Skin color influences transcutaneous bilirubin measurements: a systematic in vitro evaluation.

OBJECTIVE: Concerns have been raised about the effect of skin color on the accuracy of transcutaneous bilirubin (TcB) measurements, a widely used method for hyperbilirubinemia diagnosis in newborns. Literature is inconclusive, with both reported under- and overestimations of the TcB with increasing skin pigmentation. Therefore, the influence of skin color on TcB measurements was systematically evaluated in a controlled, in vitro setting. METHODS: A bilirubin meter (JM-105) was evaluated on layered phantoms that mimic neonatal skin with varying dermal bilirubin concentrations (0-250 µmol/L) and varying epidermal melanosome volume fractions (0-40%; light-dark skin color). RESULTS: TcB measurements were influenced by skin pigmentation. Larger mimicked melanosome volume fractions and higher bilirubin levels led to larger underestimations of the measured TcB, compared to an unpigmented epidermis. In the in vitro setting of this study, these underestimations amounted to 26-132 µmol/L at a TcB level of 250 µmol/L. CONCLUSION: This in vitro study provides insight into the effect of skin color on TcB measurements: the TcB is underestimated as skin pigmentation increases and this effect becomes more pronounced at higher bilirubin levels. Our results highlight the need for improved TcB meter design and cautious interpretation of TcB readings on newborns with dark skin. IMPACT: Key message: Skin color influences transcutaneous bilirubin measurements: the darker the skin, the larger the underestimation. What this study adds to existing literature: Existing literature is inconclusive regarding the influence of skin color on transcutaneous bilirubin measurements. This study systematically evaluates and clarifies the influence of skin color on transcutaneous bilirubin measurements in a controlled, in vitro setting. IMPACT: This study aids to better interpret the measured TcB level in patients with varying skin colors, and is particularly important when using TcB meters on patients with dark skin colors.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia.

BACKGROUND: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH. METHODS: The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed. RESULTS: The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters. CONCLUSIONS: The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.

Quantification of cephalocaudal progression of jaundice in preterm infants.

BACKGROUND: The cephalocaudal progression (CCP) of neonatal jaundice is a well-known phenomenon, but quantitative information on CCP in preterm infants is absent. In this study, CCP was quantified in preterm infants as a function of postnatal age and body location. METHODS: 5.693 transcutaneous bilirubin (TcB) measurements were performed in 101 preterm infants from birth until postnatal day seven at five body locations (forehead, sternum, hipbone, tibia, ankle). Multi-level linear regression analysis was performed to evaluate the CCP as a function of body location and postnatal age. TcB measurements at all body locations and postnatal days were compared to total serum bilirubin (TSB) levels (N = 1.113). RESULTS: The overall average change in ratio of TcB compared to forehead was for sternum +0.04 [95% CI -0.02;0.09]; hipbone +0.05 [0.00;0.01]; tibia -0.33 [-0.38;-0.27] and ankle -0.62 [-0.68;-0.57]. No effect modification of CCP by sex, gestational age, birthweight, phototherapy, and TSB was found. The TcB maximally underestimated the TSB at the ankle -79.5 µmol [-0.1;159.2]. CONCLUSIONS: CCP is present in preterm infants and is relatively stable over time. Since TcB measurements on the tibia and ankle underestimate TSB significantly, we advise to use only measurement locations cephalic from the tibia; i.e., hipbone, sternum, and forehead. IMPACT: Cephalocaudal progression (CCP) of jaundice in preterm infants, assessed by transcutaneous bilirubin (TcB) measurements, is substantial and rather stable over postnatal day 0 to 7. To the best of our knowledge, this study is the first to investigate CCP of jaundice in preterm infants as a function of postnatal age in preterm infants. Our results demonstrate that TcB measurements at the tibia and ankle differ from the TSB beyond the clinically used TcB safety margins. We advise to perform TcB measurements only at locations cephalic from the tibia; i.e., hipbone, forehead, and sternum.

Irradiance footprint of phototherapy devices: a comparative study.

