Predicting CPAP failure after less invasive surfactant administration (LISA) in preterm infants by machine learning model on vital parameter data: a pilot study.

Objective. Less invasive surfactant administration (LISA) has been introduced to preterm infants with respiratory distress syndrome on continuous positive airway pressure (CPAP) support in order to avoid intubation and mechanical ventilation. However, after this LISA procedure, a significant part of infants fails CPAP treatment (CPAP-F) and requires intubation in the first 72 h of life, which is associated with worse complication free survival chances. The aim of this study was to predict CPAP-F after LISA, based on machine learning (ML) analysis of high resolution vital parameter monitoring data surrounding the LISA procedure.Approach. Patients with a gestational age (GA) <32 weeks receiving LISA were included. Vital parameter data was obtained from a data warehouse. Physiological features (HR, RR, peripheral oxygen saturation (SpO2) and body temperature) were calculated in eight 0.5 h windows throughout a period 1.5 h before to 2.5 h after LISA. First, physiological data was analyzed to investigate differences between the CPAP-F and CPAP-Success (CPAP-S) groups. Next, the performance of two types of ML models (logistic regression: LR, support vector machine: SVM) for the prediction of CPAP-F were evaluated.Main results. Of 51 included patients, 18 (35%) had CPAP-F. Univariate analysis showed lower SpO2, temperature and heart rate variability (HRV) before and after the LISA procedure. The best performing ML model showed an area under the curve of 0.90 and 0.93 for LR and SVM respectively in the 0.5 h window directly after LISA, with GA, HRV, respiration rate and SpO2as most important features. Excluding GA decreased performance in both models.Significance. In this pilot study we were able to predict CPAP-F with a ML model of patient monitor signals, with best performance in the first 0.5 h after LISA. Using ML to predict CPAP-F based on vital signals gains insight in (possibly modifiable) factors that are associated with LISA failure and can help to guide personalized clinical decisions in early respiratory management.

Prognostic model for predicting survival in very preterm infants: an external validation study.

OBJECTIVE: To perform a temporal and geographical validation of a prognostic model, considered of highest methodological quality in a recently published systematic review, for predicting survival in very preterm infants admitted to the neonatal intensive care unit. The original model was developed in the UK and included gestational age, birthweight and gender. DESIGN: External validation study in a population-based cohort. SETTING: Dutch neonatal wards. POPULATION OR SAMPLE: All admitted white, singleton infants born between 23+0 and 32+6 weeks of gestation between 1 January 2015 and 31 December 2019. Additionally, the model's performance was assessed in four populations of admitted infants born between 24+0 and 31+6 weeks of gestation: white singletons, non-white singletons, all singletons and all multiples. METHODS: The original model was applied in all five validation sets. Model performance was assessed in terms of calibration and discrimination and, if indicated, it was updated. MAIN OUTCOME MEASURES: Calibration (calibration-in-the-large and calibration slope) and discrimination (c statistic). RESULTS: Out of 6092 infants, 5659 (92.9%) survived. The model showed good external validity as indicated by good discrimination (c statistic 0.82, 95% CI 0.79-0.84) and calibration (calibration-in-the-large 0.003, calibration slope 0.92, 95% CI 0.84-1.00). The model also showed good external validity in the other singleton populations, but required a small intercept update in the multiples population. CONCLUSIONS: A high-quality prognostic model predicting survival in very preterm infants had good external validity in an independent, nationwide cohort. The accurate performance of the model indicates that after impact assessment, implementation of the model in clinical practice in the neonatal intensive care unit could be considered. TWEETABLE ABSTRACT: A high-quality model predicting survival in very preterm infants is externally valid in an independent cohort.

Introduction of less invasive surfactant administration (LISA), impact on diagnostic and therapeutic procedures in early life: a historical cohort study.

