A recommendation for the use of electrical biosensing technology in neonatology.

Non-invasive cardiac output monitoring, via electrical biosensing technology (EBT), provides continuous, multi-parameter hemodynamic variable monitoring which may allow for timely identification of hemodynamic instability in some neonates, providing an opportunity for early intervention that may improve neonatal outcomes. EBT encompasses thoracic (TEBT) and whole body (WBEBT) methods. Despite the lack of relative accuracy of these technologies, as compared to transthoracic echocardiography, the use of these technologies in neonatology, both in the research and clinical arena, have increased dramatically over the last 30 years. The European Society of Pediatric Research Special Interest Group in Non-Invasive Cardiac Output Monitoring, a group of experienced neonatologists in the field of EBT, deemed it appropriate to provide recommendations for the use of TEBT and WBEBT in the field of neonatology. Although TEBT is not an accurate determinant of cardiac output or stroke volume, it may be useful for monitoring longitudinal changes of hemodynamic parameters. Few recommendations can be made for the use of TEBT in common neonatal clinical conditions. It is recommended not to use WBEBT to monitor cardiac output. The differences in technologies, study methodologies and data reporting should be addressed in ongoing research prior to introducing EBT into routine practice. IMPACT STATEMENT: TEBT is not recommended as an accurate determinant of cardiac output (CO) (or stroke volume (SV)). TEBT may be useful for monitoring longitudinal changes from baseline of hemodynamic parameters on an individual patient basis. TEBT-derived thoracic fluid content (TFC) longitudinal changes from baseline may be useful in monitoring progress in respiratory disorders and circulatory conditions affecting intrathoracic fluid volume. Currently there is insufficient evidence to make any recommendations regarding the use of WBEBT for CO monitoring in neonates. Further research is required in all areas prior to the implementation of these monitors into routine clinical practice.

Retinal blood flow velocities in infants with retinopathy of prematurity after intravitreal administration of bevacizumab.

BACKGROUND/OBJECTIVES: Progression of retinopathy of prematurity (ROP) is associated with increased retinal blood flow velocities. We investigated changes of central retinal arterial and venous blood flow after intravitreal administration of bevacizumab. SUBJECTS/METHODS: Prospective observational study using serial ultrasound Doppler imaging in preterm infants with bevacizumab-treated ROP. Eyes were examined 1 [0-2] days before injection (median [interquartile range]), and at three time points after injection (1 [1-2] days, 6 [3-8] days, and 17 [9-28] days). Preterm infants with ROP stage 2 displaying spontaneous regression served as controls. RESULTS: In 21 eyes of 12 infants with bevacizumab-treated ROP, peak arterial systolic velocity declined from 13.6 [11.0-16.3] cm/s prior to intravitreal bevacizumab to 11.2 [9.4-13.9] cm/s, 10.6 [9.2-13.3] cm/s and 9.3 [8.2-11.0] cm/s at discharge (p = .002). There was also a decline of the arterial velocity time integral (from 3.1 [2.3-3.9] cm to 2.9 [2.4-3.5], 2.7 [2.3-3.2] cm and 2.2 [2.0-2.7], p = .021) and mean velocity in the central retinal vein (from 4.5 [3.6-5.8] cm/s to 3.7 [2.6-4.1] cm/s, 3.5 [3.0-4.3] cm/s, and 3.2 [2.8-4.6] cm/s, p = .012). Arterial end-diastolic velocity and resistance index remained unchanged. Blood flow velocities in bevacizumab-treated eyes examined before injection were significantly higher than those measured in untreated eyes that ultimately showed spontaneous regression of ROP. Sequential examinations in these controls did not reveal any declines of retinal blood flow velocities. CONCLUSION: Increased retinal arterial and venous blood flow velocities in infants with threshold ROP decline following intravitreal bevacizumab injection.

[Evaluation of the Endotracheal Tube by Ultrasound in Neonates]. / Ultraschallgestützte Lagekontrolle des Endotrachealtubus bei Neugeborenen.

The reliable evaluation of a correctly placed endotracheal tube is an essential challenge in neonatology. Point-of-care ultrasound is an emerging method to address this concern with the following advantages: less time-consuming, no exposure to radiation, less staff-intensive, and high tolerability by the patients. This article focuses on the evaluation of the clinical application of point-of-care ultrasound to examine the position of the endotracheal tube with regard to visualization, consistency compared to the chest X-ray, and the level of training to obtain sufficient results. We identified nine studies relevant to these questions. The visualization of the endotracheal tube by using point-of-care ultrasound is highly effective. The assessment of a correctly placed endotracheal tube is comparable to the results of a chest X-ray. The technique is suitable for any examiner with previous ultrasound experience. Future applications such as emergency intubations, implementation in the standard care of extremely low birth weight preterm babies, and use in low-resource settings could be promising. This article offers a practical guideline to promote the level of awareness and the clinical application.

