Cumulative Doses Predict the Risk of Furosemide-Induced Electrolyte Abnormalities in Critically Ill Neonates

Abstract

Background Furosemide has limited indications in the term neonates. Its use in preterm neonates is off-label. Considering the dearth of data, we carried out a retrospective study evaluating the furosemide use and its effects on the electrolyte abnormalities in critically ill neonates. Methods Critically ill neonates receiving at least one dose of furosemide during their stay in the NICU were recruited. The following details were obtained: demographic characteristics and furosemide details (dose, frequency, route, and duration). Urine output, body weight, serum creatinine, electrolytes (sodium, potassium, calcium, bicarbonate, chloride, and magnesium) during furosemide therapy were extracted. Results Ninety neonates were recruited. Elevated serum creatinine was observed in 21.1% of the patients, and electrolyte disturbances were observed in 52.2%. Those with electrolyte disturbances had significantly greater cumulative doses compared to those without [5.5 (1–34) vs 3.9 (0.9–30.2) mg/kg; p = 0.01]. Cumulative doses adjusted to body-weight were significantly lower in very preterm and extremely preterm neonates compared to late preterm category. A significant area-under-the-curve was observed for the cumulative dose (0.66; 95% CI: 0.54–0.78; p = 0.01) in predicting the risk of electrolyte abnormalities with a cut-off value of 4 mg/kg. Eight neonates received more than 10 mg/kg cumulative dose of furosemide of which one died. No significant differences were observed between the proportion of neonates with electrolyte disturbances with cumulative furosemide dose above 10 mg/kg ( p = 0.3) and with mortality ( p = 0.3). Conclusion We observed that our critically ill neonates received relatively higher cumulative doses of furosemide and electrolyte disturbances were observed in nearly half of the population. A cumulative dose of 4 mg/kg increases the risk of electrolyte abnormalities, particularly in preterm neonates. More diligence in the dose titration coupled with deprescribing and intense monitoring of all the potential adverse effects in this vulnerable population is needed.

Diuretic drug utilization in neonates: a French prescription database analysis

“…In our study, the rate of children with a furosemide treatment duration >14 days was 9.7%, and unfortunately, we do not have information on the follow-up of our cohort. There is a low rate of side effects in our cohort compared to other studies ( Gimpel et al, 2010 ; Sridharan et al, 2022 ). It is likely that reporting of side effects based on the Logipren ® database is underestimated, as it can only be done at the time of drug discontinuation, while the deleterious consequences of diuretic exposure (especially ototoxicity and nephrocalcinosis) can manifest several days or weeks post-treatment.…”

“…The cumulative dose of furosemide and the duration of exposure can be risk factors for adverse events. Previous research in small, single-center observational studies, has reported that patients experienced electrolyte disturbances after exposure to furosemide at a cumulative dose >4 mg/kg ( Sridharan et al, 2022 ), and newborns had a 48 times higher risk of developing nephrocalcinosis after exposure to furosemide at a cumulative dose >10 mg/kg ( Gimpel et al, 2010 ). We noticed that 43% of exposed patients in our study received a cumulative dose >4 mg/kg, and nearly a quarter received a dose >10 mg/kg.…”

“…This loop diuretic is often administered at doses higher than recommended ( Manfredini et al, 2020 ), and it is one of the most frequently prescribed off-label drugs in the neonatal intensive care unit (NICU) ( Krzyżaniak et al, 2016 ). Neonatal exposure to furosemide is associated to electrolyte disorders ( Sridharan et al, 2022 ) and nephrocalcinosis ( Gimpel et al, 2010 ). Furthermore, several studies report that exposure to high doses of furosemide is a risk factor for ototoxicity, even if the exact dose causing hearing loss has not been determined yet for newborn infants ( Wang et al, 2018 ; Manfredini et al, 2020 ; Khan et al, 2023 ).…”