A multicentre neonatal interventional randomised controlled trial of nebulized surfactant for preterm infants with respiratory distress: Neo-INSPIRe trial protocol.

INTRODUCTION: Respiratory distress syndrome in preterm infants is an important cause of morbidity and mortality. Less invasive methods of surfactant administration, along with the use of continuous positive airway pressure (CPAP), have improved outcomes of preterm infants. Aerosolized surfactant can be given without the need for airway instrumentation and may be employed in areas where these skills are scarce. Recent trials from high-resourced countries utilising aerosolized surfactant have had a low quality of evidence and varying outcomes. METHODS AND ANALYSIS: The Neo-INSPIRe trial is an unblinded, multicentre, randomised trial of a novel aerosolized surfactant drug/device combination. Inclusion criteria include preterm infants of 27-34+6 weeks' gestational age who weigh 900-1999g and who require CPAP with a fraction of inspired oxygen (FiO2) of 0.25-0.35 in the first 2-24 h of age. Infants are randomised 1:1 to control (CPAP alone) or intervention (CPAP with aerosolized surfactant). The primary outcome is the need for intratracheal bolus surfactant instillation within 72 h of age. Secondary outcomes include the incidence of reaching failure criteria (persistent FiO2 of > 0.40, severe apnoea or severe work of breathing), the need for and duration of ventilation and respiratory support, bronchopulmonary dysplasia and selected co-morbidities of prematurity. Assuming a 40% relative risk reduction to reduce the proportion of infants requiring intratracheal bolus surfactant from 45 to 27%, the study will aim to enrol 232 infants for the study to have a power of 80% to detect a significant difference with a type 1 error of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at University of Cape Town (HREC 681/2022), University of the Witwatersrand HREC (221112) and Stellenbosch University (M23/02/004). TRIAL REGISTRATION: PACTR202307490670785.

Effect of a Multi-Strain Probiotic on the Incidence and Severity of Necrotizing Enterocolitis and Feeding Intolerances in Preterm Neonates.

Background: Necrotizing enterocolitis (NEC) is a multifactorial disease, causing inflammation of the bowel. The exact root of NEC is still unknown, but a low weight and gestational age at birth are known causes. Furthermore, antibiotic use and abnormal bacterial colonization of the premature gut are possible causes. Premature neonates often experience feeding intolerances that disrupts the nutritional intake, leading to poor growth and neurodevelopmental impairment. Methods: We conducted a double-blind, placebo-controlled, randomized clinical trial to investigate the effect of a multi-strain probiotic formulation (LabinicTM) on the incidence and severity of NEC and feeding intolerances in preterm neonates. Results: There were five neonates in the placebo group who developed NEC (Stage 1A−3B), compared to no neonates in the probiotic group. Further, the use of probiotics showed a statistically significant reduction in the development of feeding intolerances, p < 0.001. Conclusion: A multi-strain probiotic is a safe and cost-effective way of preventing NEC and feeding intolerances in premature neonates.

Accuracy and Trending Ability of Electrical Biosensing Technology for Non-invasive Cardiac Output Monitoring in Neonates: A Systematic Qualitative Review.

Background: Electrical biosensing technology (EBT) is an umbrella term for non-invasive technology utilizing the body's fluctuating resistance to electrical current flow to estimate cardiac output. Monitoring cardiac output in neonates may allow for timely recognition of hemodynamic compromise and allow for prompt therapy, thereby mitigating adverse outcomes. For a new technology to be safely used in the clinical environment for therapeutic decisions, it must be proven to be accurate, precise and be able to track temporal changes. The aim of this systematic review was to identify and analyze studies that describe the accuracy, precision, and trending ability of EBT to non-invasively monitor Left ventricular cardiac output and/or stroke volume in neonates. Methods: A qualitative systematic review was performed. Studies were identified from PubMed NCBI, SCOPUS, and EBSCOHost up to November 2021, where EBT technologies were analyzed in neonates, in comparison to a reference technology. Outcome measures were bias, limits of agreement, percentage error for agreement studies and data from 4-quadrant and polar plots for trending studies. Effect direction plots were used to present results. Results: Fifteen neonatal studies were identified, 14 for agreement and 1 for trending analysis. Only thoracic electrical biosensing technology (TEBT), with transthoracic echocardiography (TTE) as the comparator, studies were available for analyzes. High heterogeneity existed between studies. An equal number of studies showed over- and underestimation of left ventricular output parameters. All studies showed small bias, wide limits of agreement, with most studies having a percentage error >30%. Sub-analyses for respiratory support mode, cardiac anomalies and type of technology showed similar results. The single trending study showed poor concordance, high angular bias, and poor angular concordance. Discussion: Overall, TEBT shows reasonable accuracy, poor precision, and non-interchangeability with TTE. However, high heterogeneity hampered proper analysis. TEBT should be used with caution in the neonatal population for monitoring and determining therapeutic interventions. The use of TEBT trend monitoring has not been sufficiently studied and requires further evaluation in future trials.

