Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies

Abstract

Background: We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).

Methods: Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.

Results: Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05).

Conclusion: The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

Figure 1

Paracetamol-induced constriction of the ex vivo ductus arteriosus. The ductus arteriosus (arrow) of fetal mice (a) was sharply excised from surrounding tissues. The ductus of term (day 19) and preterm (day 15) fetuses were removed along with a vascular segment extending from the base of the pulmonary artery to the transverse aortic arch (b) (shown with 100 μm dissecting pins). This vascular bloc was mounted on glass pipette tips and secured by tying back the branch pulmonary arteries and the aortic arch, in order to isolate the entire length of the ductus for myography studies (c). Pressure myography was performed to study ductus tone and examine drug-induced changes in lumen diameter (d). After pressurization and equilibration, mounted vessels were briefly exposed to 50 mmol/l KCl to verify contractile potential, then allowed to return to baseline tone. Cumulative exposure to increasing paracetamol demonstrated concentration-dependent constriction of the day 19 ductus (d). Constricted vessels were then exposed to sodium nitroprusside, a potent nitric oxide donor, to document vasodilatory capacity. Terminal exposure to KCl ensured viability of the preparation at the end of each experiment.

Figure 2

Response of the ex vivo ductus arteriosus to paracetamol and indomethacin. The isolated ductus of preterm mice (a) displayed limited response to increasing concentrations of paracetamol (black squares, n = 12) whereas indomethacin (white circles, n = 12) induced a modest, significant constriction (*P < 0.05). The isolated ductus of term gestation mice (b) showed significant concentration-dependent constriction in response to either drug (**P < 0.01). Indomethacin (white circles, n = 9) was more effective than paracetamol (black squares, n = 9) at term gestation (^†P < 0.001). Each drug was more potent at term than preterm gestation (P < 0.01). Mean ± SEM.

Figure 3

Inhibition of ductus arteriosus prostaglandin synthesis. Freshly isolated term gestation ductus explants were incubated in the presence of drug or the appropriate vehicle. Prostaglandin synthetic activity was measured by the formation of 6-keto PGF1α, the stable metabolite of prostacyclin (PGI2) (a), or PGE2 (b) after exposure to exogenous 2 μmol/l arachidonic acid for 40 min. Vessels treated with paracetamol (Para) had insignificant reduction in prostaglandin synthesis compared to vehicle (water). Indomethacin-treated vessels (Indo) produced significantly less PGI2 and PGE2 compared to controls (ethanol). *P < 0.01.