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PubMed2002

Factors associated with permanent closure of the ductus arteriosus: a role for prolonged indomethacin therapy.

BACKGROUND: The most important factor determining anatomic remodeling and permanent closure of the ductus arteriosus is the degree of ductus constriction after indomethacin treatment. Muscular constriction produces a region of ischemic hypoxia in the middle of the ductus muscle media that initiates the process of permanent closure. Previous studies have shown that infants delivered before 28 weeks' gestation, who still have evidence of ductus flow on Doppler examination (performed after the standard 3-dose course of indomethacin), have a high likelihood (>85% chance) of reopening their ductus in the future. In contrast, if there is no evidence of luminal patency on the posttreatment Doppler examination, the incidence of ductus reopening is <20%. In the following study, we examined infants who still had a patent ductus on Doppler examination after a 3-dose course of indomethacin, to identify which factors might be associated with permanent ductus closure. We hypothesized that infants who received additional doses of indomethacin after the standard 3-dose course might develop an even tighter degree of ductus constriction and increase their chance of developing permanent closure. METHODS: We performed a retrospective cohort study of preterm infants (< or =26; weeks' gestation) who were treated with indomethacin. Between 12 and 24 hours after the third dose of indomethacin, infants were examined for the presence or absence of ductus-related signs, and an echocardiogram was performed. Infants responded to the initial 3 doses of indomethacin in 1 of 3 ways: 1) the ductus was closed clinically (absent clinical signs) with no evidence of luminal flow on Doppler examination ("clinically closed"; n = 214); 2) the ductus was closed clinically, but a small amount of left-to-right luminal flow was evident on Doppler examination ("partially closed"; n = 69); 3) or the ductus was open clinically and echocardiographically ("nonresponder"; n = 30). Nonresponders underwent surgical ligation (n = 30). Infants with a partially closed ductus formed our study population. We used a hierarchical regression model to identify which, if any, of the following factors might be associated with permanent anatomic closure in the 69 infants with a partially closed ductus: 1) gestational age, 2) exposure to antenatal steroids, 3) birth weight, 4) sex, 5) presence and severity of respiratory distress, 6) fluid administration during the first 96 hours after birth, 7) indomethacin treatment approach (prophylactic vs symptomatic), 8) year of birth, 9) use of surfactant, 10) preeclampsia, 11) chorioamnionitis, 12) bacterial septicemia, 13) necrotizing enterocolitis, or 14) duration of indomethacin treatment (standard 3-dose course vs prolonged 6-dose course). Infants who received the standard 3-dose course of indomethacin treatment were given 0.2, 0.1, and 0.1 mg/kg indomethacin during a 48-hour period. Infants who received the prolonged 6-dose course of indomethacin treatment were given a fourth, fifth, and sixth dose of 0.1 mg/kg at 24 hour-intervals, starting 24 hours after the third dose. RESULTS: Sixty-eight of the 69 infants survived long enough to complete all of the study evaluations. Seventy-five percent (51/68) reopened their ductus and became symptomatic; 71% (48/68) were eventually ligated. Only gestational age and duration of indomethacin treatment were significantly and independently associated with permanent closure. A prolonged 6-dose course of indomethacin was more likely than the standard 3-dose course to be associated with an increased incidence of echocardiographic closure, a decreased incidence of symptomatic reopening (odds ratio: 0.19; 95% confidence interval: 0.04-0.96), and a decreased incidence of ductus ligation (odds ratio: 0.14; 95% confidence interval: 0.03-0.68). DISCUSSION: Several older studies have suggested that a longer initial course of indomethacin therapy may be more effective in producing permanent ductus closure than the standard 3-dose course. In contrast, more recent studies have found that a longer course of indomethacin is no more effective than the standard 3-dose course in producing permanent closure. We hypothesize that the different outcomes among these studies may be attributable to differences in the degree of ductus constriction during the standard 3-dose course of indomethacin. Both the increased use of antenatal steroids and the earlier use of indomethacin has increased the effectiveness of the standard 3-dose course of indomethacin in recent years. We hypothesize that, in contrast with earlier studies, a significant proportion of the infants in the recent studies may have developed complete Doppler closure with just 3 doses of indomethacin (as occurred in 214 of the 313 infants treated with the standard 3-dose course in our study). Because the degree of ductus constriction seems to determine the rate of anatomic remodeling and permanent closure, daily echocardiographic evaluations of ductal patency may be the best way to decide when indomethacin therapy is no longer needed. Our study suggests that infants who still have evidence of luminal patency, after a standard 3-dose course of indomethacin, may be likely to benefit from a longer course of indomethacin. Future randomized trials that examine the benefits of different lengths of indomethacin treatment may wish to take this into consideration. CONCLUSIONS: Despite the increased effectiveness of a prolonged course of indomethacin, the rates of ductus reopening and surgical ligation were still very high in infants with a partially closed ductus. Other therapeutic approaches will need to be developed before permanent closure is likely to occur in this group of immature infants.