Pulmonary Echinococcus in children: A descriptive study in a LMIC.

BACKGROUND: Echinococcus granulosus is a major public health problem in lower middle-income countries (LMIC). Children are commonly diagnosed with cysts in the lungs and/or the liver. OBJECTIVES: The purpose of this study was to describe a pediatric cohort diagnosed with pulmonary Cystic Echinococcus (CE) and treated with a combination of medical and surgical therapy. METHODS: This was a retrospective study performed between July 2017 and December 2020 at Tygerberg Hospital, South Africa. Clinical, laboratory, radiological, medical, and surgery-related outcomes were reviewed. RESULTS: The cohort consisted of 35 children, 17 (49%) were male, with a mean age of 9 ± 5.4 years. The most frequently encountered presenting symptom was cough (93%) followed by fever (70%). Isolated pulmonary CE accounted for the majority of cases (74%) with left lower lobe predominance. A significant proportion of the cohort exhibited chest computed tomography (CT) characteristics consistent with complicated pulmonary CE. Eighteen (58%) children had a positive indirect hemagglutination assay (IHA) test result. All children received medical treatment whilst 30 (86%) of children required surgery. Children with complicated pulmonary CE stayed a mean of 12.5 ± 6.6 days, while those with simple cysts stayed 6.8 ± 1.5 days. CONCLUSION: Isolated pulmonary CE is common in children, whereas extrapulmonary cysts are uncommon. Pulmonary CE is diagnosed using chest X-ray and, CT imaging. IHA serology has limited diagnostic utility for pulmonary CE. Combined surgery and chemotherapy remains the gold standard for treating pulmonary CE.

Bioreactance-derived haemodynamic parameters in the transitional phase in preterm neonates: a longitudinal study.

Bioreactance (BR) is a novel, non-invasive technology that is able to provide minute-to-minute monitoring of cardiac output and additional haemodynamic variables. This study aimed to determine the values for BR-derived haemodynamic variables in stable preterm neonates during the transitional period. A prospective observational study was performed in a group of stable preterm (< 37 weeks) infants in the neonatal service of Tygerberg Children's Hospital, Cape Town, South Africa. All infants underwent continuous bioreactance (BR) monitoring until 72 h of life. Sixty three preterm infants with a mean gestational age of 31 weeks and mean birth weight of 1563 g were enrolled. Summary data and time series graphs were drawn for BR-derived heart rate, non-invasive blood pressure, stroke volume, cardiac output and total peripheral resistance index. All haemodynamic parameters were significantly associated with postnatal age, after correction for clinical variables (gestational age, birth weight, respiratory support mode). To our knowledge, this is the first paper to present longitudinal BR-derived haemodynamic variable data in a cohort of stable preterm infants, not requiring invasive ventilation or inotropic support, during the first 72 h of life. Bioreactance-derived haemodynamic monitoring is non-invasive and offers the ability to simultaneously monitor numerous haemodynamic parameters of global systemic blood flow. Moreover, it may provide insight into transitional physiology and its pathophysiology.

Bioreactance Cardiac Output Trending Ability in Preterm Infants: A Single Centre, Longitudinal Study.

