission tomography, we conducted a prospective, controlled, parallel-design study comparing patients with coronary artery disease with healthy volunteers. Eight subjects, four Canadian Class II-III coronary artery disease (CAD) with luminal narrowing of > 80% in a minimum of two vessels, and four healthy volunteers were evaluated. Baseline global myocardial blood flow was equivalent between the groups. NTG produced a 49.3 +/- 4.7% increase in myocardial blood flow in healthy volunteers (p = 0.006) and an -0.5 +/- 19.8% decrease in the group with CAD (p = 0.62 between groups). After indomethacin, both groups had a 24% decline in myocardial blood flow (CAD, p = 0.25; healthy, p = 0.03). One patient with CAD had acute ischemia after indomethacin. The study demonstrated that short-term intravenous indomethacin decreases NTG-induced myocardial blood flow to the same degree in both subjects with CAD and healthy individuals. Impairment of myocardial blood flow from this pharmacologic combination may be most important in patients with severe fixed lesions.     

Effect of indomethacin suppositories on rectal polyposis in patients with familial adenomatous polyposis

BACKGROUND: Oral sulindac is known to reduce polyps in patients with familial adenomatous polyposis (FAP). The authors speculated that rectal administration of indomethacin would be effective therapy for adenomas in the rectal remnant of FAP. METHODS: Eight patients with FAP who had been treated by total colectomy with ileorectal anastomosis were administered an indomethacin suppository (50 mg) once or twice daily during a period of 4 or 8 weeks. The number of polyps at the same site within the rectum was counted under proctoscopy prior to, at the end of, and after the treatment. In four patients, proliferative activity of the rectal mucosa was assessed by immunohistochemical staining for MIB-1. RESULTS: In six of the eight patients who initially had ten or more polyps, the number of polyps decreased to fewer than five, whereas such a decrease could not be observed in the remaining two patients. In the six patients, the number of polyps increased after indomethacin was discontinued. The proliferative activity of the rectal mucosa was higher at the end of treatment than it was prior to indomethacin administration. CONCLUSIONS: Indomethacin suppositories may be effective in the management of rectal adenomatosis in patients with FAP.     

Maternal treatment with indomethacin and severe neonatal pulmonary hypertension (author's transl)

The authors report five cases of premature newborns whose mothers had been treated with indomethacin. In all patients, clinical and biological symptoms were those of pulmonary hypertension with persistence of the fetal circulation. In two cases, autopsy showed an important reduction of the lumen of pulmonary arterioles due to a thickening of the tunica media. The role of indomethacin in such respiratory syndrome is very likely. Therefore, indications for that treatment in pregnant women should be reduced.     

Surgical management of patent ductus arteriosus in low body weight infants]

Between January 1980 and December 1994, seventeen premature infants weighing less than 2500 g underwent surgical management for the isolated patent ductus arteriosus (PDA). Indometacine therapy for closure of PDA was not effective for all these patients. In terms of the body weight at birth, they were divided into two groups; Group I (G-I) consisted of ten patients with birth weight less than 1000 g and Group II (G-II) of seven patients weighing more than 1000 g. The age at operation was 22.1 +/- 15.4 days in the G-I and 14.3 +/- 11.4 days in the G-II. The ductus was ligated in all patients but one of the G-II, in whom it was divided. There were five (50%) hospital deaths in the G-I and none in the G-II. The causes of death in the G-I were related to necrotizing enterocolitis (NEC) in two and infant respiratory distress syndrome (IRDS), acute renal failure, and broncho-esophagial fistula in each. The age at operation tended to be older in nonsurvivors rather than in survivors in the G-I (28.0 +/- 16.8 days vs. 16.2 +/- 14.0 days, respectively, but the difference did not reach significance). Before surgery, all patients in the G-I required mechanical ventilator support and nine of them were associated with IRDS. In contrast, only two patients in the G-II needed mechanical ventilation preoperatively. The postoperative period of intubation was also significantly longer in the G-I than in the G-II (51.6 +/- 35.2 days vs. 2.2 +/- 1.5 days, respectively, p < 0.05). In conclusions, the surgery for PDA can be safely performed even in small premature babies weighing less than 1000 g. When medical therapy for PDA is not effective in the premature patients, the surgical management should be considered as early as possible before their conditions become worse due to such critical complications as NEC, IRDS, and renal failure.     