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia.

BACKGROUND: To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. METHODS: Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. RESULTS: RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. CONCLUSIONS: Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

[Lung Ultrasound in Neonatology to diagnose a Pneumothorax (part one): Evidence - Time for a New Standard Protocol]. / Lungenultraschall in der Neonatologie zur Diagnostik eines Pneumothorax (Teil 1): Eine Evidenzanalyse ­ Zeit für einen neuen Goldstandard.

Lung ultrasound is a well-studied diagnostic procedure in emergency medicine. Over the last several years, international research groups have investigated the role of lung ultrasound to evaluate neonatal respiratory diseases. Specific diagnostic algorithms and key features of a neonatal pneumothorax have been released. Compared to X-ray examination, lung ultrasound has many advantages, such as faster diagnostic time, lack of exposure to ionizing radiation, and excellent sensitivity and specificity. Thus, lung ultrasound contributes to the improvement of medical healthcare in the neonatal intensive care unit. We consider the use of lung ultrasound as a new standard procedure to diagnose a pneumothorax in neonatology.

[Lung Ultrasound in Neonatology to diagnose a Pneumothorax (part two): A Guideline]. / Lungenultraschall in der Neonatologie zur Diagnostik eines Pneumothorax (Teil 2): Eine Praxisanleitung.

Lung ultrasound is a fast and reliable diagnostic tool in the detection of a neonatal pneumothorax. This tutorial provides basic information for understanding and detecting the generated artefacts, such as A-lines, B-lines, and the lung point. Essential knowledge of these artefacts allows for rule-in and rule-out criteria of a pneumothorax diagnosis. Lung ultrasound could help to reduce the use of radiation in neonatology in the future.

Hazards to avoid in future neonatal studies of nasal high-frequency oscillatory ventilation: lessons from an early terminated trial.

OBJECTIVE: To investigate whether nasal high-frequency oscillatory ventilation (nHFOV) started immediately after extubation of mechanically ventilated very low birth weight infants reduces the partial pressure of carbon dioxide at 72 h after extubation in comparison with nasal continuous positive airway pressure. This randomised controlled single-centre trial aimed to include 68 preterm infants at high risk of extubation failure. RESULTS: Implementation of the study protocol was feasible. However, from 2015 to 2017, only six patients could be recruited, leading to early termination of the trial. The slow recruitment was due to the introduction of new strategies to avoid endotracheal mechanical ventilation, which reduced the number of eligible infants. Moreover, the included infants failed their extubation more often than anticipated, thereby increasing the required sample size. Based on our single-centre experience, we provide information for study planning and discuss the specific requirements for future trial protocols on nHFOV. The extubation of high-risk infants into nHFOV could well be beneficial, but a multicentric approach is necessary to investigate this hypothesis. Trial Registration Clinicaltrials.gov NCT02340299, on 16 January 2015.

Non-Invasive Ventilation in Neonatology.

BACKGROUND: Invasive mechanical ventilation (IMV) has been replaced by early continuous positive airway pressure (CPAP) in the treatment of respiratory distress syndrome (RDS) in preterm infants aiming to reduce the rate of bronchopulmonary dysplasia (BPD). Subsequently, modern non-invasive ventilation strategies (NIV) were introduced into clinical practice with limited evidence of effects on pulmonary and neurodevelopmental outcomes. METHODS: We performed a selective literature search in PubMed including randomized controlled trials (RCT) (n ≥ 200) and meta-analyses published in the field of NIV in neonatology and follow-up studies focusing on long term pulmonary and neurodevelopmental outcomes. RESULTS: Individual studies do not show a significant risk reduction for the combined endpoint death or BPD in preterm infants caused by early CPAP in RDS when compared to primary intubation. One meta-analysis comparing four studies found CPAP significantly reduces the risk of BPD or death (relative risk: 0.91; 95% confidence interval [0.84;0.99]). Nasal intermittent positive pressure ventilation (NIPPV) as a primary ventilation strategy reduces the rate of intubations in infants with RDS (RR: 0.78 [0.64;0.94]) when compared to CPAP but does not affect the rate of BPD (RR: 0.78 [0.58;1.06]). CONCLUSION: Early CPAP reduces the need for IMV and the risk of BPD or death in preterm infants with RDS. NIPPV may offer advantages over CPAP regarding intubation rates. Networking-based follow-up programs are required to assess the effect of NIV on long term pulmonary and neurodevelopmental outcomes.