BACKGROUND: In preterm infants with Respiratory Distress Syndrome (RDS), Less Invasive Surfactant Administration (LISA) has been established to reduce the need of mechanical ventilation and might improve survival rates without bronchopulmonary dysplasia. The aim of this study was to investigate whether NICU care has changed after introduction of less invasive surfactant administration (LISA), with regard to diagnostic and therapeutic procedures in the first week of life. METHODS: Infants with gestational age < 32 weeks who received surfactant by LISA (June 2014 - December 2017, n = 169) were retrospectively compared to infants who received surfactant after intubation (January 2012 - May 2014, n = 155). Local protocols on indication for surfactant, early onset sepsis, blood transfusions and enteral feeding did not change between both study periods. Besides, as secondary outcome complications of prematurity were compared. Data was collected from electronic patient files and compared by univariate analysis through Students T-test, Mann Whitney-U test, Pearson Chi-Square test or Linear by Linear Association. RESULTS: All baseline characteristics of both groups were comparable. Compared to controls, LISA patients received a higher total surfactant dose (208 vs.160 mg/kg; p < 0.001), required redosing more frequently (32.5% vs. 21.3%; p = 0.023), but needed less mechanical ventilation (35.5% vs. 76.8%; p < 0.001). After LISA, infants underwent fewer X-rays (1.0 vs. 3.0, p < 0.001), blood gas examinations (3.0 vs. 5.0, p < 0.001), less inotropic drugs (9.5% vs. 18.1%; p = 0.024), blood transfusions (24.9% vs. 41.9%, p = 0.003) and had shorter duration of antibiotic therapy for suspected early onset sepsis (3.0 vs. 5.0 days, p < 0.001). Moreover, enteral feeding was advanced faster (120 vs. 100 mL/kg/d, p = 0.048) at day seven. There were no differences in complications of prematurity. CONCLUSION: The introduction of LISA is associated with significantly fewer diagnostic and therapeutic procedures in the first week of life, which emphasizes the beneficial effects of LISA.

Oxytocin levels in the saliva of preterm infant twins during Kangaroo care.

BACKGROUND AND PURPOSE: To investigate whether Kangaroo care (KC) influences the salivary oxytocin (OT) concentration in preterm infants, and which correlates affect the OT response. METHODS: Eleven twin pairs participated in a study in which we collected saliva using cotton swabs twice a day, once during KC and once during baseline conditions (lying in bed or incubator). The total study duration was five days. The saliva of twin siblings were pooled to obtain vials with sufficient volumes of either saliva collected during KC or at baseline. OT levels were measured using a radio-immuno assay. The infants' state of comfort and parent-infant interaction were examined using previously developed Likert-scales, amongst other correlates such as the KC duration, gestational age and birth weight. RESULTS: During KC, OT was lower compared to baseline (mean 1.39 pg/ml (SD 0.58 pg/ml) versus 2.40 pg/ml (SD 1.64 pg/ml), p =  0.03). Comfort at baseline and parent-infant interaction seemed to influence OT responses. CONCLUSION: The OT concentration in the pooled saliva of preterm infant twins decreased during KC. This response of the OT system might be explained by stress during baseline.

DOSE EVALUATION FOR DIGITAL X-RAY IMAGING OF PREMATURE NEONATES.

X-ray radiography is a commonly used diagnostic method for premature neonates. However, because of higher radiosensitivity and young age, premature neonates are more sensitive to the detrimental effects of ionising radiation. Therefore, it is important to monitor and optimise radiation doses at the neonatal intensive care unit (NICU). The number of x-ray examinations, dose-area product (DAP) and effective doses are evaluated for three Dutch NICUs using digital flat panel detectors. Thorax, thorax-abdomen and abdomen protocols are included in this study. Median number of examinations is equal to 1 for all three hospitals. Median DAP ranges between 0.05 and 1.02 µGy m2 for different examination types and different weight categories. These examinations result in mean effective doses between 4 ± 4 and 30 ± 10 µSv per examination. Substantial differences in protocols and doses can be observed between hospitals. This emphasises the need for up-to-date reference levels formulated specifically for premature neonates.