INTRODUCTION: It is unknown whether bioreactance (BR) can accurately track cardiac output (CO) changes in preterm neonates. METHODS: A prospective observational longitudinal study was performed in stable preterm infants (<37 weeks) during the first 72 h of life. Stroke volume (SV) and CO, as measured by BR and transthoracic echocardiography, were compared. RESULTS: The mean gestational age (GA) was 31.3 weeks and mean birth weight (BW) was 1,563 g. Overall, 690 measurements were analysed for trending ability by 4-quadrant and polar plots. For non-weight-indexed measurements, 377 (54.6%) lay outside the 5% exclusion zone, the concordance rate was poor (77.2%) with a high mean angular bias (28.6°), wide limits of agreement and a poor angular concordance rate (17.4%). Neither GA, BW nor respiratory support mode affected trending data. Patent ductus arteriosus, postnatal age, and CO level had variable effects on trending data. Trending data for 5 and 10% exclusion zones were also compared. CONCLUSION: The ability of BR to track changes in CO is not interchangeable with CO changes as measured by echocardiography. BR, as a trend monitor for changes in CO or SV to determine clinical decisions around interventions in neonatology, should be used with caution.

Somatic Growth of Enteral-Only Fed Extremely Low Birth Weight Infants in a Resource-Restricted Setting.

AIM: To determine the growth and prevalence of extrauterine growth restriction (EUGR) in extremely low birth weight (ELBW) infants receiving enteral-only nutrition in a resource-restricted (RR) environment. METHODS: Information on nutritional intake, provided largely from fortified breastmilk, was collected retrospectively for 72 ELBW (<1000 g) infants admitted to Tygerberg Hospital, Cape Town, South Africa over a 1 year period. Anthropometric data for the first 49 postnatal days were compared to gender-specific INTERGROWTH-21st standards. RESULTS: Full enteral feeds (150 ml/kg) were reached by Day 10-14 with energy >100 Kcal/kg/day from Day 10, and protein >3.5 mg/kg/day from Day 14, onwards. Growth velocity remained below 15 g/kg/day at Day 49. INTERGROWTH-21st Z-scores decreased from -0.8 ± 1.1 at birth to -2.4 ± 1.5 at Day 49. Adequate weight growth velocity (≥15 g/kg/day) was associated with maternal hypertension, completed antenatal steroids, caesarean section delivery and small for gestational age status. CONCLUSION: This is the first study to evaluate growth of ELBW infants in a RR setting where enteral-only nutrition, principally from fortified breastmilk, was the primary feeding option. The incidence of EUGR, although high, was similar to the incidence in well-resourced settings, where total parenteral nutrition is routinely provided. Lay summaryExtra-uterine growth restriction (EUGR) is high in extremely low birth weight infants receiving enteral-only nutrition. However, EUGR rates are similar to infants receiving parenteral nutrition. Despite developmental immaturity, it is possible for these infants to achieve fetal growth rates. More aggressive feeding and fortification strategies may be necessary and will need to be balanced against the risk and fear of necrotizing enterocolitis. Enteral-only feeding regimens, especially in resource-restricted environments, should be audited regularly to ensure provision of feeds with the most optimal protein, and protein to energy ratios possible.

Bronchoscopy in children with COVID-19: A case series.

INTRODUCTION: The coronavirus disease-2019 (COVID-19) era is a challenging time for respiratory teams to protect their patients and staff. COVID-19 is predominantly transmitted by respiratory droplets; in the clinical setting, aerosol generating procedures pose the greatest risk for COVID-19 transmission. Bronchoscopy is associated with increased risk of patient-to-health care worker transmission, owing to aerosolized viral particles which may be inhaled and also result in environmental contamination of surfaces. METHODS: We describe our experience with the use of modified full-face snorkeling masks for pediatric bronchoscopy procedures in four COVID-19 infected children when filtering facepieces/respirators were in limited supply. RESULTS: Bronchoscopy was urgently required in four children, and could not be delayed until COVID-19 test results were available. During the pandemic peak, when respirators were in short supply, modified full-face snorkel masks (SEAC Libera, SEAC, Italy) were worn by the bronchoscopy team. Each mask was fitted with an O-ring, adapter, and heat and moisture exchanger filter. To date, there have been no COVID-19 infections among the bronchoscopy team staff, whereas the overall Hospital staff COVID-19 prevalence rate has exceeded 13.5% (667/4949). CONCLUSION: Emergency bronchoscopy procedures on COVID-19 infected patients or patients with unknown infection status can be safely performed using modified full-face snorkel masks.

Optimal Ventilation and Surfactant Therapy in Very-Low-Birth-Weight Infants in Resource-Restricted Regions.

