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

Abstract

Objective Limited data exist on the effects of therapeutic hypothermia (TH) on renal function and pharmacokinetics in pediatric patients after cardiac arrest (CA). The objective was to describe the differences in vancomycin disposition in pediatric patients following CA treated with either TH or normothermia (NT) using population pharmacokinetic modeling. Design Single-center, retrospective cohort study Setting A tertiary care hospital pediatric and cardiac intensive care unit Patients Fifty-two pediatric patients (30 days to 17 years old) who experienced a CA, received vancomycin, and were treated with TH (32–34°C) or NT (36.3–37.6°C) between January 1st, 2010 and September 30th, 2014 were reviewed. Interventions None. Measurements/Results A two-compartment model with linear elimination, weight effects on clearance (CL), inter-compartmental 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/h (0.19 L/h/kg0.75) for a normothermic patient weighing 70kg and a glomerular filtration rate (GFR) of 90 mL/min/1.73m2. Patients treated with normothermia, but with reduced or poor renal function (≤90 mL/min/1.73m2) had up to an 80% reduction in vancomycin clearance compared to those with normal renal function (90–140 mL/min/1.73m2). Patients with normal renal function, but treated with TH versus NT experienced up to 25% reduction in vancomycin clearance. Patients treated with TH and with poor renal function experienced up to an 84% reduction in vancomycin clearance. Conclusion 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.

Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature

“…A logic next step seems to incorporate both age-and disease related co-variates in dosing guidelines using modelling and simulation. Most of the PopPK modelling studies in this review have incorporated (allometrically scaled) age and/or weight covariates in their final models [21,25,26,28,51,52,55,57,61,65]. However, models incorporating (bio) markers of organ failure (e.g.…”

“…eGFR, serum creatinin, albumin, C-reactive protein, transaminases) as covariate were limited [21,25,26,28,51,52,55,57]. Of the 48 studies, only 5 PK models have incorporated eGFR in their estimations for drug Cl [21,26,51,55,57] and only 3 additional studies found a significant relation between serum creatinine and drug concentration [29,45,60]. Other studies have either not investigated this relationship or found the addition of creatinine clearance to be non-significant.…”

“…A total of 17 studies reporting PK-parameters of vancomycin in critically ill children were identified by the search, with more than 1000 PICU patients included in total over the whole pediatric age range [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Most studies included a mixed population, but also specific populations (such as patients with hematologic/oncologic [43,45], cardiac [51,53,56,57], traumatic [50] and infectious diseases [44,48]) being studied separately. Four studies [42,43,46,48] were prospective PK studies and the remaining 13 studies were based on TDM data.…”

“…Other PK-parameters presented in several studies include Cl and Vd in 7 studies [43,45,46,48,51,52,57], with 2 studies reporting data on vancomycin t½ [48,52]. Mean Vd within each study ranged from 0.44 to 1.04 l/kg, with a median Vd among studies of 0.77 l/kg.…”

Untoward Effects in the Practice of Therapeutic Hypothermia: A Literature Update

“…Known effects of hypothermia include urinary diuresis, renal tubular dysfunction, reduced creatinine clearance and increased excretion of electrolytes which result in depletion of important elements [17,31,[48][49][50][51]. Zane et al recently published data on the differences in vancomycin disposition in pediatric patients following cardiac arrest treated with either TH or normothermia [52]. They noted that children receiving hypothermia and/or with decreased renal function had lower vancomycin clearances based on a retrospectively fitted twocompartment model in children who experience cardiac arrest.…”