Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

Haan, Timo R. de; Bijleveld, Yuma A.; Lee, Johanna H. van der; Groenendaal, Floris; Broek, Marcel P. H. van den; Rademaker, Carin M. A.; Straaten, H.L.M. van; Weissenbruch, Mirjam M. van; Vermeulen, R. Jeroen; Dijk, Peter H.; Dudink, Jeroen; Rijken, Monique; Heijst, Arno van; Dijkman, Koen P.; Gavilanes, Antonio W. D.; Kaam, Anton H. van; Offringa, Martin; Mathôt, Ron A. A.

doi:10.1186/1471-2431-12-45

Cited by 46 publications

(57 citation statements)

References 28 publications

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“…We show that hypothermia significantly decreases phenytoin metabolism and identified time window of greatest concern. Results should be confirmed and correlated with relevant clinical parameters in larger populations and in children receiving cooling for other conditions such as in the recently proposed PharmaCool multicenter study (41). …”

Section: Discussionmentioning

confidence: 80%

Therapeutic Hypothermia Decreases Phenytoin Elimination in Children with Traumatic Brain Injury*

Empey

Mendizábal

Bell

et al. 2013

Critical Care Medicine

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Objective Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurological injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome p450(CYP)-mediated drug metabolism and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by CYP2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of the study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe TBI. Design Pharmacokinetic analysis of subjects participating in a multicenter randomized Phase III study of therapeutic hypothermia for severe TBI. Setting Intensive care unit at the Children’s Hospital of Pittsburgh Patients Nineteen children with severe TBI. Interventions None Measurements and Main Results A total of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia- and 9 normothermia-treated children who were randomized to 48h of cooling to 32–33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and post-treatment periods(8 days). A trend towards elevated free phenytoin levels in the hypothermia group(p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism(Vmax) 4.6-fold(11.6 to 2.53 mg/h) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period. Conclusions Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe TBI leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.

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Section: Discussionmentioning

confidence: 80%

Therapeutic Hypothermia Decreases Phenytoin Elimination in Children with Traumatic Brain Injury*

Empey

Mendizábal

Bell

et al. 2013

Critical Care Medicine

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“…In total, 125 out of 187 newborns included in the PharmaCool Study 11 received amoxicillin during moderate hypothermia. Demographic and clinical characteristics, and samples drawn of the total-, index-, and validation datasets are presented in Table 1.…”

Section: Results Patientsmentioning

confidence: 99%

“…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). All newborns undergoing moderate hypothermia were eligible for inclusion.…”

Section: Methods Patientsmentioning

confidence: 99%

“…Data were collected from a multicenter prospective observational cohort study conducted in 10 Dutch and 2 Belgian NICUs (the "PharmaCool Study," 11 November 2010 until October 2014). 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.…”

Section: Methods Patientsmentioning

confidence: 99%

“…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.…”

Section: What This Study Adds To Our Knowledgementioning

confidence: 99%

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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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Pharmacological interventions for pain and sedation management in newborn infants undergoing therapeutic hypothermia

Bäcke

Bruschettini

Sibrecht

et al. 2021

Cochrane Database of Systematic Reviews

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Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

Cited by 46 publications

References 28 publications

Therapeutic Hypothermia Decreases Phenytoin Elimination in Children with Traumatic Brain Injury*

Therapeutic Hypothermia Decreases Phenytoin Elimination in Children with Traumatic Brain Injury*

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Pharmacological interventions for pain and sedation management in newborn infants undergoing therapeutic hypothermia

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