[Two-year follow-up of infants born at 24 weeks gestation; first outcomes following implementation of the new 'Guideline for perinatal policy in cases of extreme prematurity']. / Follow-up na 2 jaar van kinderen geboren bij 24 weken.

OBJECTIVE: Since 2010 the guideline 'Guideline for perinatal policy in cases of extreme prematurity' has advised an active policy in infants born at 24 weeks gestation. We investigated how infants born at 24 and 25 weeks gestation in the first year following the implementation of the guideline had developed by the age of 2 years. DESIGN: Retrospective national cohort study. METHOD: The study population consisted of all surviving infants born in the Netherlands at 24 or 25 weeks gestation in the period from 1 October 2010 to 1 October 2011. At a corrected age of 2 years the children underwent a general physical and neurological examination, and their cognitive scores were determined on the 'Bayley scales of infant and toddler development' (Bayley III). Examinations took place in the 10 neonatal intensive care units (NICU's) in the Netherlands. RESULTS: Of 185 extremely premature infants, 166 were admitted to a NICU. A total of 95 survived to a corrected age of 2 years; 78 (82%) children were examined. Their average cognitive score on the Bayley III scale was 88 (SD: 16). Among the children born at 24 weeks gestation, 20% had mild disabilities and 20% had moderate to severe disabilities. Among the children born at 25 weeks gestation, 17% had mild disabilities and 12% had moderate to severe disabilities. CONCLUSION: Of the children born at 24 weeks gestation in the first year after the introduction of active policy in the Netherlands and surviving to 2 years of age (46%), more than half had developed without disabilities. This was comparable to children born at 25 weeks gestation. Of all children born at 24 weeks gestation, 25% survived to 2 years of age without disabilities.

Pilot study demonstrates that salivary oxytocin can be measured unobtrusively in preterm infants.

AIM: This study assessed the feasibility and obtrusiveness of measuring salivary oxytocin in preterm infants receiving Kangaroo care, because this is a period of maximal bonding or co-regulation. We also analysed possible influential determinants, including maternal oxytocin. METHODS: The saliva of preterm infants and their mothers was collected prior to, and during, Kangaroo care using cotton swabs and pooled into vials until sufficient volumes were obtained to measure oxytocin levels using a radioimmunoassay. The obtrusiveness of the infants' collections was measured with a Likert scale. RESULTS: Saliva was collected unobtrusively prior to, and during, 30 Kangaroo care sessions in 21 preterm infants. This resulted in three vials with sufficient volumes of before-Kangaroo care saliva and three with during-Kangaroo care saliva. Oxytocin was detectable in all six vials. The Kangaroo care duration and the intensity of the mother-infant interaction before and during Kangaroo care seemed to be the most important determinants, and these should preferably be standardised in any future trials. CONCLUSION: Oxytocin was measured unobtrusively in the pooled saliva of preterm infants both before and during Kangaroo care and could therefore be investigated as a biomarker in future studies.

Interhemispheric connectivity estimated from EEG time-correlation analysis in preterm infants with normal follow-up at age of five.

Brain connectivity is associated with axonal connections between brain structures. Our goal was to quantify the interhemispheric neuronal connectivity in healthy preterm infants by automated quantitative EEG time-correlation analysis. As with advancing postmenstrual age (PMA, gestational age + postnatal age) the neuronal connectivity between left and right hemisphere increases, we expect to observe changes in EEG time-correlation with age. Thirty-six appropriate-for-gestational age preterm infants (PMA between 27-37 weeks) and normal neurodevelopmental follow-up at 5 years of age were included. Of these, 22 infants underwent 3-8 repeated EEG recordings at weekly intervals. The reduced 10-20 EEG electrode system for newborns was used with five sets of bipolar channels: central-temporal, frontal polar-temporal, frontal polar-central, temporal-occipital and central-occipital. We performed EEG time-correlation analysis between homologous channels of the brain hemispheres to identify interhemispheric similarity in EEG signal shape. For each 8 s epoch of the EEG the time-correlation values and the corresponding lag times were calculated for homologous channels on both hemispheres. In all channels, the median correlation value decreased significantly (between -40% and -60% decrease) from 27 to 37 weeks PMA, for gestational maturation. For the postnatal maturation only the central-temporal channel showed a significantly decreasing trend. In contrast, the median lag time showed no uniform change with PMA. The decreasing median correlation values in all homologous channels indicate a decrease in similarity in signal shape with advancing PMA. This finding may reflect greater functional differentiation of cortical areas in the developing preterm brain and may be explained by the increase of complex neural networks with excitatory and inhibitory circuitries.