Prenatal maternal indomethacin use resulting in prolonged neonatal renal insufficiency

The short-term use of indomethacin has been shown to be relatively safe and effective in halting premature labor. Its use has been associated with adverse renal effects in both the fetal and newborn periods that are generally transient and resolve on discontinuation of the drug. However, limited data suggest that prolonged prenatal exposure to indomethacin may be harmful to the fetus. We report a case of prolonged severe renal dysfunction characterized by oligohydramnios and postnatal anuria, azotemia, and ultrasonographic kidney abnormalities associated with the long-term prenatal use of indomethacin. Although partial resolution was observed, a moderate decrease in renal function persists. Prenatal maternal indomethacin use represents a potential cause of renal dysfunction in the newborn infant that may be only partially reversible.     

Acute and chronic effects of different bile acids on indomethacin-induced intestinal inflammation

The role of bile acids in the pathogenesis of bowel inflammation is unknown. The objective of this study was to determine whether urso- (UDC), cheno- (CDC), and taurochenodeoxycholic acid (TCDC) exert a pro- or antiinflammatory action in the acute and chronic phase of the indomethacin model of a long lasting ileitis in rats. Short-term and long-term inflammatory responses (48 h and 10 days, respectively) after two subcutaneous indomethacin (Indo) injections were elicited in rat small bowel and mesentery. To distinguish between common and model-specific effects bile acids were tested also in another model of acute inflammation induced by mesenteric superfusion with leukotriene B4(LTB4). The number of adherent and emigrated leukocytes, leukocyte rolling velocity, and venular wall shear rate were monitored in normal and inflamed postcapillary venules, and fecal pH of ileal contents which has been shown to correlate with degree of inflammation was measured, 6.5- and 2.3-fold increases in leukocyte adherence and comparable increments in leukocyte emigration were observed 48 h and ten days after indomethacin treatment, respectively. UDC, CDC, and TCDC (10 mg/kg) given daily from Indo administration until the experiment attenuated the leukocyte adherence and emigration responses elicited by indomethacin in short- and long-term inflammation. This effect was accompanied by a significant increase of fecal pH which had been lowered by indomethacin. None of the bile acids reduced the LTB4-induced increases in adherence and emigration. Oral administration of UDC, CDC, and TCDC reduces leukocyte adhesion and emigration in acute and chronic stages of Indo-induced inflammation. This could be due to the alkalizing effect of these bile acids on fecal pH which has been shown to correlate with a decrease of leukocyte-endothelial cell interactions but--according to the missing effectiveness in another model of intestinal inflammation--not to specific influences on leukocyte-endothelial cell adhesion.     

Night medication in rheumatoid arthritis: II. Combined therapy with indomethacin and diazepam

Seventeen of eighteen patients hospitalized for active rheumatoid arthritis completed a three-day randomized, double-blind comparison of 100 mg indomethacin, 100 mg indomethacin with 10 mg diazepam and matching placebo as night medication. The results showed a consistent pattern in the four functions measured--pain, morning stiffness, sleep score and patient preference. In each, indomethacin proved superior to placebo and the combined therapy better than indomethacin alone. From this it has been concluded that the combination of indomethacin and diazepam should now be considered the treatment of choice for maximum control of night pain and morning stiffness in rheumatoid arthritis.     

Effect of topically applied cyclosporin A on arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation in mouse ear

Topical cyclosporin A (CsA) was compared with dexamethasone, indomethacin and phenidone in edema, increases in vascular permeability, eicosanoids and cell-influx induced by arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) in mouse ears. CsA ED(50) on AA-edema (7.7 micrograms/ear) was similar to dexamethasone and lower than indomethacin and phenidone. CsA ED(50) in TPA edema (21 micrograms/ear) was higher than dexamethasone and lower than indomethacin or phenidone. All drugs equally reduce the AA-induced increase in vascular permeability, but CsA and dexamethasone had more activity on TPA. AA-increase in vascular 6-keto-PGF1 alpha was reduced by dexamethasone, indomethacin and phenidone but not by CsA; only phenidone reduced LTB4. TPA-increase in 6-keto-PGF1 alpha was reduced by CsA and indomethacin while CsA, dexamethasone and phenidone decreased LTB4. CsA, indomethacin and phenidone, but not dexamethasone, suppressed AA-neutrophil influx. In TPA-ears all drugs produced similar reduction in neutrophil influx. CsA was shown to be a good topical anti-inflammatory drug.     

A rare case of patent ductus arteriosus in a dog with glomerular mesangiolysis

Rare case of patent ductus arteriosus (PDA) was observed in a 2-year and 9 month-old Miniature Dachshund which had been diagnosed as severe cardiac failure. Pulmonary artery from the right ventricle connected to dilated ductus arteriosus, and pulmonary artery-ductus arteriosus-descending aorta formed a continuous duct, which seemed to be the main route of bloodstream. Ascending aorta from the left ventricle was hypoplastic, and connected to the dilated ductus arteriosus. Glomerular mesangiolysis due to heart failure was also observed in the kidney.