Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients?

Dhont, Evelyn; Heggen, Tatjana Van Der; Jaeger, Annick De; Walle, Johan Vande; Paepe, Peter De; Cock, Pieter De

doi:10.1007/s00467-018-4120-2

Cited by 63 publications

(66 citation statements)

References 123 publications

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“…This is in line with several studies in this review showing extremely high drug Cl and/or eGFR in this patient population [21,26,50,52]. A recent review by Dhont et al on ARC in children shows that time-dependent antibiotics, like β-lactam antibiotics, which require drug concentrations above an MIC-threshold for a prolonged period of time, could be at the highest risk for non-target attainment due to this phenomenon [9]. However, a correlation between ARC and subtherapeutic drug concentrations or clinical outcome could not be made due to multiple confounding factors that also contribute to subtherapeutic drug concentrations and adverse outcome of critically ill children.…”

Section: Discussionsupporting

confidence: 89%

“…This non-target attainment in critically ill patients is caused by pathophysiological changes in volume of distribution (Vd), protein binding and/ or drug clearance (Cl) [4][5][6]. Contrary to renal dysfunction, an increased renal clearance caused by hemodynamic alterations during critical illness, described as augmented renal clearance (ARC), is reported in up to 65% of critically ill adults [7,8] and children [9,10].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Background Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. Methods Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. Results 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. Conclusion The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Although lidocaine has shown to be an effective anticonvulsant, cardiac toxicity associated with plasma concentrations >9 mg/L have limited its wide scale use. 1 Previous studies from our group have proposed a dosing regimen for effective and safe lidocaine use in term and preterm neonates with plasma concentrations not exceeding 9 mg/L. 2,3 Aim The present study evaluated lidocaine use as anticonvulsant in neonates and prospectively validated the new dosing regimen.…”

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confidence: 98%

“…Background The past years augmented renal clearance (ARC), observed in the critically ill paediatric population, has received an increased attention by researchers due to its major impact on drug exposure. 1 Since a recent report demonstrated that the maturation of the glomerular filtration rate (GFR) in juvenile pigs is comparable to children, pigs may be a potential animal model to investigate the impact and mechanisms of ARC on drug pharmacokinetics (PK) in children. 2 In this pilot study, the contribution of intravenous (IV) fluid administration on the development of ARC was investigated in piglets.…”

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confidence: 99%

O16 Piglets as animal model to assess the contribution of fluid therapy to the development of augmented renal clearance in children

et al. 2019

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BackgroundThe past years augmented renal clearance (ARC), observed in the critically ill paediatric population, has received an increased attention by researchers due to its major impact on drug exposure.1 Since a recent report demonstrated that the maturation of the glomerular filtration rate (GFR) in juvenile pigs is comparable to children, pigs may be a potential animal model to investigate the impact and mechanisms of ARC on drug pharmacokinetics (PK) in children.2 In this pilot study, the contribution of intravenous (IV) fluid administration on the development of ARC was investigated in piglets.MethodsEight seven-week-old pigs underwent an experiment without fluid therapy and two consecutive fluid treatments as CRI of a 0.9% NaCl solution (3 mL/kg/h and 6 mL/kg/h) over 36 hours, each time combined with IV administration of a cocktail of renal markers after 4 and 24 h of fluid administration. This cocktail consisted of iohexol (64.7 mg/kg body weight (BW), Omnipaque 300®, marker for GFR) and para-aminohippuric acid (10 mg/kg BW, marker for effective renal plasma flow). To assess the impact of ARC on the PK of antimicrobials, amikacin (7,5 mg/kg BW, Amukin®) was administered after 24 h of fluid therapy. PK modelling was performed with Phoenix® WinNonlin®.ResultsGenerally, an increase in GFR was observed after fluid administration when compared to the GFR values observed without fluid administration. 4 and 2 out of 7 pigs demonstrated ARC after 4 h of a CRI at 3 mL/kg/h and 6 mL/kg/h, respectively. 4 out of 7 pigs displayed ARC after 24 h of a CRI at 3 mL/kg/h and 6 mL/kg/h. Similar results were obtained for amikacin clearance.ConclusionAn important effect of fluid therapy on the development of ARC was observed in juvenile pigs. Further research is necessary to confirm this results in critically ill children.ReferencesDhont E, et al. Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients? Pediatric Nephrology 2018.Gasthuys E, et al. Postnatal Maturation of the Glomerular Filtration Rate in Conventional Growing Piglets As Potential Juvenile Animal Model for Preclinical Pharmaceutical Research. Frontiers in Pharmacology 2017;8.Disclosure(s)This study was funded by the Special Research Fund of Ghent University (BOF16/DOC/285).

