Improved Closure of Patent Ductus Arteriosus With High Doses of Ibuprofen

Abstract

The patent ductus arteriosus (PDA) is associated with various complications of prematurity. Cyclooxygenase-inhibitors are the first-line intervention for closure of the PDA. However, the rates of PDA closure still are unsatisfactory. Therefore, an individual trial was performed by changing the strategy for treating neonates with ibuprofen to induce the closure of PDA. In a retrospective study, patients receiving 20, 10, and 10 mg/kg bodyweight ibuprofen (group 1) were compared by chart review with those receiving 10, 5, 5 mg/kg (group 2). The rate of PDA closure, the incidence of side effects related to the use of ibuprofen, and the need for surgical intervention for closure of the PDA were analyzed. A higher rate of closure after three doses in group 1 could be observed (60.9 vs 52.6%; p = 0.75), which was not significant but indicated a clear positive trend. If closure of the PDA was unsuccessful, intravenous ibuprofen was continued for an additional 2 days. After 5 days, 91.3% of PDA in group 1 was closed compared with 68.4% PDA in group 2. In summary, only 8.7% of the group 1 neonates needed surgical closure of PDA after insufficient medicamentous closure compared with 31.6% in group 2 (p = 0.25). Although not statistically significant, a clear positive trend for using the higher-dose medication can be seen. More work dealing with the limitations of a retrospective study must be done. Based on the data from this study, high-dose ibuprofen seems able to increase the rate of effective medicamentous PDA closure without any further unwanted side effects.

Educational paper: Do we need neonatal clinical pharmacologists?

“…Megalin, a low-density lipoprotein receptor in the renal proximal tubule and in the labyrinth epithelium, is involved in aminoglycoside accumulation and toxicity [20, 28]. Since aminoglycoside binding to proximal renal tubular and cochlear cells is saturable, strategies including the one pulse strategy and the shortening in duration of aminoglycoside treatment when combined with other antibiotics likely increase the anti-infectious efficacy and decrease the risk of toxicities in neonates[20, 30, 33]. Because renal tubular uptake capacity is not yet mature, nephrotoxicity related to accumulation by aminoglycoside is less pronounced in neonates when compared to other populations [20, 28].…”

“…After birth, modifications in prostaglandins, its receptors, and the postnatal increase in arterial oxygen tension results in muscular constriction with subsequent anatomic closure of the ductus [6, 14, 18, 30, 41, 46, 48]. These processes (constriction and closure) may be delayed or even fail in preterm infants.…”

“…From a clinical pharmacology perspective (Fig. 1), we would like to make the point that integration of the available knowledge on PK and PD of ibuprofen has not yet been optimized [6, 14, 18, 30, 41, 46, 48]. …”

“…However, the PK information on covariates (age, weight) has not yet been introduced in prospective studies—“one dose still seems to fit all neonates” [14, 18, 30]. …”

“…More recently, some groups introduced plasma biomarkers as a more valid indicator for symptomatic PDA. It is hereby striking that there was extensive variability in cutoff values between the different studies since the cutoff values of N-terminal fragment of pro-brain-type natriuretic peptide (NT-proBNP) varied with up to tenfold differences [6, 30, 48]. We claim that further evaluation of the impact of sample handling and validation of quantification methods are needed before such PDA biomarkers can be introduced in clinical care.…”