Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance

on behalf of the ALBINO Study Group

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Background: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. Objectives: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. Methods: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. Results: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). Conclusions: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. Trial Registration: identifier NCT03162653.

Original languageEnglish
Pages (from-to)897-906
Number of pages10
JournalClinical Pharmacokinetics
Issue number7
Early online date21 Feb 2021
Publication statusPublished - Jul 2021

Bibliographical note

Funding Information:
The ALBINO project is funded under the Horizon 2020 Framework EU Program call H2020-PHC-2015-two-stage, grant 667224. The research on the pharmacokinetics during whole body hypothermia (Karel Allegaert, Pieter Annaert, Anne Smits) is further supported by the iPREDICT project (FWO Senior research project, fundamental research, G0D0520N).

Funding Information:
The ALBINO coordinating investigators are Axel R. Franz (University Hospital T?bingen, T?bingen, Germany) and Mario R?diger (University Hospital CG Carus, Medizinische Fakult?t der TU Dresden, Dresden, Germany). The beneficiaries and national coordinators are Axel R. Franz and Christian F. Poets (T?bingen, Germany), Mario R?diger (Dresden, Germany), Manon Benders and Frank van Bel (Utrecht, the Netherlands), Karel Allegaert and Gunnar Naulaers (Leuven, Belgium), Dirk Bassler (Zurich, Switzerland), Katrin Klebermass-Schrehof (Vienna, Austria), Maximo Vento (Valencia, Spain), Hercilia Guimaraes (Porto, Portugal), Tom Stiris (Oslo, Norway), Isabella Mauro (Udine, Italy), Marjo Mets?ranta (Helsinki, Finland), Sampsa Vanhatalo (Helsinki, Finland), Jan Mazela (Poznan, Poland), Tuuli Metsvaht (Tartu, Estonia), and Yannique Jacobs (ACE Pharmaceuticals, Zeewolde, the Netherlands).

Publisher Copyright:
© 2021, The Author(s).


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