Safe patient monitoring is challenging but still feasible in a neonatal intensive care unit with single family rooms.

AIM: Patient monitoring generates a large number of alarms. The aim of this study was to evaluate the rate, type and management of alarms and to determine the risks of a distributed alarm system in a neonatal intensive care unit (NICU) with single family rooms. METHODS: A risk analysis was performed before implementation. Alarms from patient monitors recorded for a year were identified, classified and counted. The first alarms, which went to the nurse responsible for the patient, were distinguished from the repeat alarms that were generated if the nurse failed to respond within 45 sec. RESULTS: The alarm handling protocol was changed as staff felt they needed a greater overview of the NICU alarms to avoid risks. In 1 year, 222 751 critical alarms including 12 309 repeat alarms were generated by patient monitors, equivalent to two alarms per patient per hour. Most of the alarms were oxygen desaturation alarms, followed by bradycardia alarms. About 3% of the desaturation alarms and 0.2% of the bradycardia alarms were repeated. CONCLUSION: Safe patient monitoring was challenging in a NICU with single family rooms, but possible by employing a distributed alarm system. The low number of repeat alarms indicated quick response times.

Functional connectivity in preterm infants derived from EEG coherence analysis.

OBJECTIVE: To quantify the neuronal connectivity in preterm infants between homologous channels of both hemispheres. METHODS: EEG coherence analysis was performed on serial EEG recordings collected from preterm infants with normal neurological follow-up. The coherence spectrum was divided in frequency bands: δnewborn(0-2 Hz), θnewborn(2-6 Hz), αnewborn(6-13 Hz), ßnewborn(13-30 Hz). Coherence values were evaluated as a function of gestational age (GA) and postnatal maturation. RESULTS: All spectra show two clear peaks in the δnewborn and θnewborn-band, corresponding to the delta and theta EEG waves observed in preterm infants. In the δnewborn-band the peak magnitude coherence decreases with GA and postnatal maturation for all channels. In the θnewborn-band, the peak magnitude coherence decreases with GA for all channels, but increases with postnatal maturation for the frontal polar channels. In the ßnewborn-band a modest magnitude coherence peak was observed in the occipital channels, which decreases with GA. CONCLUSIONS: Interhemispherical connectivity develops analogously with electrocortical maturation: signal intensities at low frequencies decrease with GA and postnatal maturation, but increase at high frequencies with postnatal maturation. In addition, peak magnitude coherence is a clear trend indicator for brain maturation. SIGNIFICANCE: Coherence analysis can aid in the clinical assessment of the functional connectivity of the infant brain with maturation.

Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants.

AIM: The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32 weeks' gestation. METHODS: Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5 mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites. RESULTS: A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764 ± 0.225 L/kg, elimination rate constant (ke ) 0.117 ± 0.091/h and intercompartment rate constants k12 0.607 ± 0.734/h and k21 1.105 ± 0.762/h. CONCLUSION: Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.

QRS classification and spatial combination for robust heart rate detection in low-quality fetal ECG recordings.

Non-invasive fetal electrocardiography (ECG) can be used for prolonged monitoring of the fetal heart rate (FHR). However, the signal-to-noise-ratio (SNR) of non-invasive ECG recordings is often insufficient for reliable detection of the FHR. To overcome this problem, source separation techniques can be used to enhance the fetal ECG. This study uses a physiology-based source separation (PBSS) technique that has already been demonstrated to outperform widely used blind source separation techniques. Despite the relatively good performance of PBSS in enhancing the fetal ECG, PBSS is still susceptible to artifacts. In this study an augmented PBSS technique is developed to reduce the influence of artifacts. The performance of the developed method is compared to PBSS on multi-channel non-invasive fetal ECG recordings. Based on this comparison, the developed method is shown to outperform PBSS for the enhancement of the fetal ECG.

