Jasani B¹; Weisz D²; Giesinger R¹; Jain A³; McNamara PJ¹

¹Division of Neonatology, Hospital for Sick children, Toronto, ON, Canada ²Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada ³Paediatrics, Mount Sinai Hospital, Toronto, ON, Canada

Background:

Observational studies have suggested that high dose ibuprofen may be an alternative to standard dose ibuprofen for the closure of a hemodynamically significant ductus arteriosus (hsDA) in preterm infants. To determine the efficacy and safety of high dose ibuprofen compared with standard dose ibuprofen (10,5,5mg/kg/d) for closure of a hsDA in preterm infants.

Methods:

We conducted searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL in March 2018. We identified two randomised controlled trials (RCTs) and three observational studies that compared high dose to standard dose ibuprofen for the treatment of an echocardiographically diagnosed hsDA in preterm infants. Primary outcome was failure of ductal closure after first course of ibuprofen treatment. Secondary outcomes were rates of renal insufficiency, oliguria, hyperbilirubinemia, thrombocytopenia, NEC, sepsis, IVH, mortality, duration of hospital stay and levels of serum creatinine, bilirubin, platelets post treatment.

Results:

Two RCTs and three observational studies comparing high dose versus standard dose ibuprofen for treatment of hsDA that enrolled 309 infants were included. There was significant difference between treatment with high dose versus standard dose ibuprofen favouring high dose ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.64, 95% confidence interval (CI) 0.47 to 0.87; NNTB 6, typical RD -0.15, 95% CI -0.25 to -0.05; I2 = 59% for RR and I2 = 38% for RD). On sensitivity analysis after exclusion of observational studies, there was significant difference between treatment with high dose versus standard dose ibuprofen favouring high dose ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.27, 95% confidence interval (CI) 0.11 to 0.64; NNTB 4, typical RD -0.23, 95% CI -0.36 to -0.10; I2 = 35% for RR and I2 = 0% for RD). There were no significant differences between the paracetamol and the ibuprofen groups with regards to secondary outcomes.

Conclusions:

In comparison to standard dose ibuprofen, high dose ibuprofen appears to be more effective and safe in closure of hsDA in preterm infants.