Cardiovascular Agents↗
PubMed1998

Indomethacin tocolysis increases postnatal patent ductus arteriosus severity.

UNLABELLED: Postnatally, therapeutic indomethacin administration is usually effective in mediating patent ductus arteriosus (PDA) constriction in premature infants. There are infants, however, who remain resistant to indomethacin and require more aggressive surgical intervention to facilitate ductal closure. Indomethacin tocolysis has been reported to increase the incidence of persistent PDA in premature infants. It was our impression that infants exposed to antenatal indomethacin not only suffered from an increased incidence of PDA, but that they were more symptomatic from PDA and that for them, PDA was more resistant to medical closure. It is this observation that we sought to examine in this study. METHODS: Medical records of all mothers and premature neonates with birth weight </=1500 g, admitted to the neonatal intensive care unit of the Shaare Zedek Medical Center during 1996 and 1997, who survived for at least 1 week, were reviewed retrospectively. Data on maternal indomethacin and steroid exposure, birth weight and gestational age, and ductus status and treatment were analyzed. In our obstetrics department, indomethacin is the medication of choice to inhibit premature labor. Mothers who arrive in premature labor are started on indomethacin therapy, if delivery is not imminent. All infants </=1500 g were studied by a pediatric cardiologist between 24 and 72 hours of life using two-dimensional echocardiography with color flow mapping to assess ductal patency. Decisions to treat were based on echocardiographic evidence of PDA, along with any of the following clinical signs: bounding pulses, diastolic pressure of </=25 mm Hg, pulmonary plethora and/or cardiomegaly on chest x-ray, or increasing oxygen requirement with no other explanation. Initial treatment is with indomethacin, if there are no contraindications. Our general approach is to begin therapy with a continuous indomethacin infusion, followed by a course of bolus indomethacin if the infant does not respond. However, each attending neonatologist may treat according to his/her preference (ie, bolus vs continuous). All infants with PDA are followed with serial echocardiographic examinations until the ductus is closed. RESULTS: A total of 105 premature infants met the above criteria. Thirty-six of these 105 infants had echocardiographic signs of a PDA (34.3%). Those with PDA were less mature (gestational age, 28.9 +/- 2.6 vs 30.3 +/- 2.6 weeks, respectively) and tended to be smaller (1060 +/- 270 vs 1166 +/- 261 g). Of the 36 infants with PDA, 15 (42%) resolved spontaneously and 21 (58%) were symptomatic and required treatment with indomethacin. There were no differences in gestational age or birth weight between infants whose PDA resolved spontaneously and those requiring indomethacin therapy. Four of the 21 (19%) treated infants remained unresponsive to indomethacin and required ductal ligation. Of 17 infants with PDA who responded to indomethacin therapy, 1 (6%) was treated with a single course of bolus indomethacin, to which he responded, and 16 (94%) were treated with continuous indomethacin and responded promptly. The differences in therapeutic responsiveness to initial treatment with continuous vs bolus indomethacin were not significant. Of the 105 infants, 29 were exposed to indomethacin tocolysis. Those who were exposed to antenatal indomethacin and those who were not were well-matched with respect to birth weight and gestational age. Fifteen (52%) of the 29 exposed infants versus 18 (24%) of the 76 infants not exposed to antenatal indomethacin developed a PDA postnatally (relative risk = 2.1; 95% confidence interval: 1.22-3.74), and 45% of the antenatally exposed infants versus 12% of the nonexposed infants were symptomatic and required indomethacin (relative risk = 1.9; 95% confidence interval: 1.17-3.20). Four of the exposed infants versus none of the unexposed infants required surgical ligation. (ABSTRACT TRUNCATED)

Ductus Arteriosus, Patent↗
PubMed1979

Immunoassay of indomethacin: the use of [125I] protein A to detect specific serologic binding.

