A Population Pharmacokinetic Analysis to Study the Effect of Therapeutic Hypothermia on Vancomycin Disposition in Children Resuscitated From Cardiac Arrest.

OBJECTIVES: Limited data exist on the effects of therapeutic hypothermia on renal function and pharmacokinetics in pediatric patients after cardiac arrest. The objective was to describe the differences in vancomycin disposition in pediatric patients following cardiac arrest treated with either therapeutic hypothermia or normothermia using population pharmacokinetic modeling. DESIGN: Single-center, retrospective cohort study. SETTING: A tertiary care hospital pediatric and cardiac ICU. PATIENTS: Fifty-two pediatric patients (30 d to 17 yr old) who experienced a cardiac arrest, received vancomycin, and were treated with therapeutic hypothermia (32-34°C) or normothermia (36.3-37.6°C) between January 1, 2010, and September 30, 2014, were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data despite high variability due to the small sample size. The typical value of clearance in this study was 4.48 L/hr (0.19 L/hr/kg) for a normothermic patient weighing 70 kg and a glomerular filtration rate of 90 mL/min/1.73 m. Patients treated with normothermia but with reduced or poor renal function (≤ 90 mL/min/1.73 m) had up to an 80% reduction in vancomycin clearance compared to those with normal renal function (90-140 mL/min/1.73 m). Patients with normal renal function but treated with therapeutic hypothermia versus normothermia experienced up to 25% reduction in vancomycin clearance. Patients treated with therapeutic hypothermia and with poor renal function experienced up to an 84% reduction in vancomycin clearance. CONCLUSIONS: Patients receiving hypothermia and/or with decreased renal function had lower vancomycin clearances based on a retrospectively fitted two-compartment model in children who experience cardiac arrest.

Vancomycin Prescribing and Therapeutic Drug Monitoring in Children With and Without Acute Kidney Injury After Cardiac Arrest.

BACKGROUND: Acute kidney injury (AKI) commonly occurs after cardiac arrest. Those subsequently treated with vancomycin are at additional risk for drug-induced kidney injury. OBJECTIVE: We aimed to determine whether opportunities exist for improved drug monitoring after cardiac arrest. METHODS: This was a retrospective cohort study of children aged 30 days-17 years treated after cardiac arrest in an intensive care unit from January 2010 to September 2014 who received vancomycin within 24 h of arrest. Vancomycin dosing and monitoring were compared between those with and without AKI, with AKI defined as pRIFLE (pediatric risk, injury, failure, loss, end-stage renal disease) stage 2-3 AKI at day 5 using Schwartz formula-calculated estimated glomerular filtration rate (eGFR). RESULTS: Of 43 children, 16 (37%) had AKI at day 5. Age, arrest duration, median time to first vancomycin dose, and the number of doses before and time to first vancomycin concentration measurement were similar between groups. Children with AKI had higher initial vancomycin concentrations than those without AKI (median 16 vs. 7 mg/L; p = 0.003). A concentration was not measured before the second dose in 44% of children with AKI. Initial eGFR predicted day 5 AKI. In children with AKI, the initial eGFR was lower in those with than those without a concentration measurement before the second dose (29 mL/min/1.73 m2 [interquartile range (IQR) 23-47] vs. 52 [IQR 50-57]; p = 0.03) but well below normal in both. CONCLUSIONS: In children with AKI after cardiac arrest, decreased vancomycin clearance was evident early, and early monitoring was not performed universally in those with low initial eGFR. Earlier vancomycin therapeutic drug monitoring is indicated in this high-risk population.