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.

Non-pharmacological interventions for the prevention of pain during endotracheal suctioning in ventilated neonates.

BACKGROUND: Pain, when treated inadequately, puts preterm infants at a greater risk of developing clinical and behavioural sequelae because of their immature pain system. Preterm infants in need of intensive care are repeatedly and persistently exposed to noxious stimuli, and this happens during a critical window of their brain development with peak rates of brain growth, exuberant synaptogenesis and the developmental regulation of specific receptor populations. Nearly two-thirds of infants born at less than 29 weeks' gestation require mechanical ventilation for some duration during the newborn period. These neonates are endotracheally intubated and require repeated endotracheal suctioning. Endotracheal suctioning is identified as one of the most frequent and most painful procedures in premature infants, causing moderate to severe pain. Even with improved nursing performance and standard procedures based on neonatal needs, endotracheal suctioning remains associated with mild pain. OBJECTIVES: To evaluate the benefits and harms of non-pharmacological interventions for the prevention of pain during endotracheal suctioning in mechanically ventilated neonates. Non-pharmacological interventions were compared to no intervention, standard care or another non-pharmacological intervention. SEARCH METHODS: We conducted searches in June 2023 in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, Embase, CINAHL and three trial registries. We searched the reference lists of related systematic reviews, and of studies selected for inclusion. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and cluster-RCTs that included term and preterm neonates who were mechanically ventilated via endotracheal tube or via tracheostomy tube and required endotracheal suctioning performed by doctors, nurses, physiotherapists or other healthcare professionals. DATA COLLECTION AND ANALYSIS: Our main outcome measures were validated composite pain scores (including a combination of behavioural, physiological and contextual indicators). Secondary outcomes included separate physiological and behavioural pain indicators. We used standard methodological procedures expected by Cochrane. For continuous outcome measures, we used a fixed-effect model and reported mean differences (MDs) with 95% confidence intervals (CIs). For categorical outcomes, we reported the typical risk ratio (RR) and risk difference (RD) and 95% CIs. We assessed risk of bias using the Cochrane RoB 1 tool, and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included eight RCTs (nine reports), which enroled 386 infants, in our review. Five of the eight studies were included in a meta-analysis. All studies enrolled preterm neonates. Facilitated tucking versus standard care (four studies) Facilitated tucking probably reduces Premature Infant Pain Profile (PIPP) score during endotracheal suctioning (MD -2.76, 95% CI 3.57 to 1.96; I² = 82%; 4 studies, 148 infants; moderate-certainty evidence). Facilitated tucking probably has little or no effect during endotracheal suctioning on: heart rate (MD -3.06 beats per minute (bpm), 95% CI -9.33 to 3.21; I² = 0%; 2 studies, 80 infants; low-certainty evidence); oxygen saturation (MD 0.87, 95% CI -1.33 to 3.08; I² = 0%; 2 studies, 80 infants; low-certainty evidence); or stress and defensive behaviours (SDB) (MD -1.20, 95% CI -3.47 to 1.07; 1 study, 20 infants; low-certainty evidence). Facilitated tucking may result in a slight increase in self-regulatory behaviours (SRB) during endotracheal suctioning (MD 0.90, 95% CI 0.20 to 1.60; 1 study, 20 infants; low-certainty evidence). No studies reported intraventricular haemorrhage (IVH). Familiar odour versus standard care (one study) Familiar odour during endotracheal suctioning probably has little or no effect on: PIPP score (MD -0.30, 95% CI -2.15 to 1.55; 1 study, 40 infants; low-certainty evidence); heart rate (MD -6.30 bpm, 95% CI -16.04 to 3.44; 1 study, 40 infants; low-certainty evidence); or oxygen saturation during endotracheal suctioning (MD -0.80, 95% CI -4.82 to 3.22; 1 study, 40 infants; low-certainty evidence). No studies reported SRB, SDB or IVH. White noise (one study) White noise during endotracheal suctioning probably has little or no effect on PIPP (MD -0.65, 95% CI -2.51 to 1.21; 1 study, 40 infants; low-certainty evidence); heart rate (MD -1.85 bpm, 95% CI -11.46 to 7.76; 1 study, 40 infants; low-certainty evidence); or oxygen saturation (MD 2.25, 95% CI -2.03 to 6.53; 1 study, 40 infants; low-certainty evidence). No studies reported SRB, SDB or IVH. AUTHORS' CONCLUSIONS: Facilitated tucking / four-handed care / gentle human touch probably reduces PIPP score. The evidence of a single study suggests that facilitated tucking / four-handed care / gentle human touch slightly increases self-regulatory and approach behaviours during endotracheal suctioning. Based on a single study, familiar odour and white noise have little or no effect on any of the outcomes compared to no intervention. The use of expressed breast milk or oral sucrose suggests that there is no discernible advantage of one method over the other for reducing pain during endotracheal suctioning. None of the studies reported on any of the prespecified secondary outcomes of adverse events.

Cause of death and making end-of-life decisions in preterm infants has not changed over time: A mortality follow-back survey.

