Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders

Groenendaal, Floris; Casaer, Alexandra; Dijkman, Koen P.; Gavilanes, Antonio Wd; Haan, Timo R. de; Horst, Henk J. ter; Laroche, Sabrina; Naulaers, Gunnar; Rijken, Monique; Straaten, H.L.M. van; Steiner, Katerina; Swarte, Renate; Zecic, Alexandra; Zonnenberg, Inge A.

doi:10.1159/000348823

Cited by 74 publications

(69 citation statements)

References 24 publications

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“…According to national protocol, 35 term newborns were cooled within 6 h after birth to a core TEMP of 33.58C for 72 h if they met the criteria of perinatal asphyxia and ensuing encephalopathy. 11 Thereafter, patients were slowly (0.48C/h) rewarmed to normothermia (378C).…”

Section: Methods Patientsmentioning

confidence: 99%

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Bijleveld

Mathôt

Lee

et al. 2017

Clin Pharma and Therapeutics

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The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N 5 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.58C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.08C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively. Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ To date, there are no data on the effect of moderate hypothermia on the pharmacokinetics (PK) of amoxicillin in term neonates. Only few studies have been performed to evaluate the PK of this antibiotic in noncooled (pre)term neonates. WHAT QUESTION DID THIS STUDY ADDRESS? þ To our knowledge, this is the first prospective study evaluating and describing the PK of amoxicillin during all phases of controlled hypothermia in newborns, e.g., the hypothermic, rewarming, and normothermic phases.WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ A description of the PK properties of amoxicillin in term newborns with hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia receiving hypothermia treatment. Gestational age (GA), postnatal age (PNA), urine output, and body temperature were significant covariates on amoxicillin clearance (Cl). HOW THIS MIGHT CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE þ Based on the newly developed PK-model, we advise an amoxicillin dosing regimen of 50 or 75 mg/kg/24h in three doses for patients with GA 36 or GA 38-42 weeks, respectively.Term neonates who experience a severe hypoxic-ischemic insult during birth and develop encephalopathy are treated with hypothermia.1,2 This improves long-term outcomes and reduces mortality rates.2-9 These patients may suffer from early-onset sepsis with Streptococcus agalactiae (incidence rate 0.43% (95% confidence interval (CI) 0.37-0.49)), while Listeria monocytogenes should also be considered.10 Because asphyxia due to infection is difficult to distinguish from asphyxia without infection, antibiotics, such as amoxicillin, are frequently used.11 For efficacy, as a surrogate marker, the time that the nonprotein-bound concentration in blood exceeds the minimum inhibitory concentration (T>MIC) should be at least 40-50% in these patients.12 Although b-lactam antibiotics such as amoxicillin are considered safe due to the wide therapeutic range, excessive accumulation can lead to the development of adverse drug events, such as seizures and crystalluria. 13Despi...

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Section: Methods Patientsmentioning

confidence: 99%

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Bijleveld

Mathôt

Lee

et al. 2017

Clin Pharma and Therapeutics

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“…Term newborns were eligible for inclusion if they had severe perinatal asphyxia followed by neonatal encephalopathy, qualifying for treatment with hypothermia as published recently [11]. They received midazolam for seizure control (second line) according to the standard protocol of the Dutch-Flemish Working Group on Neonatal Neurology, or for sedation.…”

Section: Methodsmentioning

confidence: 99%

Anticonvulsant Effectiveness and Hemodynamic Safety of Midazolam in Full-Term Infants Treated with Hypothermia

et al. 2015

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Background: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients. Objectives: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance. Methods: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia. Results: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%. Conclusions: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia.

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“…Perinatal brain injury often results in severe and long-lasting disabilities, like motor deficits, seizures and severe cognitive, psychological and behavioral problems, which represent an enormous burden for the child, its parents and society [1,2,3]. Importantly, the risk of developing neonatal encephalopathy is strongly increased after maternal intrapartum fever or other antenatal inflammatory conditions like chorioamnionitis [4,5,6,7].…”

Section: Introductionmentioning

confidence: 99%

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

Bonestroo¹,

Heijnen²,

Groenendaal

et al. 2015

Dev Neurosci

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Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.

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Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders

Cited by 74 publications

References 24 publications

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Anticonvulsant Effectiveness and Hemodynamic Safety of Midazolam in Full-Term Infants Treated with Hypothermia

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

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