In resource-restricted regions, respiratory distress syndrome (RDS) data are often underreported, making the determination of effective interventions and their outcome difficult. The combination of oxygen, nasal continuous positive airway pressure (CPAP) and surfactant therapy has the potential to prevent 42% of RDS-related deaths in sub-Saharan Africa, despite the financial implications. This article provides a brief overview on the status of RDS management, mainly nasal CPAP and surfactant therapy in very-low-birth-weight infants, in resource-restricted regions of sub-Saharan Africa. Data from the public health sector, as compared to the private health sector, of the Western Cape province, South Africa, are used to illustrate what RDS management strategies are able to accomplish in a resource-restricted region. Upscaling of all components (antenatal care, antenatal corticosteroids, prevention of hypothermia and RDS management strategies) are required to decrease premature infant mortality rates in resource-restricted areas.

Management of children with tuberculous broncho-esophageal fistulae.

INTRODUCTION: Broncho-esophageal fistula (BOF) is a rare complication of Mycobacterium tuberculosis (MTB). TB-associated BOF presents either as acute respiratory failure, aspiration pneumonia or as a complication of surgical decompression of thoracic lymph nodes. METHODS: All children with TB- associated BOF were included. TB was diagnosed if MTB was cultured from respiratory secretions, Ziehl-Neelsen (ZN) smear was positive, GeneXpert MTB/RIF was positive or a chest radiograph revealed radiographic features typical of TB. BOF was diagnosed by a contrast swallow study and/or flexible bronchoscopy. Chest computed tomography (CT) scan was performed, if required. RESULTS: Total of 20 children were diagnosed with TB-associated BOF between 1999 and 2019, with a 75% survival. A total of 85% BOF involved the left main bronchus. A total of 80% of patients were MTB culture or ZN smear-positive. Chest X-ray abnormalities included: extensive parenchymal disease (80%) and lymph gland enlargement (45%). CT features included visualization of the BOF (60%), esophageal air (73%) and pneumomediastinum (40%). BOF closure was achieved by surgical closure (46%), spontaneous closure (26%), fibrin glue (13%), and esophageal stent (13%). Multivariant regression analysis showed that C- reactive protein (CRP), albumin and CRP/albumin ratio were associated with mortality. CONCLUSION: Most TB-associated BOF are left-sided. It presents either acutely, with respiratory failure, or with chronic respiratory symptoms of aspiration. Children requiring invasive ventilation have high mortality. Most TB-associated BOF requires surgical intervention, although the use of fibrin glue offers an attractive alternative option.

Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates.

BACKGROUND: The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients. OBJECTIVE: The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen. METHODS: This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration-time curve up to 24 h (AUC0-24h) of ≥ 400 mg × h/L. RESULTS: In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3-58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC0-24h of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h. CONCLUSION: The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC0-24h target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.

Agreement of Cardiac Output Measurements between Bioreactance and Transthoracic Echocardiography in Preterm Infants during the Transitional Phase: A Single-Centre, Prospective Study.

INTRODUCTION: Bioreactance cardiac output (CO) monitors are able to non-invasively and continuously monitor CO. However, as a novel tool to measure CO, it must be proven to be accurate and precise. OBJECTIVE: To determine the agreement between CO measured with a bioreactance monitor and transthoracic echocardiography-derived left ventricular output parameters in preterm infants. METHODS: This is a prospective observational study in 63 preterm neonates with non-invasive respiratory support, not requiring inotrope support. The infants underwent continuous bioreactance monitoring of CO and stroke volume (SV) and simultaneous transthoracic echocardiography every 6 h until 72 h of life. RESULTS: The agreement between bioreactance and transthoracic echocardiography, for both SV and CO, was poor. The percentage error was 67.5% for SV and 71.6% for CO. The mean error was 60.4% for SV and 69.8% for CO. Bias was affected by numerous variables. After correcting for time, CO and SV bias were significantly affected by the presence of an open patent ductus arteriosus and the level of CO. CONCLUSION: Bioreactance cannot be considered interchangeable with transthoracic echocardiography to measure CO in preterm infants during the transition phase. Agreement between bioreactance and other CO metrics should be assessed before concluding its accuracy or inaccuracy in neonates.