AIM: This study aimed to evaluate changes over time in cause of death and making end-of-life decisions in preterm infants. METHODS: A follow-back survey was conducted of all preterm infants who died between September 2016 and December 2017 in Flanders and Brussels, Belgium. Cause of death was obtained from the death certificate and information on end-of-life decisions (ELDs) through an anonymous questionnaire of the certifying physician. Results were compared with a previous study performed between August 1999 and July 2000. RESULTS: In the cohort 1999-2000 and 2016-2017, respectively, 150 and 135 deaths were included. A significantly higher proportion of infants born before 26 weeks of gestation was found in the 2016-2017 cohort (53% vs. 24% in 1999-2000, p < 0.001). Extreme immaturity (<26 weeks) remained the most prevalent cause with a significant increase in the 2016-2017 cohort (48% vs. 28% in 1999-2000, p < 0.001). The overall prevalence of ELDs was similar across study periods (61%). Non-treatment decisions remained the most common ELD (36% and 37%). CONCLUSION: Infants born at the limits of viability have become more prevalent among infant deaths, possibly due to a change in attitude towards periviable births. Neither the process of making ELDs nor the cause of death has changed over time.

Synthetic magnetic resonance-based relaxometry and brain volume: cutoff values for predicting neurocognitive outcomes in very preterm infants.

BACKGROUND: Early neurorehabilitation can enhance neurocognitive outcomes in very preterm infants (<32 weeks), and conventional magnetic resonance imaging (MRI) is commonly used to assess neonatal brain injury; however, the predictive value for neurodevelopmental delay is limited. Timely predictive quantitative biomarkers are needed to improve early identification and management of infants at risk of neurodevelopmental delay. OBJECTIVE: To evaluate the potential of quantitative synthetic MRI measurements at term-equivalent age as predictive biomarkers of neurodevelopmental impairment and establish practical cutoff values to guide clinical decision-making. MATERIALS AND METHODS: This retrospective study included 93 very preterm infants who underwent synthetic MRI at term-equivalent age between January 2017 and September 2020. Clinical outcomes were assessed using the Bayley-III scale of infant development (mean age 2.1 years). The predictive value for impaired development was analyzed using receiver operating characteristic curves for synthetic MRI-based volumetry and T1 and T2 relaxation measurements. RESULTS: The T1 relaxation time in the posterior limb of the internal capsule was a potent predictor of severe (sensitivity, 92%; specificity, 80%; area under the curve (AUC), 0.91) and mild or severe (AUC, 0.75) developmental impairment. T2 relaxation time in the posterior limb of the internal capsule was a significant predictor of severe impairment (AUC, 0.76), whereas the brain parenchymal volume was a significant predictor of severe (AUC, 0.72) and mild or severe impairment (AUC, 0.71) outperforming the reported qualitative MRI scores (AUC, 0.66). CONCLUSION: The proposed cutoff values for T1 relaxation time in the posterior limb of the internal capsule and for total brain volume measurements, derived from synthetic MRI, show promise as predictors of both mild and severe neurodevelopmental impairment in very preterm infants.

A Retrospective Study Evaluating Guideline Adherence of Neonatal Parenteral Nutrition in a Belgian Neonatal Intensive Care Unit.

Introduction Clinical nutrition for preterm and critically ill neonates remains a challenge. Preterms are often hemodynamically and metabolically compromised, which limits infusion volumes of nutrients and hinders achieving recommended nutrient intakes. While guidelines provide recommended ranges for parenteral nutrition (PN) intakes, they generally recommend enteral nutrition as soon as possible. Thus, in clinical practice, gradually increasing EN intakes complicates assessments of PN guideline adherence. Via a pragmatic approach, we assessed adherence to PN recommendations for macronutrients and energy as stated in the 2018 guidelines of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Methods In this retrospective study, we assessed the nutrition of preterm and critically ill term neonates from the neonatal intensive care unit of the University Hospital Brussels. We analyzed intakes for the first week of life, in which critically ill neonates at our center usually receive the majority of nutrients via PN. The PN-based provision of macronutrients and energy was analyzed descriptively in relation to the ESPGHAN 2018 recommendations. Results Macronutrients and energy provision gradually increased until they reached recommended or targeted values. Compared to term neonates, energy and lipid provision for preterms increased faster, while amino acid provision exceeded the ESPGHAN 2018 recommendations. Conclusions This study adds clinical practice data to the severely understudied field of the ESPGHAN 2018 PN guideline compliance. Using a pragmatic assessment of our nutrition protocols, we found the need to reduce the amount of amino acids per kg body weight per day to meet guideline recommendations.

Neurally adjusted ventilatory assist in preterm infants: A systematic review and meta-analysis.

To compare the effects of neurally adjusted ventilatory assist (NAVA) with other forms of synchronized artificial ventilation in preterm infants. A systematic review of randomized and quasi-randomized controlled trials with individual group allocation, both parallel-group trials as well as crossover trials, that included preterm infants born at less than 37 weeks gestational age and compared NAVA with any other form of synchronized mechanical ventilation with or without volume guarantee. Primary outcomes were death or bronchopulmonary dysplasia (BPD) at 36 weeks, total duration of respiratory support and neurodevelopmental outcome at 2 years. Secondary outcomes consisted of important procedural and clinical outcomes. Seven studies with a total of 191 infants were included, five randomized crossover trials and two parallel group randomized trials. No significant difference in the primary outcome of death or BPD (RR: 1.08, 95% CI: 0.33-3.55) was found. Peak inspiratory pressures were significantly lower with NAVA than with other forms of ventilation (MD -1.83 cmH2O [95% CI: -2.95 to -0.71]). No difference in any other clinical or ventilatory outcome was detected. Although associated with lower peak inspiratory pressures, the use of NAVA does not result in a reduced risk of death or BPD as compared to other forms of synchronized ventilation in preterm infants. However, the certainty of evidence is low due to imprecision of the effect estimate. Larger studies are needed to detect possible short- and long-term differences between ventilation modes.