BACKGROUND: Phototherapy (PT) is the standard treatment of neonatal unconjugated hyperbilirubinemia. The irradiance footprint, i.e., the illuminated area by the PT device with sufficient spectral irradiance, is essential for PT to be effective. Irradiance footprint measurements are not performed in current clinical practice. We describe a user-friendly method to systematically evaluate the high spectral irradiance (HSI) footprint (illuminated area with spectral irradiance of ≥30 µW cm-2 nm-1) of PT devices in clinical practice. MATERIALS AND METHODS: Six commercially available LED-based overhead PT devices were evaluated in overhead configuration with an incubator. Spectral irradiance (µW cm-2 nm-1) and HSI footprint were measured with a radiospectrometer (BiliBlanket Meter II). RESULTS: The average measured spectral irradiance ranged between 27 and 52 µW cm-2 nm-1 and HSI footprint ranged between 67 and 1465 cm2, respectively. Three, two, and one PT devices out of six covered the average BSA of an infant born at 22, 26-32, and 40 weeks of gestation, respectively. CONCLUSION: Spectral irradiance of LED-based overhead PT devices is often lower than manufacturer's specifications, and HSI footprints not always cover the average BSA of a newborn infant. The proposed measurement method will contribute to awareness of the importance of irradiance level as well as footprint measurements in the management of neonatal jaundice. IMPACT: While a sufficient spectral irradiance footprint is essential for PT to be effective, some PT devices have spectral irradiance footprints that are too small to cover the entire body surface area (BSA) of a newborn infant. This study introduces a user-friendly, accessible method to systematically evaluate the spectral irradiance level and footprint of PT devices. This study supports awareness on the role of the spectral irradiance footprint in the efficacy of PT devices. Irradiance footprint can be easily measured during phototherapy with the proposed method.

Inter-device reproducibility of transcutaneous bilirubin meters.

BACKGROUND: Transcutaneous bilirubinometry is a widely used screening method for neonatal hyperbilirubinemia. Deviation of the transcutaneous bilirubin concentration (TcB) from the total serum bilirubin concentration (TSB) is often ascribed to biological variation between patients, but variations between TcB meters may also have a role. This study aims to provide a systematic evaluation of the inter-device reproducibility of TcB meters. MATERIALS AND METHODS: Thirteen commercially available TcB meters (JM-105 and JM-103) were evaluated in vitro on phantoms that optically mimic neonatal skin. The mimicked TcB was varied within the clinical range (0.5-181.3 µmol/L). RESULTS: Absolute differences between TcB meter outcomes increased with the measured TcB, from a difference of 5.0 µmol/L (TcB = 0.5 µmol/L phantom) up to 65.0 µmol/L (TcB = 181.3 µmol/L phantom). CONCLUSION: The inter-device reproducibility of the examined TcB meters is substantial and exceeds the specified accuracy of the device (±25.5 µmol/L), as well as the clinically used TcB safety margins (>50 µmol/L below phototherapy threshold). Healthcare providers should be well aware of this additional uncertainty in the TcB determination, especially when multiple TcB meters are employed in the same clinic. We strongly advise using a single TcB meter per patient to evaluate the TcB over time. IMPACT: Key message: The inter-device reproducibility of TcB meters is substantial and exceeds the clinically used TcB safety margins. What this study adds to existing literature: The inter-device reproducibility of transcutaneous bilirubin (TcB) meters has not been reported in the existing literature. This in vitro study systematically evaluates this inter-device reproducibility. IMPACT: This study aids in a better interpretation of the measured TcB value from a patient and is of particular importance during patient monitoring when using multiple TcB meters within the same clinical department. We strongly advise using a single TcB meter per patient to evaluate the TcB over time.

Randomized Controlled Early versus Late Ventricular Intervention Study in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years.

OBJECTIVE: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability. STUDY DESIGN: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores <-2 SDs at 24 months corrected age. RESULTS: Outcomes were assessed in 113 of 126 infants. The composite adverse outcome was seen in 20 of 58 infants (35%) in the low threshold group and 28 of 55 (51%) in the high threshold (P = .07). The low threshold intervention was associated with a decreased risk of an adverse outcome after correcting for gestational age, severity of intraventricular hemorrhage, and cerebellar hemorrhage (aOR, 0.24; 95% CI, 0.07-0.87; P = .03). Infants with a favorable outcome had a smaller fronto-occipital horn ratio (crude mean difference, -0.06; 95% CI, -0.09 to -0.03; P < .001) at term-equivalent age. Infants in the low threshold group with a ventriculoperitoneal shunt, had cognitive and motor scores similar to those without (P = .3 for both), whereas in the high threshold group those with a ventriculoperitoneal shunt had significantly lower scores than those without a ventriculoperitoneal shunt (P = .01 and P = .004, respectively). CONCLUSIONS: In a post hoc analysis, earlier intervention was associated with a lower odds of death or severe neurodevelopmental disability in preterm infants with progressive posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen.

