Evidence map›Paper›PMID 31256150›Full record

ArticleNeonatology2019

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.

Laurent M A Favié, Floris Groenendaal, Marcel P H van den Broek, Carin M A Rademaker, Timo R de Haan, Henrica L M van Straaten, Peter H Dijk, Arno van Heijst, Sinno H P Simons, Koen P Dijkman and 10 more

Open access · hybridAbstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Neonatology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed, 2 pooled it
7.3field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

19 citing papers in PubMed, 2 syntheses or guidelines pooled it, 40 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 12 institutions in 2 countries.

Laurent M A FaviéDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands, L.M.A.Favie@umcutrecht.nl.
Floris GroenendaalDepartment of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
Marcel P H van den BroekDepartment of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
Carin M A RademakerDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Timo R de HaanDepartment of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Henrica L M van StraatenDepartment of Neonatology, Isala Clinics, Zwolle, The Netherlands.
Peter H DijkDepartment of Neonatology, Groningen University Medical Centre, Groningen, The Netherlands.
Arno van HeijstDepartment of Neonatology, Radboud University Medical Center-Amalia Children's Hospital, Nijmegen, The Netherlands.
Sinno H P SimonsDivision of Neonatology, Department of Pediatrics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
Koen P DijkmanDepartment of Neonatology, Máxima Medical Center Veldhoven, Veldhoven, The Netherlands.
Monique RijkenDepartment of Neonatology, Leiden University Medical Center, Leiden, The Netherlands.
Inge A ZonnenbergDepartment of Neonatology, VU University Medical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Filip CoolsDepartment of Neonatology, UZ Brussel - Vrije Universiteit Brussel, Brussels, Belgium.
Alexandra ZecicDepartment of Neonatology, University Hospital Gent, Gent, Belgium.
Johanna H van der LeePaediatric Clinical Research Office, Emma Children's Hospital, Academic Medical Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Debbie H G M NuytemansClinical Research Coordinator PharmaCool Study, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Frank van BelDepartment of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
Toine C G EgbertsDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Alwin D R HuitemaDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
on behalf of the PharmaCool study group
Utrecht University · NLAmsterdam UMC Location University of Amsterdam · NLRadboud University Nijmegen · NLAmsterdam UMC Location Vrije Universiteit Amsterdam · NLAmsterdam University Medical Centers · NLErasmus MC - Sophia Children’s Hospital · NLGhent University Hospital · BEIsala · NLLeiden University Medical Center · NLSt. Antonius Ziekenhuis · NLUniversity Medical Center Groningen · NLVrije Universiteit Brussel · BE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundPhenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance.

objectivesTo assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines.

methodsData were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs.

resultsData were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam.

conclusionsTherapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.

Indexed as

Hypothermia, InducedAnticonvulsantsAsphyxia NeonatorumDrug InteractionsDrug Therapy, CombinationFemaleHumansHypoxia-Ischemia, BrainInfant, NewbornMaleMetabolic Clearance RateMidazolamPhenobarbitalPractice Guidelines as TopicProspective StudiesAnticonvulsantsMidazolamPhenobarbitalHypoxic-ischaemic encephalopathyMidazolamNeonatesPharmacokineticsPhenobarbital

Identifiers

PMID31256150
PMCPMC6878731
OpenAlexW2955602757

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.