الفهرس 
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Abstract
The ductus arteriosus is a vital structure during fetal life, shunting blood from the high-resistance pulmonary circulation to the aorta bypassing the lung to support the systemic circulation. In full-term infants, the DA usually closes within 48 hours after delivery. The failure of its closure is inversely proportionate to the gestational age, becoming more hemodynamically significant in neonates below 1000 g or gestational age less than 28 weeks and may need either medical or surgical intervention.
The definition of hsPDA is still a controversy as well as the identification of the infants’ candidate for therapy and the treatment regimen.
A consensus on the management of PDA in premature neonates remains indefinable. The exact impact of PDA treatment on meaningful short- and long-term outcomes is still unknown despite multiple trials.
There are no guidelines for the ideal treatment of PDA. Treatment options include conservative, pharmacologic, surgical management, and catheter closure.
Conservative PDA or “watchful waiting” is based on the premise that in most preterm infants the PDAs spontaneously close before discharge. It integrates various strategies to ease the degree of left-to-right ductal shunting without using active PDA closure with medical or surgical treatment.
Indomethacin and ibuprofen have been used for treating PDA. In recent times, acetaminophen has been recommended as an alternative to ibuprofen and indomethacin.
The safety and efficacy of these drugs are still being studied and no clear guidelines for management have been suggested.
This double blinded RCT study compared the conservative management recently favored with oral ibuprofen which is a standard treatment in our unit in terms of ductal closure and morbidity and mortality at discharge. As far as we know this is one of the few randomized control trials where a placebo is used, and watchful waiting of ductus closure is performed in preterm neonates with older gestational age.
The aim of this work is to compare oral Ibuprofen with placebo in PDA closure in preterm infants less than 34 weeks after one course of treatment.
This study was conducted on 80 preterm neonates with gestational age ≤ 34 weeks with a hemodynamically significant PDA. They were randomized into two groups: The treatment group and the placebo group.
Both groups received conservative therapy in the form of fluid restriction, PEEP, and/or diuretics. The treatment group received oral ibuprofen and the Placebo group received an oral placebo with the same dose.
Both groups were followed up according to our NICU protocols. Echocardiography was done on day 1 of recruitment (48-72 hours) and on day 5 of recruitment. The first echocardiography was done by a cardiologist and the following were by an experienced neonatologist (targeted neonatal echo).
The open-label option was only offered during the first week if there are concerns by the attending physician over the poor patient condition that was attributed to persistent PDA and only after meeting certain criteria like signs of pulmonary hyperperfusion and signs of systemic hypoperfusion in the form of prolonged use of inotropes or vasopressors or escalation of the doses
After Open Label, both groups were offered further management (Extended Therapy) in the form of oral ibuprofen or acetaminophen.
The patients were followed up regarding outcomes like duration of NICU admission, mortality and morbidities like NEC, gastrointestinal bleeding, intake of inotropes, detecting their types and duration, bronchopulmonary dysplasia, duration of respiratory support, IVH, and the Adverse effects of Ibuprofen.
The results of our study showed that the demographic data was comparable in both groups. The gestational age was comparable in both groups of our study, however, the patients in the placebo group showed an increase in the rate of closure with an increase in the gestational age.
The maternal data were comparable in both groups, however, the patients in the treatment group received more antenatal steroids (35% full course and 40% incomplete course) compared to the Placebo group (20% full course and 25% incomplete course). In the treatment group, antenatal steroids were associated with a higher incidence of ductal closure but were not proven in a univariate log regression analysis.
This study showed no significant differences between early medical treatment with Ibuprofen compared to placebo in ductal closure after the first course of treatment and the percentage of closure between the treatment group and placebo group after the first course of oral ibuprofen was 62.5% and 65% respectively.
The rate of spontaneous closure in our study was 65%. Open-label therapy during the first course of treatment was discouraged in this study, however, 5% of both groups met the open-label criteria. After the physicians were offered the open-label option at the end of the first course, they chose to give extended therapy to all the patients with failed closure with similar results in both groups. Thirty seven percent of the patients in the treatment group received extended therapy (30% in the form of 2nd course of Ibuprofen and 7.5% received Acetaminophen), and 35% of patients in the placebo group received the first course of treatment (20% received 1st course of Ibuprofen as rescue therapy and 15% received Acetaminophen).
In this study, the patients with failed ductal closure after medical treatment, extended therapy, and rescue therapy were not offered surgical or catheter closure due to their bad general condition. Three patients from the placebo group survived with hemodynamically insignificant open ductus and followed up in the cardiology clinic despite receiving rescue therapy.
Our results showed no difference in mortality or morbidity between the two groups. The Mortality rate in our study was 35% in both groups and our results showed a high mortality rate in the patients with failed closure in both groups
Both groups show no difference in the duration of hospitalization with a mean of 13.5 days in the treatment group and 14 days in the placebo group.
Our results show that there is no difference in different morbidities like BPD, NEC, and IVH between the treatment group and placebo group (p-values for all parameters > 0.05).
The rate of patients with BPD in this study is very low with only 2 patients that developed this complication one in each group and both with successful duct closure.
Both groups were comparable in the modes and duration of ventilation, however, those with failure of duct closure in both groups were more likely to be invasively ventilated than those with duct closure and were more likely to have received surfactant. The patients with failure of closure in the treatment group were also more likely to be intubated at 24 hours. However, the univariate and multivariate log regression results were non-significant.
Regarding GIT complications, the risk of NEC was the same in both study groups and did not increase with treatment failure and there was no difference in the duration to reach full feeds in both groups (p-values for all parameters > 0.05).
In this study, the placebo group showed an association between failure of treatment and increased feeding intolerance in a multivariate analysis.
There were three patients with GIT bleeding in the form of hematemesis one in the treatment group and two in the placebo group who received ibuprofen as rescue therapy.
No difference in both study groups regarding the incidence of IVH regardless of treatment outcome (p-value > 0.05).
Concerning the use of inotropes and vasopressors both groups were comparable. However, the placebo group used diuretics, vasopressors, and inotropes for a significantly longer (p value 0.041,0.053,0.013 respectively).
In this current study, both groups were comparable in patients with EOS and LOS (p-values for all parameters > 0.05). Also, the presence of sepsis didn’t change the closure rate in both groups, but the placebo group was associated with a higher risk of LOS in case of non-closure of the PDA in univariate analysis but was not significant in the multivariate analysis.
There was no rise in serum creatinine in both groups in this study.
In conclusion, conservative treatment is non-inferior to early medical treatment of hsPDA with oral ibuprofen in ductal closure after one course of treatment, mortality, and morbidities.