In critically ill children, severely altered pharmacokinetics may result in subtherapeutic β-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for β-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome. DESIGN:Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012(NCT02456974, -2019. Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis. SETTING:The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital. PATIENTS:One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillinclavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure.CONCLUSIONS: Subtherapeutic β-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.
BackgroundAccurate assessment of renal function is crucial in intensive care to guide therapy. Both acute kidney injury and augmented renal clearance (ARC) may compromise outcome. Common formulas to estimate glomerular filtration rate (GFR) are unreliable in critically ill adults.1 A comparison of a gold standard technique to assess GFR with these formula-based estimations has never been reported in pediatric intensive care (PICU) patients. Our aim was to evaluate the feasibility of measuring plasma iohexol clearance (CLIOHEX) for GFR assessment in critically ill children and to compare CLIOHEX with estimated GFR using the modified Schwartz formula (eGFRSchwartz).MethodsA prospective, interventional study was conducted at the PICU of the Ghent University Hospital, Belgium. Critically ill children without chronic kidney disease were included. After injection of a weight-dependent bolus of iohexol, serial blood samples (n=6) were taken over a 6-hours interval. CLIOHEX was compared to eGFRSchwartz. Correlation between both methods was assessed by a Pearson´s correlation coefficient (r).Bland-Altman plots were evaluated to assess bias and limits of agreement (LOA). ARC was defined as a GFR exceeding normal values for age plus two standard deviations.Results40 patients, median age 16 months (range 15 days -13,6 years), 72,5% males, were included. No adverse effects related to iohexol were observed. Median CLIOHEX was 121 ml/min/1.73m2 (range: 43–221 ml/min/1.73m2). ARC was present in 20 patients based on CLIOHEX. Median eGFRSchwartz was 81 ml/min/1.73m2 (range: 31–131 ml/min/1.73m2). Only 1 patient was identified with ARC by eGFRSchwartz. eGFRSchwartz was systematically lower than CLIOHEX. There was a good correlation between CLIOHEX and eGFRSchwartz (r = 0,69; p< 0,01). Bias was 34 ml/min/1.73m2 with LOA (-24,5; 93 ml/min/1.73m2)ConclusionCLIOHEX was safely used to measure true GFR in critically ill children. eGFRSchwartz systematically underestimates GFR, especially in patients with ARC and seems not reliable in this patient population.ReferenceBaptista JP, Neves M, Rodrigues L, Teixeira L, Pinho J, Pimentel J ( 2014) Accuracy of the estimation of glomerular filtration rate within a population of critically ill patients. J Nephrol. 27:403–410.Disclosure(s)Nothing to disclose
Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CL iohexol ) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CL iohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland-Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CL iohexol was measured in 98 patients. Mean CL iohexol (± SD) was 115 ± 54 ml/min/1.73m 2 . Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC-and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of − 18 ± 51% (95% confidence interval (CI) − 29; − 9), poor precision with 95% LoA from − 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58). Conclusion:In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings. ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022. What is Known: • Both acute kidney injury and augmented renal clearance may be present in PICU patients an...
IntroductionAugmented renal clearance(ARC) of hydrophilic drugs is frequent in PICU patients and warrants adjustment of standard dosing regimens to prevent therapeutic failure. Knowledge of patient-, disease- and therapy-related factors associated with ARC, would allow to predict before the start of treatment, which patients would benefit from higher drug doses. We aimed to identify predictors of ARC in critically ill children with normal serum creatinine(Scr) using iohexol plasma clearance (CLiohexol) to quantify renal function.MethodsWe performed a post hoc analysis of data collected from an interventional study conducted at our academic PICU, which measured glomerular filtration rate (GFR) by CLiohexol in patients with normal Scr. ARC was defined as GFR exceeding normal values for age plus 2 standard deviations. Multivariable logistic regression analysis was performed to identify predictors of ARC.ResultsGFR was measured in 85 patients, median age was 16 [IQR 5;89] months, 59% had a surgical profile. Median CLiohexol was 122[IQR 75;152] ml/min/1.73m2. Fourthy patients out of 85 (47%) expressed ARC. Postoperative status was identified as independent predictor of ARC (p=0.014, OR 4.253, 95%CI 1.338–13.517). However, in patients after cardiac surgery the odds of developing ARC were significantly lower (p=0.010, OR 0.163, 95%CI 0.041 –0.644). There was a trend suggesting more ARC in male patients and in those without need for vaso-active drugs, however, this was not statistically significant.ConclusionOur findings raise clinicians’ awareness about ARC potentially being present in children after major surgery. This knowledge allows to anticipate on enhanced elimination of drugs by using empirically adjusted dosing regimens immediately from the start of treatment.
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