Acquired progressive hypotonia in infancy: consider compressive cervical myelopathy.

UNLABELLED: This case report presents a rare cause of progressive hypotonia due to a congenital bony defect of the atlas in a 2-month-old girl. The patient was initially referred to the paediatric department with feeding problems. Within days after admission she developed progressive hypotonia and showed decreased reflexes of the upper extremities. Magnetic resonance imaging showed compressive myelopathy at the level of vertebra C1. After laminectomy of the C1-vertebra the neurological symptoms resolved. CONCLUSION: Most anomalies of the vertebras are asymptomatic. Only symptomatic anomalies with compression and neurological symptoms need surgery.

Quantitative analysis of maturational changes in EEG background activity in very preterm infants with a normal neurodevelopment at 1 year of age.

BACKGROUND: The electroencephalographic (EEG) background pattern of preterm infants changes with postmenstrual age (PMA) from discontinuous activity to continuous activity. However, changes in discontinuity have been investigated by visual analysis only. AIM: To investigate the maturational changes in EEG discontinuity in healthy preterm infants using an automated EEG detection algorithm. STUDY DESIGN: Weekly 4h EEG recordings were performed in preterm infants with a gestational age (GA)<32weeks and normal neurological follow-up at 1year. The channel C3-C4 was analyzed using an algorithm which automatically detects periods of EEG inactivity (interburst intervals). The interburst-burst ratio (IBR, percentage of EEG inactivity during a moving time window of 600s) and mean length of the interburst intervals were calculated. Using the IBR, discontinuous background activity (periods with high IBR) and continuous background activity (periods with low IBR) were automatically detected and their mean length during each recording was calculated. Data were analyzed with regression and multivariate analysis. RESULTS: 79 recordings were performed in 18 infants. All recordings showed a cyclical pattern in EEG discontinuity. With advancing PMA, IBR (R(2)=0.64; p<0.001), interburst interval length (R(2)=0.43; p<0.001) and length of discontinuous activity (R(2)=0.38; p<0.001) decreased, while continuous activity increased (R(2)=0.50; p<0.001). Multivariate analysis showed that all EEG discontinuity parameters were equally influenced by GA and postnatal age. CONCLUSION: Analyzing EEG background activity in preterm infants is feasible with an automated algorithm and shows maturational changes of several EEG derived parameters. The cyclical pattern in IBR suggests brain organisation in preterm infant.

Quantitative analysis of amplitude-integrated electroencephalogram patterns in stable preterm infants, with normal neurological development at one year.

BACKGROUND: The amplitude-integrated EEG (aEEG) is feasible for monitoring cerebral activity in preterm infants. However, quantitative data on normal patterns in these infants are limited. OBJECTIVE: To study maturational aEEG changes in a cohort of stable preterm infants by automated quantification. METHODS: In a cohort of stable preterm infants with gestational age (GA) <32 weeks and normal neurological follow-up at 1 year, weekly 4 h EEG recordings were performed. aEEG traces were obtained from channel C(3)-C(4). The upper margin amplitude (UMA), lower margin amplitude (LMA) and bandwidth (BW) were quantitatively calculated using an expert software system. In addition, the relative duration of discontinuous background pattern (discontinuous background defined as activity with LMA <5 microV, expressed as DC-%) was calculated. RESULTS: 79 aEEG recordings (4-6 recordings/infant) were obtained in 18 infants. Analysis of the first week recordings demonstrated a strong positive correlation between GA and LMA, while DC-% decreased significantly. Longitudinally, all infants showed increase of LMA. Multivariate analysis showed that GA and postnatal age (PA) both contributed independently and equally to LMA and DC-%. We found a strong correlation between postmenstrual age (GA + PA) and LMA and DC-%, respectively. CONCLUSION: To our knowledge, this is the first study where aEEG development was studied by automated quantification of aEEG characteristics in a cohort of stable preterm infants with a normal neurological development at 1 year of age. LMA and DC-% are simple quantitative measures of neurophysiologic development and may be used to evaluate neurodevelopment in infants.