The sera of rabbits that were injected with indomethacin covalently linked to human albumin bound increasing amounts of [14C] indomethacin during the course of immunization. The serum-binding components chromatographed with the gamma-globulin fraction and were precipitated with goat-anti-rabbit-gamma-globulin. When measured by radioimmunoassay with [14C] indomethacin under optimal conditions, 34 ng (95 pmoles) of unlabeled indomethacin inhibited [14C] indomethacin binding 50%. The antibodies reacted most effectively with indomethacin and the desmethylated analogue, 1-(p-chlorobenzoyl)-2-methyl-5-hydroxyindole-3-acetic acid, but not 2-methyl-5-methoxy-indole-3-acetic acid. An immunoassay based on the use of [125I] Protein A as tracer for IgG antibody was developed for quantitative determination of indomethacin at the picogram level. Indomethacin, immobilized by covalent linkaae to a solid support, bound the rabbit anti-indomethacin. Protein A, labeled with [125I], measured the levels of the bound IgG antibody. Fluid phase indomethacin competed with solid-phase indomethacin for the anti-indomethacin, which resulted in decreased anti-indomethacin and consequently decreased [125I] Protein A on the immobilized indomethacin-anti-indomethacin complex. The serologic specificity with the immobilized ligand immunoassay was the same as that found with the [14C] indomethacin radioimmunoassay, but the sensitivity for detection of indomethacin was increased over 300-fold.

Animals↗
PubMed2006

Mode of administration-dependent brain uptake of indomethacin: sustained systemic input increases brain influx.

Nonsteroidal anti-inflammatory drugs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to an equivalent dose of free indomethacin because of limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug, or intravenous indomethacin infusion was administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 h following indomethacin administration were 0.45, 0.3, and 0.31 microg/g after the oral indomethacin, oral prodrug, and intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1, and 4 microg/ml. Therefore, brain versus plasma indomethacin level ratios were 2.5-fold higher after slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration-dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain-related pharmacodynamic effects, while avoiding the concentration-dependent adverse effects. These findings may contribute to improved therapy in Alzheimer's disease.

Administration, Oral↗
PubMed2003

Persistent Doppler flow predicts lack of response to multiple courses of indomethacin in premature infants with recurrent patent ductus arteriosus.

OBJECTIVE: Although indomethacin produces ductus arteriosus constriction in extremely premature newborns, a recurrent symptomatic patent ductus arteriosus (PDA) frequently develops after the initial course of indomethacin. Currently, there is little information available to determine the effectiveness of a second course of indomethacin in producing permanent ductus closure. The objective of this study was to determine the rate of permanent ductus closure after a second course of indomethacin for a recurrent, symptomatic PDA and to identify the factors associated with permanent ductus closure. METHODS: We identified 32 infants (<28 weeks' gestational age) 1) whose ductus was considered to be clinically closed after an initial course of indomethacin and 2) who subsequently developed a symptomatic PDA and received a second course of indomethacin. Clinical variables were evaluated for their association with failure of the second course (defined as surgical ligation after the second course for recurrence of a hemodynamically significant PDA). Data were analyzed by chi(2) analysis, Fisher's exact test, and the Mann-Whitney rank sum test. RESULTS: After the second course of indomethacin, 56% (18 of 32) of the infants had persistent or recurrent PDA-related symptoms that were considered to be hemodynamically significant. The only significant predictor of failure of the second indomethacin course was the demonstration (by Doppler echocardiogram) of persistent ductus flow within 24 hours of completing the initial indomethacin course. All of the 9 newborns with persistent Doppler ductus flow after the initial indomethacin course failed the second course of indomethacin. In contrast, only 39% (9 of 23) of newborns with absent Doppler flow after the initial indomethacin course failed the second course of indomethacin. CONCLUSIONS: Newborns who are <28 weeks' gestational age and develop a recurrent, symptomatic PDA after completion of an initial indomethacin course rarely respond to multiple courses of indomethacin if there was persistent Doppler evidence of ductus flow after completion of the initial course. Additional indomethacin treatment is unlikely to produce permanent ductus closure.

