Reopening of the ductus arteriosus after closure with indomethacin: Importance of sustained effective indomethacin serum concentrations

Gál, Péter; Ransom, J. Laurence; Shaffer, Christopher L.; Smith, McCrae; Carlos, Rita Q.; Brown, Yvonne; Schall, Stewart A.

doi:10.1016/s0022-3476(96)80149-1

Cited by 5 publications

(1 citation statement)

References 2 publications

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“…Changes in the effect of prostaglandins and a nitric oxide-like vasodilator on ductal patency and/or increased drug clearance with inadequate plasma concentrations have been proposed as causes for NSAID inefficacy in closing PDAs in the premature neonatal subpopulation. 11,18,[75][76][77][78][79] The relative effectiveness of these two vasodilators changes after birth. As postnatal age advances, it is proposed that prostaglandins may play a small or no role at all in maintaining ductal patency.…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen Lysine for the Prevention and Treatment of Patent Ductus Arteriosus

Pai

Sakadjian²,

Puthoff

2008

Pharmacotherapy

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Approximately 70-80% of newborns less than 28 weeks' gestational age require pharmacologic and/or surgical intervention to close a hemodynamically significant patent ductus arteriosus (PDA). Indomethacin has been the pharmacologic treatment of choice and has also been used prophylactically in very premature neonates to prevent PDA. The drug, however, is associated with renal and gastrointestinal adverse effects. In July 2006, intravenous ibuprofen lysine became available in the United States for treatment of hemodynamically significant PDA. The mechanism of action for both indomethacin and ibuprofen lysine is through inhibition of prostaglandin synthesis, resulting in ductal constriction. Both drugs appear to be equally efficacious in closing echocardiographically confirmed PDA. Ibuprofen lysine has demonstrated significantly less effects on cerebral, renal, and mesenteric blood flow in premature neonates when compared with indomethacin. A transient but significant increase in serum creatinine concentration, decrease in urine output, and increase in frequency of oliguria were observed with indomethacin when compared with ibuprofen lysine. However, the rate of reopening of the ductus after pharmacologic closure and the need for rescue therapy were not different between the two drugs. In addition, no differences were noted in other outcomes such as frequency of intraventricular hemorrhage, necrotizing enterocolitis, or chronic lung disease, as well as in duration of mechanical ventilation and length of hospital stay. When administered prophylactically, ibuprofen lysine did not prevent intraventricular hemorrhage nor provide any neurodevelopmental benefits. In addition, ibuprofen lysine has not been adequately studied in neonates of 27 weeks' gestational age or younger. Ibuprofen lysine is as efficacious as indomethacin in treating hemodynamically significant PDA in neonates greater than 27 weeks' gestational age.

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Section: Discussionmentioning

confidence: 99%

Ibuprofen Lysine for the Prevention and Treatment of Patent Ductus Arteriosus

Pai

Sakadjian²,

Puthoff

2008

Pharmacotherapy

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Indomethacin Pharmacodynamics Are Altered by Surfactant: A Possible Challenge to Current Indomethacin Dosing Guidelines Created Before Surfactant Availability

et al. 2010

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The effect of surfactant administration for respiratory distress syndrome (RDS) on indomethacin (INDO) pharmacodynamics and dosing requirements for patent ductus arteriosus (PDA) closure and renal toxicity was evaluated. A 22-year prospective cohort study including 442 INDO-treated patients given 466 INDO treatment courses. The database included demographic information, medical problems, and medications. Neonates with a PDA confirmed by echocardiography were treated with INDO, 0.25-0.3 mg/kg. Subsequent INDO dosing was based on a combined pharmacokinetic/pharmacodynamic (PK/PD) approach. Data were fit to an Emax model and ANOVA was used to compare mean closure levels between groups. PDA closure was successful in 405 of 442 patients (91.6%) and in 434 of 466 treatment courses (93.1%) using an individualized PK/PD dosing approach. Renal toxicity was documented in 56 of 442 patients (12.7%) or 56 of 466 treatment courses (12.0%). Patients not treated with synthetic surfactant trended toward lower mean INDO concentrations at PDA closure compared to patients treated with synthetic surfactant (1.65 vs. 2.01 mg/l; P > 0.05) and significantly lower mean INDO concentrations at PDA closure compared to patients treated with natural surfactant (1.65 vs. 2.15 mg/l; P < 0.002). This requires an increased total dose of ~0.3 mg/kg or an individual dose increase of 0.1 mg/kg. Administration of natural or synthetic surfactant for RDS may increase the INDO concentrations and doses needed for PDA closure in premature infants.

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