Differential impact of flow and mouth leak on oropharyngeal humidification during high-flow nasal cannula: a neonatal bench study.

BACKGROUND: Heated humidification is paramount during neonatal high-flow nasal cannula (HFNC) therapy. However, there is little knowledge about the influence of flow rate and mouth leak on oropharyngeal humidification and temperature. METHODS: The effect of the Optiflow HFNC on oropharyngeal gas conditioning was investigated at flow rates of 4, 6 and 8 L min-1 with and without mouth leak in a bench model simulating physiological oropharyngeal air conditions during spontaneous breathing. Temperature and absolute humidity (AH) were measured using a digital thermo-hygrosensor. RESULTS: Without mouth leak, oropharyngeal temperature and AH increased significantly with increasing flow (P < 0.001). Mouth leak did not affect this increase up to 6 L min-1, but at 8 L min-1, temperature and AH plateaued, and the effect of mouth leak became statistically significant (P < 0.001). CONCLUSIONS: Mouth leak during HFNC had a negative impact on oropharyngeal gas conditioning when high flows were applied. However, temperature and AH always remained clinically acceptable.

Nasal high-frequency oscillatory ventilation impairs heated humidification: A neonatal bench study.

OBJECTIVE: Nasal high-frequency oscillatory ventilation (nHFOV) is a novel mode of non-invasive ventilation used in neonates. However, upper airway obstructions due to viscous secretions have been described as specific adverse effects. We hypothesized that high-frequency oscillations reduce air humidity in the oropharynx, resulting in upper airway desiccation. Therefore, we aimed to investigate the effects of nHFOV ventilatory settings on oropharyngeal gas conditions. METHODS: NHFOV or nasal continuous positive airway pressure (nCPAP) was applied, along with heated humidification, to a previously established neonatal bench model that simulates oropharyngeal gas conditions during spontaneous breathing through an open mouth. A digital thermo-hygro sensor measured oropharyngeal temperature (T) and humidity at various nHFOV frequencies (7, 10, 13 Hz), amplitudes (10, 20, 30 cmH2 O), and inspiratory-to-expiratory (I:E) ratios (25:75, 33:66, 50:50), and also during nCPAP. RESULTS: Relative humidity was always >99%, but nHFOV resulted in lower mean T and absolute humidity (AH) in comparison to nCPAP (P < 0.001). Specifically, decreasing the nHFOV frequency and increasing nHFOV amplitude caused a decline in T and AH (P < 0.001). Mean T and AH were highest during nCPAP (T 34.8 ± 0.6°C, AH 39.3 ± 1.3 g · m-3 ) and lowest during nHFOV at a frequency of 7 Hz and an amplitude of 30 cmH2 O (T 32.4 ± 0.3°C, AH 34.7 ± 0.5 g · m-3 ). Increasing the I:E ratio also reduced T and AH (P = 0.03). CONCLUSION: Intensified nHFOV settings with low frequencies, high amplitudes, and high I:E ratios may place infants at an increased risk of upper airway desiccation. Future studies should investigate strategies to optimize heated humidification during nHFOV.

Influence of mouth opening on oropharyngeal humidification and temperature in a bench model of neonatal continuous positive airway pressure.

Clinical studies show that non-invasive respiratory support by continuous positive airway pressure (CPAP) affects gas conditioning in the upper airways, especially in the presence of mouth leaks. Using a new bench model of neonatal CPAP, we investigated the influence of mouth opening on oropharyngeal temperature and humidity. The model features the insertion of a heated humidifier between an active model lung and an oropharyngeal head model to simulate the recurrent expiration of heated, humidified air. During unsupported breathing, physiological temperature and humidity were attained inside the model oropharynx, and mouth opening had no significant effect on oropharyngeal temperature and humidity. During binasal CPAP, the impact of mouth opening was investigated using three different scenarios: no conditioning in the CPAP circuit, heating only, and heated humidification. Mouth opening had a strong negative impact on oropharyngeal humidification in all tested scenarios, but heated humidification in the CPAP circuit maintained clinically acceptable humidity levels regardless of closed or open mouths. The model can be used to test new equipment for use with CPAP, and to investigate the effects of other methods of non-invasive respiratory support on gas conditioning in the presence of leaks.

Nasal high-frequency oscillation ventilation in neonates: a survey in five European countries.

