Inge Zonnenberg

Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders

Background: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. Objectives: The aim of this study was to analyse complications and outcome after implementation. Methods: Data were retrieved from an online database to which all centres had contributed. Results: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. Conclusions: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.

A simple quantitative method analysing amikacin, gentamicin, and vancomycin levels in human newborn plasma using ion-pair liquid chromatography/tandem mass spectrometry and its applicability to a clinical study

Neuroprotective controlled therapeutic hypothermia is the standard of care for newborns suffering perinatal asphyxia. Antibiotic drugs, such as amikacin, gentamicin, and vancomycin are frequently administered during controlled hypothermia, which possibly alters their pharmacokinetic (PK) and pharmacodynamic (PD) profiles. In order to examine this effect an LC-MS/MS method for the simultaneous quantification of amikacin, the major gentamicin components (gentamicin C, C1a and C2), and vancomycin in plasma was developed. In 25μL plasma proteins were precipitated with trichloroacetic acid (TCA) and detection of the components was achieved using ion-pair reversed phase chromatography coupled with electrospray ionization tandem mass spectrometry. The chromatographic runtime was 7.5min per sample. Calibration standards were prepared over a range of 0.3-50mgL(-1) for amikacin and gentamicin and 1.0-100mgL(-1) for vancomycin. At LLOQ accuracy was between 103 and 120% and imprecision was less than 19%. For concentrations above LLOQ accuracy ranged from 98% to 102% and imprecision was less than 6%. Process efficiency, ionization efficiency, and recovery were acceptable. Samples and stock solutions were stable during the time periods and at the different temperatures examined. The applicability of the method was shown by analysing plasma samples from 3 neonatal patients. The developed method allows accurate and precise simultaneous quantification of amikacin, gentamicin, and vancomycin in a small volume (25μL) of plasma.

Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia

AIM(S) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively.

Severe Neonatal Anaemia, MRI Findings and Neurodevelopmental Outcome

Background and Objective: Severe neonatal anaemia can impair cerebral oxygen supply. Data on long-term outcomes following severe neonatal anaemia are scarce. Methods: Clinical data and neurodevelopmental outcome of 49 (near) term infants with haemoglobin concentration after birth <6.0 mmol/l were retrospectively collected and analysed. In a subgroup of 28 patients, amplitude-integrated EEG was available and in 25 infants cerebral MRI was obtained. Infants were followed up at 14-35 months of age and assessed with the Griffiths Scale of Mental Development or Bayley Scale of Infant Development. Results: Eighteen patients (37%) died during the neonatal period. In 25 patients MRI was performed. A predominant pattern of injury on MRI was seen in the basal ganglia and thalami in 7 patients (28%), whereas some form of white matter injury was present in 16 (64%) and a combination in 3 (12%). Follow-up data were available for 26 patients (84% of survivors). Formal assessment of neurodevelopmental outcome was performed in 20 of 31 (65%) infants who survived (median age: 19 months, range: 14-35). Sixteen infants (80%) had a developmental quotient appropriate for age in the first 2 years after birth. On motor outcome, 1 patient (5%) scored below average (Z-score -1.10). One patient developed cerebral palsy. Conclusion: Early neurodevelopmental outcome in surviving patients with severe neonatal anaemia was within the normal range in the majority of the survivors. MRI showed mild-to-moderate white matter injury in two thirds of the infants. Prospectively collected data with a longer follow-up period are needed.

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 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 33.5°C), 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 37.0°C. 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.