Neonatal airway obstruction caused by rapidly growing nasopharyngeal teratoma.

UNLABELLED: A case report is presented of a rapidly growing congenital nasopharyngeal teratoma (epignathus) in a preterm infant, leading to severe upper airway obstruction. Prenatal diagnosis by ultrasonography did not reveal the condition because the tumour masses were initially small and there was no polyhydramnios. Epignathus is a rare cause of upper airway obstruction of the newborn that can grow rapidly in the neonatal period and should be treated surgically. CONCLUSION: Epignathus is a rare cause of upper airway obstruction of the newborn that can grow rapidly in the neonatal period.

Systemic air embolism after cardiopulmonary resuscitation in a preterm infant.

UNLABELLED: We report a preterm infant with extensive systemic air embolism after cardiopulmonary resuscitation for cardiac arrest due to an occluding thrombus in the inferior vena cava. After excluding other potential causes (air infusion, necrotizing enterocolitis or pulmonary leakage syndrome), we postulate that the pressure gradient needed for air embolism to occur is related to the resuscitation procedure. An important clue of air embolism was noted on the chest X-ray taken before death showing intracardial air. CONCLUSION: Systemic air embolism may occur as a very rare complication after cardiopulmonary resuscitation.

Amplitude-integrated electroencephalographic changes in a newborn induced by overdose of morphine and corrected with naloxone.

UNLABELLED: The amplitude-integrated electroencephalogram (aEEG) is a useful tool to assess brain function after perinatal asphyxia in term infants. We report a full-term newborn with moderate perinatal asphyxia, who accidentally received an overdose of morphine (5000 microg/kg). The overdose of morphine resulted in a clear and immediate change of aEEG background activity from a continuous (C) to discontinuous (DC) background pattern. After administration of naloxone, the background activity restored immediately to continuous background pattern. The aEEG was used to monitor the stepwise reduction in continuous naloxone infusion. CONCLUSION: An overdose of morphine leads to clear and immediate changes in aEEG which restore after naloxone treatment. The aEEG can be used to monitor naloxone infusion.

An algorithm for the automatic detection of seizures in neonatal amplitude-integrated EEG.

AIM: To develop and evaluate an algorithm for the automatic screening of electrographic neonatal seizures (ENS) in amplitude-integrated electroencephalography (aEEG) signals. METHODS: CFM recordings were recorded in asphyxiated (near)term newborns. ENS of at least 60 sec were detected based on their characteristic pattern in the aEEG signal, an increase of its lower boundary. The algorithm was trained using five CFM recordings (training set) annotated by a neurophysiologist, observer1. The evaluation of the algorithm was based on eight different CFM recordings annotated by observer1 (test set observer 1) and an independent neurophysiologist, observer2 (test set observer 2). RESULTS: The interobserver agreement between observer1 and 2 in interpreting ENS from the CFM recordings was high (G coefficient: 0.82). After dividing the eight CFM recordings into 1-min segments and classification in ENS or non-ENS, the intraclass correlation coefficient showed high correlations of the algorithm with both test sets (respectively, 0.95 and 0.85 with observer1 and 2). The algorithm showed in five recordings a sensitivity > or = 90% and approximately 1 false positive ENS per hour. However, the algorithm showed in three recordings much lower sensitivities: one recording showed ENSs of extremely high amplitude that were incorrectly classified by the algorithm as artefacts and two recordings suffered from low interobserver agreement. CONCLUSION: This study shows the feasibility of automatic ENS screening based on aEEG signals and may facilitate in the bed-side interpretation of aEEG signals in clinical practice.