AIMS: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. METHODS: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. RESULTS: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. CONCLUSION: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.

Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial.

OBJECTIVE: To compare the effect of early and late intervention for posthemorrhagic ventricular dilatation on additional brain injury and ventricular volume using term-equivalent age-MRI. STUDY DESIGN: In the Early vs Late Ventricular Intervention Study (ELVIS) trial, 126 preterm infants ≤34 weeks of gestation with posthemorrhagic ventricular dilatation were randomized to low-threshold (ventricular index >p97 and anterior horn width >6 mm) or high-threshold (ventricular index >p97 + 4 mm and anterior horn width >10 mm) groups. In 88 of those (80%) with a term-equivalent age-MRI, the Kidokoro Global Brain Abnormality Score and the frontal and occipital horn ratio were measured. Automatic segmentation was used for volumetric analysis. RESULTS: The total Kidokoro score of the infants in the low-threshold group (n = 44) was lower than in the high-threshold group (n = 44; median, 8 [IQR, 5-12] vs median 12 [IQR, 9-17], respectively; P < .001). More infants in the low-threshold group had a normal or mildly increased score vs more infants in the high-threshold group with a moderately or severely increased score (46% vs 11% and 89% vs 54%, respectively; P = .002). The frontal and occipital horn ratio was lower in the low-threshold group (median, 0.42 [IQR, 0.34-0.63]) than the high-threshold group (median 0.48 [IQR, 0.37-0.68], respectively; P = .001). Ventricular cerebrospinal fluid volumes could be calculated in 47 infants and were smaller in the low-threshold group (P = .03). CONCLUSIONS: More brain injury and larger ventricular volumes were demonstrated in the high vs the low-threshold group. These results support the positive effects of early intervention for posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.

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 36­40 weeks and GA 42 weeks, respectively.

Hearing loss by week of gestation and birth weight in very preterm neonates.

OBJECTIVE: To gain insight into health and related costs associated with very preterm births, one needs accurate information about the prevalence of the disabling conditions, including neonatal hearing loss (NHL). STUDY DESIGN: We assessed the prevalence of NHL by week of gestation and categories of birth weight in very preterm neonates. Results of the 2-stage Automated Auditory Brainstem Response nationwide Newborn Hearing Screening Program in Dutch Neonatal Intensive Care Units and diagnostic examinations were centrally registered between October 1998 and December 2012 and included in this study. NHL was defined as impaired when the neonate conventional Auditory Brainstem Response level exceeded 35 dB near Hearing Level at diagnostic examination. Birth weight was stratified into <750 g, 750-999 g, 1000-1249 g, 1250-1499 g, and ≥ 1500 g, and by small for gestational age (SGA; <10th percentile) vs appropriate for gestational age. Logistic regression analyses and recursive partitioning were performed. RESULTS: In total, 18,564 very preterm neonates were eligible. The prevalence of NHL consistently increased with decreasing week of gestation (1.2%-7.5% from 31 to 24 weeks) and decreasing birth weight (1.4%-4.8% from ≥ 1500 g to <750 g, all P < .002). Most vulnerable to NHL were girls <28 weeks, boys <30 weeks, and SGA neonates. The SGA effect started at 27 weeks. CONCLUSIONS: Gestational age and birth weight quantify the risk of NHL. This information can be used at the individual level for parent counseling and at the population level for medical decision making.

Glucosuria as an early marker of late-onset sepsis in preterms: a prospective cohort study.

BACKGROUND: Early and accurate diagnosis of late-onset sepsis (LONS) in preterm infants is difficult since presenting signs are subtle and non-specific. Because neonatal sepsis may be accompanied by glucose intolerance and glucosuria, we hypothesized that glucosuria may be associated with LONS in preterms, in an early stage. We aim to evaluate the association of glucosuria and late-onset neonatal sepsis (LONS) in preterm infants, in an attempt to improve early and accurate diagnosis of LONS. METHODS: We performed a prospective observational cohort study in 316 preterms (<34 weeks). We daily measured glucosuria and followed patients for occurrence of LONS, defined as clinical and blood culture-proven sepsis occurring after 72 h. Attending physicians were blinded to glucosuria results. We assessed the diagnostic value of glucosuria for clinical and blood culture-proven LONS using logistic regression analysis. RESULTS: Glucosuria was found in 65.8% of 316 preterm patients, and sepsis was suspected 157 times in 123 patients. LONS was found in 47.1% of 157 suspected episodes. The presence of glucosuria was associated with LONS (OR 2.59, 95% CI 1.24-5.43, p = 0.012) with sensitivity 69.0% and specificity 53.8% (Likelihoodratio 1.49). After adjustment for gestational age, birth weight, and postnatal age, this association weakened and was no longer significant (adjusted OR 2.16; 95% CI 0.99-1.85, p = 0.055). An increase in glucosuria 48-24 h before onset of symptoms was not associated with LONS. CONCLUSION: In preterms glucosuria is associated with LONS within 24 h, however this association is too weak to be of diagnostic value.

