Trial Of Indomethacin Prophylaxis In Preterms Research Articles

Patent ductus arteriosus and effects of low oxygen saturation limits

Patent ductus arteriosus and effects of low oxygen saturation limits

Neurosensory Impairment after Surgical Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms

To determine whether surgical closure of a patent ductus arteriosus (PDA) is a risk factor for bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP), and neurosensory impairment in extremely low birth weight (ELBW) infants. We studied 426 infants with a symptomatic PDA, 110 of whom underwent PDA ligation and 316 of whom received medical therapy only. All infants participated in the multicenter Trial of Indomethacin Prophylaxis in Preterms (TIPP) and were observed to a corrected age of 18 months. Of the 95 infants who survived after PDA ligation, 50 (53%) had neurosensory impairment, compared with 84 of the 245 infants (34%) who survived after receiving only medical therapy (adjusted odds ratio, 1.98; 95% CI, 1.18-3.30; P = .0093). BPD (adjusted odds ratio, 1.81; 95% CI, 1.09-3.03; P = .023) and severe ROP (adjusted odds ratio, 2.20; 95% CI, 1.19-4.07; P = .012) were also more common after surgical PDA closure. PDA ligation may be associated with increased risks of BPD, severe ROP, and neurosensory impairment in ELBW infants.

Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: Further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

To determine the risk of bronchopulmonary dysplasia (BPD) in subgroups of infants with and without patent ductus arteriosus (PDA) who were randomized to indomethacin prophylaxis or placebo, and to examine whether adverse drug effects on edema formation and oxygenation may explain why indomethacin prophylaxis does not reduce BPD. We studied 999 extremely low birth weight infants who participated in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) and who survived to a postmenstrual age of 36 weeks. The incidence of BPD in the 2 subgroups of infants with PDA was 52% (55/105) after indomethacin prophylaxis and 56% (137/246) after placebo. In contrast, rates of BPD in the 2 subgroups without a PDA were 43% (170/391) after indomethacin prophylaxis and 30% (78/257) after placebo (P [interaction] = .015). Logistic regression analysis with adjustment for prognostic baseline factors showed that adverse and independent effects of indomethacin prophylaxis on the need for supplemental oxygen and on weight loss by the end of the first week of life may increase the risk of BPD in infants without PDA. Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent BPD even though it reduces PDA.

Indomethicin and BPD

The outcome of bronchopulmonary dysplasia (BPD) in very low birth weight infants (VLBW) has many clinical associations. However, treatments to avoid or decrease adverse effects of those associations have not consistently decreased BPD. For example, antenatal corticosteroids or surfactant treatments to decrease RDS have not decreased the incidence of BPD, although each therapy has decreased mortality and has decreased the severity of BPD. The presumed explanation for the lack of effect on incidence of BPD is that increased survival has put more marginal infants at risk of developing BPD. Similarly, different ventilation strategies have not consistently decreased BPD. BPD is thought to result from injury resulting in lung inflammation, and anti-inflammatory corticosteroids have been used to treat BPD. A patent ductus arteriosis (PDA) also is linked to BPD. However, the cyclo-oxygenase inhibitors, which close the PDA and are anti-inflammatory, have not decreased PDA.Schmidt et al have revisited the Trial of Indomethacin Prophylaxis in Preterms (TIPP) database to demonstrate that randomization of infants to indomethacin may increase BPD because of decreased weight loss and increased supplemental oxygen need. In a very thoughtful editorial, Carl Bose reflects on what other mechanisms might explain why indomethacin does not decrease (and may increase) BPD. The clinical associations with BPD may primarily indicate the immaturity of the infant at risk, and BPD seems to result from interference in the development of the immature lung.Effective therapies to decrease BPD may need to be directed at the abnormal development rather than other associations with immaturity. The outcome of bronchopulmonary dysplasia (BPD) in very low birth weight infants (VLBW) has many clinical associations. However, treatments to avoid or decrease adverse effects of those associations have not consistently decreased BPD. For example, antenatal corticosteroids or surfactant treatments to decrease RDS have not decreased the incidence of BPD, although each therapy has decreased mortality and has decreased the severity of BPD. The presumed explanation for the lack of effect on incidence of BPD is that increased survival has put more marginal infants at risk of developing BPD. Similarly, different ventilation strategies have not consistently decreased BPD. BPD is thought to result from injury resulting in lung inflammation, and anti-inflammatory corticosteroids have been used to treat BPD. A patent ductus arteriosis (PDA) also is linked to BPD. However, the cyclo-oxygenase inhibitors, which close the PDA and are anti-inflammatory, have not decreased PDA. Schmidt et al have revisited the Trial of Indomethacin Prophylaxis in Preterms (TIPP) database to demonstrate that randomization of infants to indomethacin may increase BPD because of decreased weight loss and increased supplemental oxygen need. In a very thoughtful editorial, Carl Bose reflects on what other mechanisms might explain why indomethacin does not decrease (and may increase) BPD. The clinical associations with BPD may primarily indicate the immaturity of the infant at risk, and BPD seems to result from interference in the development of the immature lung. Effective therapies to decrease BPD may need to be directed at the abnormal development rather than other associations with immaturity.