UNLABELLED: Nasal high-frequency oscillation ventilation (nHFOV) is a non-invasive ventilation mode that applies an oscillatory pressure waveform to the airways using a nasal interface. nHFOV has been shown to facilitate carbon dioxide expiration, but little is known about its use in neonates. In a questionnaire-based survey, we assessed nHFOV use in neonatal intensive care units (NICUs) in Austria, Switzerland, Germany, the Netherlands, and Sweden. Questions included indications for nHFOV, equipment used, ventilator settings, and observed side effects. Of the clinical directors of 186 NICUs contacted, 172 (92 %) participated. Among those responding, 30/172 (17 %) used nHFOV, most frequently in premature infants <1500 g (27/30) for the indication nasal continuous positive airway pressure (nCPAP) failure (27/30). Binasal prongs (22/30) were the most common interfaces. The median (range) mean airway pressure when starting nHFOV was 8 (6-12) cm H2O, and the maximum mean airway pressure was 10 (7-18) cm H2O. The nHFOV frequency was 10 (6-13) Hz. Abdominal distension (11/30), upper airway obstruction due to secretions (8/30), and highly viscous secretions (7/30) were the most common nHFOV side effects. CONCLUSION: In a number of European NICUs, clinicians use nHFOV. The present survey identified differences in nHFOV equipment, indications, and settings. Controlled clinical trials are needed to investigate the efficacy and side effects of nHFOV in neonates.

Development of left ventricular longitudinal speckle tracking echocardiography in very low birth weight infants with and without bronchopulmonary dysplasia during the neonatal period.

OBJECTIVES: In preterm infants, postnatal myocardial adaptation may be complicated by bronchopulmonary dysplasia (BPD). We aimed to describe the development of left ventricular function by serial 2D, Doppler, and speckle tracking echocardiography (2D-STE) in infants with and without BPD during the neonatal period and compare these to anthropometric and conventional hemodynamic parameters. STUDY DESIGN: Prospective echocardiography on day of life (DOL) 1, 7, 14, and 28 in 119 preterm infants <1500 g birth weight of whom 36 developed BPD (need for oxygen supplementation at 36 weeks gestational age). Non-BPD and BPD infants differed significantly in median (IQR) gestational age (25.5(24-26.5) weeks vs. 29(27-30) weeks, p<0.001) and birth weight (661(552-871) g vs. 1100(890-1290) g, p<0.001). RESULTS: The intra- and inter-observer variability of the 2D-STE parameters measured did not depend on time of measurement, although there were significant differences in the reproducibility of the parameters. Low intra- and inter-observer variability was seen for longitudinal systolic strain and strain rate mid septum with a median CV (coefficient of variation) of <4.6%. Much higher CVs (>10%) were seen for the apical segment. While anthropometric parameters show rapid development during the first 4 weeks of life, the speckle tracking parameters did not differ statistically significantly during the neonatal period. Infants with and without BPD differed significantly (p<0.001) in the development of anthropometric parameters, conventional hemodynamic parameters except for heart rate, and 2D-STE parameters: global longitudinal systolic strain rate (GLSSR) and longitudinal systolic strain for the mid left wall (LSSR). The largest differences were seen at DOL 1 and 7 in GLSSR (p<0.001) and in LSSR (p<0.01). CONCLUSIONS: Reproducible 2D-STE measurements are possible in preterm infants <1500 g. Cardiac deformation reveals early (DOL 1 and 7) ventricular changes (GLSSR and LSSR) in very low birth weight infants who develop BPD.

Tissue Doppler-derived strain and strain rate during the first 28 days of life in very low birth weight infants.

BACKGROUND: Preterm infants may have cardiac stress related to patent ductus arteriosus (PDA) or bronchopulmonary dysplasia (BPD). In this study, we examined the development of cardiac function in preterm infants by measuring tissue Doppler-derived peak systolic strain (PSS) and strain rate (PSSR) in the first 28 days of life. METHODS: Peak systolic strain and strain rate were measured in series in the free wall of the right (RV) and left (LV) ventricles on days 1, 7, 14, and 28 of life in 119 preterm infants <1500 g birth weight along with weight, heart rate, and presence of hemodynamically significant (hs) PDA or BPD. Both were assigned retrospectively. HsPDA was defined as a PDA requiring intervention whereas BPD was determined based on an infant's need for supplemental oxygen at 36 weeks of gestational age. RESULTS: Peak systolic strain and strain rate of the RV rose significantly during the first 28 days of life (P < 0.01). Infants who developed BPD had significantly lower RV free wall PSS on days 14 and 28 (P < 0.01 and <0.05). HsPDA resulted in a significantly lower PSS in the LV free wall as of day 14 (P < 0.01). After PDA intervention (day 28), LV PSS remained significantly lower (P < 0.05), but showed a tendency to increase (P = 0.18). CONCLUSIONS: Peak systolic strain determined in preterm infants appears to reflect increased afterload (decreased RV PSS in BPD infants) and increased preload (decreased LV PSS in hsPDA infants). The merits of such measurements as a basis for making clinical decisions still need to be explored.

