Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Respiratory Support Effects over Time on Regional Lung Ventilation Assessed by Electrical Impedance Tomography in Premature Infants

Background and objectives: Respiratory distress syndrome (RDS) frequently necessitates respiratory support. While non-invasive methods are typically the preferred approach, mechanical ventilation becomes necessary for patients with insufficient response. Our study aimed to compare two common respiratory support modes, volume-targeted mechanical ventilation and non-invasive ventilation continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC), using electrical impedance tomography. Materials and Methods: Infants with very low birth weight and gestational ages of less than 32 weeks were eligible for inclusion in the study. All enrolled infants were beyond the transitional period (>72 h of age). The infants were divided into two groups: infants receiving invasive respiratory support through an endotracheal tube and infants receiving non-invasive respiratory support. We used electrical impedance tomography to assess end-expiratory lung impedance (EELZ), DeltaZ, heterogeneity, and regional ventilation distribution. Patients were evaluated at 0, 30, and 60 min after assuming the supine position to examine potential time-related effects. Results: Our study initially enrolled 97 infants, and the final analysis included a cohort of 72 infants. Ventilated infants exhibited significantly larger EELZ compared to their non-invasive counterparts (p = 0.026). DeltaZ was also greater in the invasive respiratory support group (p p = 0.005). Regional distribution in the left lung was lower than in the right lung in both groups; however, this difference was significantly more pronounced in intubated patients (p Conclusions: Our study revealed that volume-targeted mechanical ventilation results in higher EELZ and DeltaZ compared to spontaneously breathing infants receiving non-invasive respiratory support. However, lung heterogeneity was lower during mechanical ventilation. Our study also reaffirmed that spontaneous breathing promotes greater involvement of the dependent lung compared to mechanical ventilation

Brain and renal oxygenation measured by NIRS related to patent ductus arteriosus in preterm infants: a prospective observational study

Abstract Background Patent ductus arteriosus (PDA) is common among preterm neonates. Haemodynamically significant ductus arteriosus (hsPDA) can cause ductal steal and contribute to poor outcomes. Our aim was to evaluate ductus arteriosus patency and significance using two-site near-infrared spectroscopy (NIRS) measurements in preterm infants older than 72 h as a supplemental tool to echocardiography. Methods In this prospective observational study, 123 preterm infants (gestational age (GA) &lt; 32 weeks, birth weight &lt; 1500 g) were enrolled. Sixty-four newborns had closed ductus arteriosus (noPDA), and 41 and 18 patients were assigned to the PDA and hsPDA groups, respectively, per predefined echocardiographic criteria. Cerebral and renal oxygenation were assessed during NIRS monitoring. Results A higher renal mean (±SD) regional tissue oxygen saturation (rSpO2) (76.7 (±7.64)) was detected in the noPDA group than in the PDA (71.7 (±9.02)) and hsPDA (67.4 (±13.48)) groups (p &lt; 0.001). Renal fractional tissue oxygen extraction (FTOE) (0.18 (±0.079)) was lower in the noPDA group than in the PDA (0.23 (±0.092)) and hsPDA (0.24 (±0.117))0.117 groups (p = 0.002). Cerebral oxygenation was significantly lower in the hsPDA group (77.0 (±5.16)) than in the noPDA (79.3 (±2.45)) and PDA (79.7 (±2.27)) groups (p = 0.004). There was no significant difference in cerebral fractional tissue oxygen extraction (FTOE) between any of the groups. Conclusions Our results suggest that renal oxygenation is affected by ductus patency in preterm infants older than 72 h. Significant differences in cerebral oxygenation were observed between the hsPDA group and the PDA and noPDA groups. Trial registration ClinicalTrials.gov Identifier: NCT04295395. Registration date: 4 March 2020. This study was retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04295395. </jats:sec

Circadian changes in the composition of human milk macronutrients depending on pregnancy duration: a cross-sectional study