An eight-year follow-up on auditory outcomes after neonatal hearing screening.

OBJECTIVE: The aim of this study is to assess the neonatal click Auditory Brainstem Response (ABR) results in relation to the subsequently determined mean hearing loss (HL) over 1, 2 and 4 kHz, as well as over 2 and 4 kHz. METHODS: Between 2004-2009, follow-up data were collected from Visual Reinforcement Audiometry (VRA) at 1 and 2 years and playaudiometry at 4 and 8 years of newborns who had failed neonatal hearing screening in the well-baby clinics and who had been referred to a single Speech and Hearing center. Hearing Level data were compared with ABR threshold-levels established during the first months of life. The Two One-Sided Tests equivalence procedure for paired means was applied, using a region of similarity equal to 10 dB. RESULTS: Initially, in 135 out of 172 children referred for diagnostic procedures hearing loss was confirmed in the neonatal period. In 106/135 of the HL children the eight-year follow-up was completed. Permanent conductive HL was established in 5/106 cases; the hearing thresholds were predominantly stable over time. Temporary conductive HL was found in 48/106 cases and the loss disappeared by 4 years of age at the latest. Sensorineural hearing loss (SNHL) was found in 53/106 cases, of which 13 were unilateral and 40 bilateral. ABR levels were equivalent (within a 10 dB range) to VRA levels at age 1 and 2 and play audiometry levels at age 4 and 8, both when VRA and play audiometry were averaged over both frequency ranges. CONCLUSION: Long term follow-up data of children with SNHL suggest that the initial click ABR level established in the first months of life, are equivalent to the hearing threshold measured at the age of 1, 2, 4 and 8 years for both mean frequency ranges. Click ABR can reliably be used as starting point for long-term hearing rehabilitation.

Neonatal posterior cerebral artery stroke: clinical presentation, MRI findings, and outcome.

AIM: To report the clinical presentation, magnetic resonance imaging (MRI) findings, and follow-up data of newborn infants with perinatal arterial ischemic stroke in the territory of the posterior cerebral artery (PCA). METHOD: Data on 18 newborn infants from three neonatal intensive care units (11 males, seven females) with an MRI-confirmed PCA stroke were analysed and reported. Infants were born at a mean gestational age of 38.7 weeks (SD 3.4) with a mean birthweight of 3244g (SD 850). RESULTS: Fourteen infants presented with clinical seizures. Five of these had associated hypoxic-ischemic encephalopathy, four had hypoglycaemia, and five had neither hypoxic-ischemic encephalopathy nor hypoglycaemia. Subclinical seizures were present in one infant with hypoxic-ischemic encephalopathy and one with meningitis. One preterm infant presented with apnoeas and one had hypoxic-ischemic encephalopathy without seizures. Neurodevelopmental follow-up of 17 children at a median age of 36 months (SD 28, range 12-120mo) showed five with a global delay. Two children with additional injury developed postneonatal epilepsy and one child with extensive injury developed hemiplegia. A visual field defect was observed in nine children (six hemianopia, three quadrantanopia). In the 11 children with a second MRI at 3 months, the asymmetry of the optic radiation correlated with the development of a visual field deficit. INTERPRETATION: Outcome after PCA stroke is fairly good, depending on additional brain injury. Follow-up is required, as subsequent visual field defects are frequently observed. Further research will be needed to clarify the role of hypoglycaemia in perinatal arterial ischemic stroke.

Birth weight discordance in very and extremely preterm twins and the risk of neonatal hearing loss.

