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Published on: November 11, 2014
Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian
Naïm Bouazza1,2,3, Gilles Cambonie4,5, Cyril Flamant6
1EA 7323, Université Paris Cité, Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte, Paris, France. naim.bouazza@aphp.fr.
Insights
Prophylactic acetaminophen effectively closes the patent ductus arteriosus (PDA) in extremely preterm infants. This treatment was well-tolerated, establishing a minimum effective intravenous dose for this vulnerable population.
Area of Science:
- Neonatal Medicine
- Pediatric Cardiology
- Pharmacology
Background:
- Patent ductus arteriosus (PDA) in preterm infants is linked to significant morbidity and mortality.
- Previous prophylactic treatments like indomethacin and ibuprofen have shown limited clinical benefits.
- Acetaminophen presents a potential alternative for PDA management in neonates.
Purpose of the Study:
- To determine the minimum effective dose of prophylactic intravenous acetaminophen for closing PDA in extremely preterm infants (23-26 weeks gestation).
- To evaluate the safety and tolerability of this acetaminophen regimen.
- To assess the impact on hemodynamics and hepatic function.
Main Methods:
- A multicenter, dose-finding trial utilizing a Bayesian continual reassessment method.
- Enrollment of infants aged ≤12 hours and 23-26 weeks gestation.
- Intravenous acetaminophen administered at four predefined dose levels, with PDA closure assessed via echocardiography or by day 7.
Main Results:
- Twenty-nine infants were analyzed; 20 received dose level 1 and 9 received dose level 2; no higher doses were needed.
- The estimated posterior probability of PDA closure was 67.6% for dose level 2.
- Overall, 65.5% of infants achieved ductus arteriosus closure by day 7, with no adverse effects on liver function or blood pressure.
Conclusions:
- The minimum effective intravenous acetaminophen dose for PDA closure in extremely preterm infants is 25 mg/kg loading dose followed by 10 mg/kg every 6 hours for 5 days.
- This acetaminophen regimen demonstrated good tolerability and safety in the studied population.
Background:
Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option.
Objective:
This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation.
Methods:
A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function.
Results:
A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment.
Conclusions:
Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04459117.
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