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“…The authors also simulated different dosages including 400 mg/kg/day (PIP) divided into four daily doses, but this schedule also did not affect the PTA. A possible, partial explanation could be augmented renal clearance of antibiotics observable in critically ill children, including those with febrile neutropenia, a factor not considered in the study, combined with a very short infusion time.…”

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confidence: 99%

Piperacillin‐tazobactam concentration target attainment in children with cancer

Saffioti

Mesini

Cangemi

et al. 2019

Pediatric Blood & Cancer

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tration target attainment in 482 PIP samples from 43 children treated for febrile neutropenia. 1 Patients received 5 min infusion of PIP/TAZ at 100 mg/kg q8h.This dosage provided subtherapeutic drug concentration and insufficient probability of target attainment (PTA). The authors also simulated different dosages including 400 mg/kg/day (PIP) divided into four daily doses, but this schedule also did not affect the PTA. A possible, partial explanation could be augmented renal clearance of antibiotics observable in critically ill children, including those with febrile neutropenia, 2,3 a factor not considered in the study, combined with a very short infusion time. A randomized controlled trial in adults demonstrated the inadequacy of the dose of 4.5 g (PIP/TAZ) q8h to attain 100% fT >MIC and also 50% fT >MIC, 4 while a study in pediatric oncology patients with febrile neutropenia showed that a 0.5-3 h infusion of 100 mg/kg of PIP obtained a plasma concentration of at least 16 mg/L in 86.5% and 100% of cases. 5 Partially in line with these results were those obtained in a Monte Carlo simulation for Pseudomonas aeruginosa infection using 400 mg/kg/day of PIP with a loading dose followed by continuous infusion. 6 At the Istituto Giannina Gaslini, Genoa, Italy, febrile neutropenic children with cancer receive PIP/TAZ at 100 mg/kg (PIP) q6h infused over 30-60 min. We collected 49 specimens for determination of PIP plasma concentrations by volumetric absorptive microsampling (VAMS TM )-LC-MS/MS. 7 The median (first to third quartile, interquartile range [IQR]) concentration was 42.5 mg/L (IQR 4.6-72.6) with a range of 0.9-190.0. The proportion of plasma concentrations >16 mg/L (minimally inhibitory concentration breakpoint of PIP for Enterobacteriales and Pseudomonas according to EUCAST rules) 8 was 71.4%.It is likely that with prolonged infusion (3 h), an effective therapeutic concentration could be obtained in all patients, with a very low likelihood of achieving concentrations that put patients at risk of neurotoxicity. 9 In any case, our "real-life" data and previous pediatric studies demonstrate that the correct dosage of PIP/TAZ in children with cancer is 1-3 h infusion of 100 mg/kg (PIP) q6h, or a schedule with a bolus followed by continuous infusion of the same total daily dose. CONFLICT OF INTERESTThe authors report no conflict of interest. ORCID Carolina Saffiotihttps://orcid.org/0000-0001-5336-0235Alessio Mesini https://orcid.org/0000-0003-0593-4112Elio Castagnola

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Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients?

Cited by 63 publications

References 123 publications

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

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

O16 Piglets as animal model to assess the contribution of fluid therapy to the development of augmented renal clearance in children

Piperacillin‐tazobactam concentration target attainment in children with cancer

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