Variability in neonatal gentamicin administration influencing drug delivery kinetics

Abstract

Introduction: Intravenous gentamicin is frequently prescribed for the empiric treatment of early-onset sepsis in premature neonates1. The effective delivery of gentamicin may be influenced by infusion rate and flush volume2. Additional parameters affecting drug delivery kinetics may include route of administration, background infusion rate and drug measurement variability which we aimed to further quantify in this study.

Methods: A self-administered questionnaire was completed by Dunedin hospital Neonatal Intensive Care Unit (NICU) nurses to investigate: the site of administration, comparing peripheral intravenous line (PIV) or umbilical venous catheter (UVC); and which would be used for a dose of gentamicin given two clinical scenarios describing babies of 24 and 32 weeks gestation. Secondary information was collected regarding flush volume. Intravenous infusions were then designed to simulate gentamicin delivery through UVCs with a constant background flow rate of 0.5 mL/hr. Intended doses of gentamicin (2 mg or 5 mg) in syringes were weighed before and after administration and given by bolus injection over 3-5 minutes followed by a flush of 0.9% saline (1 mL or 2 mL). Samples were collected at 5 minute intervals for 1 hour and analysed by high pressure liquid chromatography. Additionally, congo red dye (1% w/v) was used to mimic the drug administration phase during one replication of each dose/flush volume combination.

Results: There were 42 nurses employed in Dunedin NICU during the survey period, of whom 37 (88%) responded. For a 24-week gestation baby, 34 nurses (92%) would administer into the primary lumen (20 ga), containing 10% dextrose (0.5 mL/hr), compared to 3 (8%) who would use the secondary lumen (23 ga), containing parenteral nutrition fluid (2.1 mL/hr). For a 32-week gestation baby 35 nurses (95%) would administer through the slow-flowing primary lumen. If a PIV was present this would be used preferentially by 35 nurses (95%) to reduce the risk of infection. Smaller flush volumes were documented following administration through the UVC compared with PIV (1.17-1.35 mL vs 2.4 mL at 24 weeks and 1.42-1.74 mL vs 3.2 mL at 32 weeks). Complete recovery of 2 mg and 5 mg intended gentamicin doses was observed following administration of both 1 mL and 2 mL flush volumes when administered via a UVC. Of the 2.15 mg administered dose recovered when a 1 mL flush is used, 85% (standard deviation, SD, 3.1%) was collected by 10 minutes and 93% (SD 1.4%) over the first 30 minutes. When a 2 mL flush was given, 99% (SD 0.5%) of the 1.88 mg administered dose was recovered in 10 minutes. Following a 5 mg intended dose, 93 % (SD 3.4%) was recovered at 10 minutes and 97% (SD 2%) in 30 minutes after a 1 mL flush, compared to 99% (SD 0.6%) recovered at 10 minutes with a 2 mL flush.

Conclusion: Variability in neonatal gentamicin pharmacokinetics may be attributable to a number of factors. Clinical variability in the route of intravenous delivery was documented by means of a survey. Experimental evidence showed that simulated gentamicin delivery by bolus injection into slow-flowing neonatal central lines resulted in >90% dose recovery at 1 hour. Additionally, variation in the volumes of drug and flush prepared for administration, and retrograde flow of dye were observed.