Fetal and neonatal samples of a precursor surfactant protein B inversely related to gestational age.

BACKGROUND: Alveolar-capillary membrane leaks can increase the amount of surfactant protein B (SP-B) in the bloodstream. The purpose of this study was to measure the concentration of C-proSP-B, a SP-B precursor that includes C-terminal domains, in various body fluids of newborn infants and determine its dependence on gestational age. METHODS: C-pro-SPB was measured in amniotic fluid and umbilical cord blood at birth, and in peripheral blood and urine on postnatal day 3 in 137 newborn infants with a median birth weight of 2015 g (range, 550-4475 g) and gestational age of 34 weeks (range, 23-42 weeks). RESULTS: C-proSP-B levels differed more than 100-fold among samples. The levels (median; interquartile range) were highest in peripheral blood (655.6 ng/mL; 419.0-1467.0 ng/mL) and lowest in urine (3.08 ng/mL; 2.96-3.35 ng/mL). C-proSP-B levels in amniotic fluid (314.9 ng/mL; 192.7-603.6 ng/mL) were approximately half of those in peripheral blood. In cord blood C-proSP-B was slightly lower (589.1 ng/mL; 181.2-1129.0 ng/mL) compared with peripheral blood. C-proSP-B levels significantly increased in all the fluids sampled except urine with decreasing gestational age (p < 0.001). CONCLUSIONS: This novel assay allows for the quantitative measurement of C-proSP-B in blood and amniotic fluid. The dependence of C-proSP-B on gestational age may hamper its use for the detection of alveolar leaks in preterm newborns.

Reproducibility and optimization of analysis parameters of tissue Doppler-derived strain and strain rate measurements for very low birth weight infants.

AIMS: To assess the effects of region of interest (ROI) size and strain length (SL) on the quality of analysis and to determine the feasibility and reproducibility of tissue Doppler-derived cardiac strain (S) and strain rate (SR) measurements for preterm infants <1500 g birth weight. METHODS AND RESULTS: The beat-to-beat variation (BBV) for different combinations of ROI width (RW), ROI length (RL), and SL was determined from 60 good quality images of left and right free walls and the interventricular septum. We examined the impact of RW, RL, and SL on BBV and estimated inter- and intra-operator variability. BBV was smallest for RW = 2 mm. Raising SL (even at the cost of RL) led to a decrease in BBV. Several combinations provided a low BBV without significant difference. Coefficients of variation for intra- and inter-operator variability ranged from 15.1% to 65.2%. Both were lower for systolic than for diastolic values. CONCLUSION: Tissue Doppler imaging-derived S and SR measurements are feasible in very low birth weight infants. Reproducibility is comparable to older infants for systolic S and SR. For optimal analysis quality, SL and RW should be high while RL should be small (though inside segment size). Best results were obtained with RW = 2 mm, RL = 1 mm, and SL = 6 mm.

Left ventricular longitudinal strain and strain rate measured by 2-D speckle tracking echocardiography in neonates during whole-body hypothermia.

The purpose of the study was to assess changes in cardiac performance in newborn infants with hypoxic-ischemic encephalopathy during therapeutic hypothermia and rewarming with two-dimensional speckle tracking echocardiography. For eight asphyxiated neonates (median birth weight (range): 3038 (2725-3253) g; umbilical artery pH: 6.9 (6.8-7.18) undergoing whole-body hypothermia (33-34°C), left ventricular longitudinal strain and strain rate, as well as heart rate, cardiac output and left ventricular fractional shortening, were determined at four points in time: the start (T1) and end of hypothermia (T2), immediately after rewarming (T3) and the age of 5 to 7 d (T4). Mean (standard deviation) heart rate increased from 93 (12) beats/min at T1 to 133 (12) beats/min at T4 (p < 0.001). Cardiac output was low during hypothermia (T1: 207 [43] mL/kg/min, T2: 240 [70] mL/kg/min) and increased significantly (p < 0.001) afterward (T3: 329 [70] mL/kg/min, T4: 388 [78] mL/kg/min). Left ventricular fractional shortening remained unchanged. Left ventricular global longitudinal peak systolic strain did not differ significantly between hypothermia and rewarming, whereas the systolic strain rate increased from -1.1 (0.3) s(-1) at T1 to -1.8 (0.26) s(-1) at T4 (p = 0.001). Hypothermia affects peak systolic strain rate, heart rate and cardiac output, with complete recovery after rewarming, whereas peak systolic strain and fractional shortening remain stable.