Retrospective economic evaluation of a controlled trial of indomethacin prophylaxis for patent ductus arteriosus in premature infants

Objective To determine the incremental cost-effectiveness of indomethacin prophylaxis in extremely low birth weight infants enrolled in the Trial of Indomethacin Prophylaxis in Preterms (TIPP). Study design Participants in this economic evaluation were 428 infants enrolled at 9 Canadian TIPP centres. The study took a third-party payer perspective. Prior to the analysis of clinical trial data, direct medical costs were derived from chart review of 89 items of resource utilization, for each day from admission to hospital discharge. Unit costs for each resource were obtained from a provincially standardized cost-accounting system. Incremental cost-effectiveness analysis was performed, with estimation of cost-effectiveness acceptability curves through non-parametric bootstrapping. Results The mean (SD) cost was $68 279 (40 317) for the placebo group and $69 629 (37 989) for the indomethacin group. Indomethacin prophylaxis cost an additional $67 500 per death or impairment averted. However, the precision of this estimate was low, such that the probability that the estimate was lower than $300 000 per death or impairment averted was only 61%. The results were similar when surgical costs were assumed to be 500% of those measured in the trial. Conclusions This study does not provide an economic rationale for the use of indomethacin prophylaxis in ELBW infants.

234 Surgical Closure of A Patient Ductus Arteriosus (PDA) is Associated with Increased Neuro-Sensory Impairment in Extremely Low Birth Weight (ELBW) Infants: Results from The Trial of Indomethacin Prophylaxis in Preterms

Background: The Victorian Infant Collaborative Study Group has reported that surgery with general anesthesia during the initial hospitalization increases the risk of adverse sensorineural outcome in ELBW infants. PDA ligation was the single most frequent type of surgery in this study. Objective: To determine whether surgical PDA closure was a risk factor for neurosensory impairment in ELBW infants who participated in the international Trial of Indomethacin Prophylaxis in Preterms (TIPP). Methods: Using the TIPP database, we studied 1180 children who survived their first day of birth. Infants were divided into 3 groups according to their PDA status in the NICU: ‘No PDA', ‘Non-surgical PDA', and ‘Surgical PDA'. As in TIPP, the primary outcome was a composite of death or neurosensory impairment at a corrected age of 18 months (cerebral palsy, cognitive delay, deafness, and blindness). Deaths and impairments were also examined separately. Odds ratios and 95% confidence intervals were calculated to estimate the differences in prognostic risk for the ‘No PDA' and the ‘Surgical PDA' groups in comparison with the ‘Non-surgical PDA' group. The analysis was adjusted for gestational age, gender, multiple birth, antenatal steroids, mother's education, and moderate to severe pulmonary hemorrhage. We also examined the relationship between the rate of surgical PDA closure in individual study centres and the 18-month outcome. Results: The results are summarized in the table. There was a significant direct correlation between the rates of surgical PDA closure in individual study centres and the prevalence of neurosensory impairments in survivors (p=0.032). Conclusion: Surgical PDA closure was associated with reduced mortality but increased neurosensory impairment in ELBW infants. It remains uncertain whether PDA ligation is a cause or a marker of adverse long-term outcome in this population.

5 Prevention and 18-Month Outcome of Serious Pulmonary Hemorrhage in Extremely-Low-Birth-Weight (ELBW) Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

5 Prevention and 18-Month Outcome of Serious Pulmonary Hemorrhage in Extremely-Low-Birth-Weight (ELBW) Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

Evaluating “old” definitions for the “new” bronchopulmonary dysplasia

Objectives: To examine the accuracy of different criteria for the diagnosis of bronchopulmonary dysplasia (BPD), based on the final age at which oxygen therapy was stopped, in predicting pulmonary and neurologic outcomes at 18-month corrected age. Study design: Data were collected prospectively on infants with birth weights between 500 and 999 g enrolled in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) who survived to discharge home. Differing postnatal ages and postmenstrual ages at which supplemental oxygen therapy was no longer required formed the criteria for defining BPD. Diagnostic accuracy of each criterion for defining BPD was calculated for both poor pulmonary and poor neurosensory outcomes. Results: The prevalence of poor pulmonary outcome was 54% and of poor neurosensory outcome was 34% in the 956 infants who were eligible for this analysis. Accuracy of different definitions of BPD was limited but greatest when using supplemental oxygen requirement at 36 weeks' postmenstrual age to predict long-term pulmonary outcome (63%) and 40 weeks to predict long-term neurosensory outcome (68%). Conclusions: Poor pulmonary outcome and poor neurosensory outcome are common late adverse outcomes in this population. BPD as defined by duration of oxygen therapy is a less accurate surrogate currently than in previous eras. (J Pediatr 2002;140:555-60)