OBJECTIVE: Birth weight (BW) discordant twins have an increased risk of mortality and morbidity. We aimed to study the effect of BW discordance on the risk of neonatal hearing loss (NHL) in very and extremely preterm twins. STUDY DESIGN: Results of the nationwide newborn hearing screening program in Dutch Neonatal Intensive Care Units and diagnostic examination were centrally registered between 2003 and 2021 and included in this study. We selected twins and singletons with a gestational age (GA) 24- < 32 weeks. Logistic regression analyses were applied to study the effect of BW discordance on the risk of NHL adjusted for BW, GA and sex. Singletons and concordant twins, defined as a BW discordance of ≤20 %, were used as two reference groups. BW discordance was further categorized as medium (>20-30 %) and high (>30 %). RESULTS: In total, 3430 twins (2694 concordant, 428 medium and 308 high BW discordant), and 23,114 singletons were available. Smaller newborns of high BW discordant twins showed an increased risk of NHL compared to singletons (adjusted odds ratio with 95 % confidence interval was 3.56 (2.26-5.60)). Also, smaller newborns of medium and high BW discordant twins showed an increased risk of NHL compared to concordant twins (adjusted odds ratio with 95 % confidence interval were 1.97 (1.13-3.44) and 4.17 (2.56-6.82), respectively). No other statistically significant differences were found. CONCLUSION: BW discordance increased the risk of NHL in the smaller of the twin born very or extremely preterm. This risk increased as the weight difference increased.

Short-term pulmonary and systemic effects of hydrocortisone initiated 7-14 days after birth in ventilated very preterm infants: a secondary analysis of a randomised controlled trial.

OBJECTIVE: Observational studies in preterm infants suggest that systemic hydrocortisone improves pulmonary condition but may also lead to systemic adverse effects. We report the short-term pulmonary and systemic effects of hydrocortisone initiated in the second week. DESIGN: Randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. INTERVENTION: Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: Data on extubation, ventilator settings, glucose levels, and blood pressure were recorded daily and analysed during the first 7 days of treatment using linear mixed-effects models. RESULTS: Infants in the hydrocortisone group (24.3%) failed extubation less often compared with placebo (38.6%, crude risk difference: -14.3% (95% CI: -23.4% to -4.8%)). The estimated difference in daily rate of change between hydrocortisone and placebo was -0.42 cmH2O (95% CI: -0.48 to -0.36) for mean airway pressure, -0.02 (95% CI: -0.02 to -0.01) for fraction of inspired oxygen, -0.37 (95% CI: -0.44 to -0.30) for respiratory index, 0.14 mmol/L (95% CI: 0.08 to 0.21) for blood glucose levels and 0.83 mm Hg (95% CI: 0.58 to 1.09) for mean blood pressure. CONCLUSIONS: Systemic hydrocortisone initiated between 7 and 14 days after birth in ventilated preterm infants improves pulmonary condition, thereby facilitating weaning and extubation from invasive ventilation. The effects of hydrocortisone on blood glucose levels and blood pressure were mild and of limited clinical relevance. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR2768; https://www.trialregister.nl/trial/2640) and European Union Clinical Trials Register (EudraCT, 2010-023777-19).

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

BACKGROUND: In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180-185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care. METHODS/DESIGN: Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance. DISCUSSION: On basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references. TRIAL REGISTRATION: NTR2529.

Validity and interobserver agreement of reagent strips for measurement of glucosuria.

BACKGROUND: Measurement of glucosuria by means of a visually readable reagent test strip is frequently used in a wide variety of clinical settings. The aim of this study was to evaluate the validity and reliability of this semi-quantitative measurement of glucosuria compared to laboratory measurements of glucose concentrations in urine. METHODS: Reagent test strips (Combur³Test® Roche) from 375 artificially supplemented samples of urine, covering a wide range of glucose concentrations, were independently read by three different observers. Scores of the strips were categorized as 0, 1+, 2+, 3+ or 4+, in ascending degree of glucosuria. Results of the test-strips were compared to the quantitative measurement of urinary glucose concentration in the laboratory. RESULTS: 21.7% of reagent strips readings were discordant with the laboratory measurements (p < 0.001). Under- or overestimating the degree of glucosuria occurs predominantly in category 1+ and 2+. In category '0' only 5.1% of the readings were incorrect. The interobserver-agreement was very good with 85% overall agreement and multirater Kappa 0.81. Interobserver-scores of the reagent strips never deviated more than one category from each other. CONCLUSION: The validity as well as the interobserver-agreement for the semi-quantitative measurement of glucosuria using reagent strips is moderate, but sufficient for excluding glucosuria. However it is too imprecise for an accurate quantitative measurement. It might only be valuable in settings where automated readings are not available or suitable.