Ductus Arteriosus, Patent↗
PubMed1999

Effect of PGF2alpha, indomethacin, tamoxifen, or estradiol-17beta on incidence of abortion, progesterone, and pregnancy-specific protein B (PSPB) secretion in 88- to 90-day pregnant sheep.

One objective of this experiment was to evaluate our hypotheses that estradiol-17beta regulates secretion of pregnancy specific protein B (PSPB) and that secretion of progesterone during pregnancy is regulated by a prostanoid by examining the effects of prostaglandin F2alpha (PGF2alpha), a luteolyic agent; indomethacin, a prostanoid synthesis inhibitor; tamoxifen, an estrogen receptor antagonist; estradiol 17-beta; and interaction of these factors on the incidence of abortion and progesterone and PSPB secretion. Another objective was to determine if there is a luteal source of PSPB. Weights of corpora lutea were decreased (P < or = 0.05) by PGF2alpha, indomethacin, PGF2alpha + tamoxifen, PGF2alpha + indomethacin, and PGF2alpha + estradiol-17beta but not (P > or = 0.05) by tamoxifen or estradiol-17beta alone. No ewe treated with PGF2alpha alone aborted (P > or = 0.05). Forty percent of ewes treated with PGF2alpha + estradiol-17beta aborted (P < or = 0.05), but ewes were not aborted by any other treatment within the 72-h sampling period. Profiles of progesterone in jugular venous blood differed (P < or = 0.05) among control, indomethacin-, tamoxifen-, and PGF2alpha + indomethacin-treated ewes. Progesterone in jugular venous blood of control ewes decreased (P < or = 0.05) by 24 h, followed by a quadratic increase (P < or = 0.05) from 24 to 62 h. Progesterone in jugular venous blood of indomethacin-, PGF2alpha-, PGF2alpha- + tamoxifen-, PGF2alpha + indomethacin-, PGF2alpha + estradiol-17beta-, and tamoxifen-treated ewes was reduced (P < or = 0.05) by 18 h and did not vary (P > or = 0.05) for the remainder of the 72-h sampling period. Progesterone in vena cava and in uterine venous blood was reduced (P < or = 0.05) at 72 h in PGF2alpha-, indomethacin-, tamoxifen-, PGF2alpha + indomethacin-, PGF2alpha + tamoxifen-, and PGF2alpha + estradiol-17beta-treated ewes. Weights of placentomes did not differ among treatment groups (P > or = 0.05). Profiles of PSPB in inferior vena cava blood differed (P < or = 0.05) among control, estradiol-17beta-, indomethacin-, tamoxifen-, PGF2alpha + indomethacin-, and PGF2alpha + tamoxifen-treated 88- to 90-day pregnant ewes. Concentrations of PSPB in inferior vena cava blood were increased (P < or = 0.05) in indomethacin-, estradiol-17beta-, tamoxifen-, PGF2alpha + tamoxifen-, and PGF2alpha + indomethacin-treated 88- to 90-day pregnant ewes within 6 h and did not vary (P > or = 0.05) for the remainder of the 72-h sampling period. Concentrations of PSPB in uterine venous blood of indomethacin-, tamoxifen-, PGF2alpha + tamoxifen-, and PGF2alpha + indomethacin-treated ewes were greater (P < or = 0.05) at 72 h than at 0 h. PSPB in ovarian venous blood did not differ (P > or = 0.05) adjacent or opposite to the ovary with the corpus luteum. It is concluded from these data that estrogen regulates placental secretion of PSPB and that a prostanoid, presumably prostaglandin E, regulates placental secretion of progesterone during 88-90 days of gestation in sheep and that there is no luteal source of PSPB.

Abortifacient Agents, Steroidal↗