Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Lutz, Isabelle Claire; Allegaert, Karel; Hoon, Jan N. de; Marynissen, Heleen

doi:10.1136/bmjpo-2020-000685

Cited by 28 publications

(24 citation statements)

References 83 publications

(94 reference statements)

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“…Renal elimination was reduced (from −25% up to −40%), as reflected by the reduced gentamicin clearance by 25-35.3% with a progressive trend to normalization after termination of WBH (>72 h after initiation of WBH). A similar pattern of decreased clearance (−40%) has been described for amikacin during WBH, or even up to −60% when these estimates were based on mannitol clearance data [22][23][24][25][26].…”

Section: Introduction: Perinatal Asphyxia Whole Body Hypothermia and Renal Impairmentsupporting

confidence: 68%

Creatinine Trends and Patterns in Neonates Undergoing Whole Body Hypothermia: A Systematic Review

et al. 2021

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Many neonates undergoing whole body hypothermia (WBH) following moderate to severe perinatal asphyxia may also suffer from renal impairment. While recent data suggest WBH-related reno-protection, differences in serum creatinine (Scr) patterns to reference patterns were not yet reported. We therefore aimed to document Scr trends and patterns in asphyxiated neonates undergoing WBH and compared these to centiles from a reference Scr data set of non-asphyxiated (near)term neonates. Using a systematic review strategy, reports on Scr trends (mean ± SD, median or interquartile range) were collected (day 1–7) in WBH cohorts and compared to centiles of an earlier reported reference cohort of non-asphyxia cases. Based on 13 papers on asphyxia + WBH cases, a pattern of postnatal Scr trends in asphyxia + WBH cases was constructed. Compared to the reference 50th centile Scr values, mean or median Scr values at birth and up to 48 h were higher in asphyxia + WBH cases with a subsequent uncertain declining trend towards, at best, high or high–normal creatinine values afterwards. Such patterns are valuable for anticipating average changes in renal drug clearance but do not yet cover the relevant inter-patient variability observed in WBH cases, as this needs pooling of individual Screa profiles, preferably beyond the first week of life.

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Section: Introduction: Perinatal Asphyxia Whole Body Hypothermia and Renal Impairmentsupporting

confidence: 68%

Creatinine Trends and Patterns in Neonates Undergoing Whole Body Hypothermia: A Systematic Review

et al. 2021

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“…Although TH has demonstrated to have beneficial effects on neurological outcomes, reducing a neonate’s body temperature may further affect physiological processes such as those involved in drug elimination [ 21 ]. The current study therefore aimed to quantify the impact of TH in addition to asphyxia on mannitol CL, as a surrogate for GFR.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Background Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderateto-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 ClinicalTrials.gov identifier NCT03162653.The ALBINO Study Group coordinating investigator names are present in Acknowledgements section.

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“…We do not know whether hyperactivity episodes impact different neuronal types that might be differently susceptible to the actions of PHB or MDZ. In clinical conditions, hypothermia, which is the most effective treatment of neonatal encephalopathy, alters clearance of PHB and MDZ to different degrees, shortening their efficacy 19 . MDZ has hypotensive effects that alter pharmacokinetics and has poor efficacy as a first‐ or second‐line AED after PHB 20 .…”

Section: Phb Mdz and Neonatal Seizures: Less Than Idealmentioning

confidence: 99%

Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details

Ben-Ari

Delpire

2021

Epilepsia

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Kaila, Löscher, and colleagues report that phenobarbital (PHB) and midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. However, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to γ‐aminobutyric acidergic (GABAergic) mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of antiepileptic drugs (AEDs) to treat this severe life‐threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM efficiently attenuates autism symptomatology notably in patients with tuberous sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.

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Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Cited by 28 publications

References 83 publications

Creatinine Trends and Patterns in Neonates Undergoing Whole Body Hypothermia: A Systematic Review

Creatinine Trends and Patterns in Neonates Undergoing Whole Body Hypothermia: A Systematic Review

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

Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details

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