Cerebral ultrasound abnormalities in preterm infants caused by late-onset sepsis

Introduction This study describes cerebral ultrasound abnormalities caused by late-onset sepsis (LOS) in very preterm infants with a gestational age of < 32 weeks and/or birthweight < 1500 grams. Methods The prospective study (“INFANT study”) included 117 preterm infants with suspected LOS. Proven LOS was defined as a positive blood culture after 72 hours of life. In case of coagulase-negative staphylococci an elevated C-reactive protein was additionally required to establish proven LOS. Patients were identified as proven LOS and patients with only clinical symptoms of LOS. Cerebral ultrasound images were obtained in the first week after birth, during/after LOS and before discharge. Cerebral findings were divided in no/minor and major abnormalities. Results Eighty-six preterm infants had proven LOS and 31 preterm infants had only clinical signs of LOS. Four infants were excluded because pre-existing major brain abnormalities. No significant differences (p = 0.624) for incidence of major brain abnormalities on cerebral ultrasound were found. Conclusion No differences were revealed in prevalence of major brain abnormalities between the groups with proven LOS and with clinical signs of LOS. Both infants with a gram negative sepsis developed major brain abnormalities, whereas only two of 66 preterm infants coagulase-negative staphylococci sepsis developed major brain abnormalities.

OC21.07: *Additional value of advanced neurosonography and magnetic resonance imaging in fetuses at risk for brain damage

(>3) sonographic findings, respectively. PPV of major or multiple minor US abnormalities in case of symptomatic congenital infection were 80,0 % in fetuses or infants with congenital infection, and 61.5% when all exposed fetuses were considered, with a specificity of 95.7% and 98.1%, respectively. Conclusions: When fetal status is unknown, any US abnormality can only predict a symptomatic congenital infection in 41.3% of cases. The classification of US semiology as major and minor infectious criteria leads to increase US prediction performance of symptomatic congenital infection when major or multiple minor criteria are found.

Placental Histology After Minor Trauma in Pregnancy: A Pilot Study

Objective Trauma in pregnancy may cause placental abruption. Consequences of moderate placental injury on neurodevelopment are unknown. The aim was to evaluate placental histology after maternal trauma. Methods A prospective study was conducted at 2 tertiary medical centers in the Netherlands. Placentas from women exposed to maternal trauma ≥ 20 weeks’ gestational age were histologically examined. Neurological follow-up of the infants was performed at 1 year of age by means of Alberta Infant Motor Scale. Histological findings were compared to placentas from pregnancies without trauma. Principal Results Thirteen placentas were investigated in the trauma group. The control group consisted of 15 placentas. Placental pathology was seen more often in the trauma cases (11 of the 13) than in the controls (6 of the 15), P = .024. Neurological follow-up was normal. Conclusions In this small population, majority of the placentas showed pathology after minor trauma in pregnancy without consequences for neurodevelopment at 1 year.

Trauma in pregnancy, obstetrical outcome in a tertiary centre in the Netherlands

Abstract Purpose: To determine obstetrical outcome and predictive value of obstetrical symptoms and diagnostic examinations on adverse outcome after maternal trauma in pregnancy. Materials and methods: Retrospective study in a Dutch tertiary medical center, including women admitted for trauma in pregnancy between 1995 and 2005 and infants born from these pregnancies. Characteristics at trauma (type of trauma, severity) and obstetrical outcome were recorded, as well as prevalence and severity of trauma; prevalence of obstetrical symptoms and abnormal diagnostic examinations. Composite adverse obstetrical outcome was defined as fetal death, placental abruption, birth <37 weeks and/or birth weight <10th percentile. The predictive value of obstetrical symptoms or abnormal diagnostic tests on an adverse pregnancy outcome was analyzed (logistic regression analysis). Results: Trauma admissions occurred in 10 per 1000 deliveries. Injuries were non-severe in 147/159 (92%). Obstetrical symptoms and/or abnormal diagnostic tests were present in 64/159 (40%) and 12/159 (8%) respectively. Adverse pregnancy outcome was encountered in 17/80 cases, mainly preterm births (13/80 (16%)). Severe injuries were predictive for an adverse pregnancy outcome. Conclusions: We found a considerable rate of trauma during pregnancy. There was an increased risk for preterm birth and severity of injuries was predictive for adverse outcome.

Spectroscopic detection of brain propylene glycol in neonates: Effects of different pharmaceutical formulations of phenobarbital: Brain Propylene Glycol in Neonates

The first choice for treatment of neonatal convulsions is intravenous phenobarbital, which contains propylene glycol (PG) as a solvent. Although PG is generally considered safe, the dosage can exceed safety thresholds in neonates. High PG levels can cause lactic acidosis.