Abstract Background The purpose of this study was to evaluate the circadian variation of human milk macronutrients and energy content depending upon pregnancy duration. Methods One hundred eighty fresh human milk samples from 45 mothers (27 of preterm and 18 of full-term newborns) were collected on a single day chosen between the 14th to 16th day after delivery. The samples were taken four times per day at 12 PM, 6 PM, 12 AM and 6 AM. Only lactating women, who could not breastfeed their hospitalized newborns and expressed milk by breast pump, were enrolled in the study. Human milk macronutrient composition and energy count were evaluated by mid-infrared spectrophotometry. Results Significant differences in macronutrient content were observed between 6 AM and 12 PM for mean protein content (t = − 4.62, df = 44, p &lt; 0.001), for mean fat content (t = − 2.10, df = 44, p = 0.04) and for mean energy content (t = − 2.24, df = 44, p = 0.03); between 6 AM and 6 PM for mean protein content (t = − 2.41, df = 43, p = 0.02), for mean fat content (t = − 3.76, df = 43, p = 0.001) and for mean energy content (t = − 3.85, df = 43, p &lt; 0.001); between 12 PM and 12 AM for mean protein content (Wilcoxon test V = 75.5, p = 0.001), for mean fat content (t = 2.50, df = 44, p = 0.02) and for mean energy content (t = 2.74, df = 44, p = 0.01); between 6 PM and 12 AM for mean protein content (V = 229, p = 0.02), for mean fat content (t = 4.39, df = 43, p &lt; 0.001) and for mean energy content (t = − 4.57, df = 43, p &lt; 0.001). The average content of carbohydrates did not change significantly during the 24 h. The samples of preterm newborns’ mothers had more apparent diurnal fluctuations in macronutrient content. Conclusions Our study revealed significant diurnal variations in protein and fat in human milk, and these circadian fluctuations were more apparent in the milk of mothers of preterm infants. </jats:sec

A Prospective Study of Nephrocalcinosis in Very Preterm Infants: Incidence, Risk Factors and Vitamin D Intake in the First Month

Background and objectives: Nephrocalcinosis (NC) is a common condition characterized by the deposition of calcium salts in the kidneys of very preterm infants due to tubular immaturity, intensive treatment and nutritional supplements. However, optimal vitamin D supplementation remains unclear. In most patients, NC spontaneously resolves within the first year of life, but long-term kidney function data are lacking. The aim was to study nephrocalcinosis in very preterm infants, assess risk factors and evaluate vitamin D’s impact during the first month with a 2-year follow-up. Material and Methods: This was a prospective observational study conducted over a 3-year period in infants with a gestational age of less than 32 weeks. The patients’ data were compared between the NC and control groups based on kidney ultrasound results at discharge. In the first month, the mean vitamin D intake from all sources as well as biochemical markers of calcium metabolism were collected. Patients diagnosed with NC were referred to a pediatric nephrologist after discharge. Results: NC was found in 35% of a cohort of 160 infants, more common in those with a gestational age p p p p Conclusions: The prevalence of NC in very preterm infants is significant, associated with lower maturity and higher morbidity. Careful vitamin D supplementation and biochemical monitoring of Ca metabolism from the first month of life should support bone health and limit the risk of nephrocalcinosis. Due to the high incidence of NC in very preterm infants, long-term follow-up is essential

Pharmacokinetics and safety of ceftobiprole in pediatric patients

Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia. METHODS: Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10–20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days). RESULTS: Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 μg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 μg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies. CONCLUSIONS: Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated

Nasal high-frequency oscillatory ventilation and CO2 removal: A randomized controlled crossover trial

Objective: To compare short-term application of nasal high-frequency oscillatory ventilation (nHFOV) with nasal continuous positive airway pressure (nCPAP). Working Hypothesis: nHFOV improves CO2 removal with respect to nCPAP in preterm infants needing noninvasive respiratory support and persistent oxygen supply after the first 72 h of life. Study Design: Multicenter non-blinded prospective randomized crossover study. Patient Selection: Thirty premature infants from eight tertiary neonatal intensive care units, of mean \ub1 SD 26.4 \ub1 1.8 weeks of gestational age and 921 \ub1 177 g of birth weight. Methodology: Infants were randomly allocated in a 1:1 ratio to receive a starting treatment mode of either nCPAP or nHFOV delivered by the ventilator CNO (Medin, Germany), using short binasal prongs of appropriate size. A crossover design with four 1-h treatment periods was used, such that each infant received both treatments twice. The primary outcome was the mean transcutaneous partial pressure of CO2 (TcCO2) value during the 2-h cumulative period of nHFOV compared with the 2-h cumulative period of nCPAP. Results: Significantly lower TcCO2 values were observed during nHFOV compared with nCPAP: 47.5 \ub1 7.6 versus 49.9 \ub1 7.2 mmHg, respectively, P = 0.0007. A different TcCO2 behavior was found according to the random sequence: in patients starting on nCPAP, TcCO2 significantly decreased from 50.0 \ub1 8.0 to 46.6 \ub1 7.5 mmHg during nHFOV (P = 0.001). In patients starting on nHFOV, TcCO2 slightly increased from 48.5 \ub1 7.8 to 49.9 \ub1 6.7 mmHg during nCPAP (P = 0.13). Conclusions: nHFOV delivered through nasal prongs is more effective than nCPAP in improving the elimination of CO2