Electrocardiographic Characteristics in 438 Neonates with Atrial Septal Defects.

Arrhythmias and electrocardiographic (ECG) abnormalities are common among patients with atrial septal defects (ASDs). We studied a large cohort of neonates with ASDs to investigate whether ECG abnormalities are present at this early stage or develop later, secondary to hemodynamic changes. We analyzed the echocardiograms and ECGs from the Copenhagen Baby Heart Study, a population-based cohort study. We compared ECG characteristics of 438 neonates with secundum ASDs to 1314 matched controls. In subgroup analyses, we investigated whether electrocardiographic characteristics were associated with age at examination. Neonates with ASDs (median age, 11 days; males, 51%) had longer P-wave durations (58 vs. 56 ms, p < 0.001), PR intervals (100 vs. 96 ms, p < 0.001), and a more rightward-shifted QRS axis (116 vs. 114 degrees, p = 0.032) compared to controls (median age, 10 days; males, 51%). There were no differences between cases and controls in the P-wave area, amplitude, or axis. Subgroup analyses showed that the differences in P-wave duration and PR interval were present in neonates examined in the first week after birth. The difference in the QRS axis was not found in neonates examined this early but was found in neonates examined at age two to four weeks. In conclusion, ASDs are associated with ECG changes from the neonatal phase. The P-wave duration and PR interval are longer in neonates with ASDs when compared to controls as early as the first week after birth, indicating that these changes are not purely secondary, but that neonates with an ASD have altered cardiac electrical activity.ClinicalTrials.gov Identifier NCT02753348 (April 27, 2016).

Age-Related Prevalence of Open Ductus Arteriosus in Full-Term Newborns.

BACKGROUND: The ductus arteriosus is part of the fetal circulation. Normally, the vessel closes during the cardiac transition. Delayed closure is associated with complications. The aim of this study was to evaluate the age-related prevalence of open ductus arteriosus in full-term neonates. METHODS: Echocardiograms were collected in the population study, the Copenhagen Baby Heart Study. The present study included full-term neonates with an echocardiogram performed within 28 days after birth. All echocardiograms were reviewed to assess ductus arteriosus patency. RESULTS: A total of 21,649 neonates were included. In neonates examined at day zero and day seven, an open ductus arteriosus was found in 36% and 0.6%, respectively. Beyond day seven, the prevalence remained stable at 0.6%. CONCLUSION: More than one-third of full-term neonates had an open ductus arteriosus on the first day of life, declining rapidly within the first week and stabilizing below 1% after day seven.

Atrial Septal Defect: Larger Right Ventricular Dimensions and Atrial Volumes as Early as in the First Month After Birth-a Case-Control Study Including 716 Neonates.

Atrial septal defect (ASD) is characterized by a left-to-right shunt causing dilatation of the right atrium and right ventricle as well as pulmonary hyperperfusion. The detection of ASDs often occurs late in childhood or adulthood. Little is known about cardiac structure and function in neonates with ASD.We analyzed neonatal echocardiograms from the Copenhagen Baby Heart Study, a multicenter, population-based cohort study of 27,595 neonates. We included 716 neonates with secundum-type ASDs and matched them 1:1 on sex and age at examination with neonates without ASD from the same birth cohort. Neonates with an ASD (median age 11 days, 52% female) had larger right ventricular (RV) dimensions than matched controls (RV longitudinal dimension end-diastole: 27.7 mm vs. 26.7 mm, p < 0.001; RV basal dimension end-diastole: 14.9 mm vs. 13.8 mm, p < 0.001; and RV outflow tract diameter 13.6 mm vs. 12.4 mm, p < 0.001). Atrial volumes were larger in neonates with ASD compared to controls (right atrial end-systolic volume: 2.9 ml vs. 2.1 ml, p < 0.001; and left atrial end-systolic volume 2.0 ml vs. 1.8 ml, p < 0.001). Tricuspid annular plane systolic excursion was larger in neonates with ASD than in controls (10.2 mm vs. 9.6 mm, p < 0.001). Left ventricular dimensions and function did not differ between neonates with ASD and controls. In conclusion, ASDs were associated with altered cardiac dimensions already in the neonatal period, with larger right ventricular dimensions and larger atrial volumes at echocardiography within the first 30 days after birth.ClinicalTrials.gov Identifier: NCT02753348 (April 27, 2016).

Hospital admissions and need for mechanical ventilation in children with respiratory syncytial virus before and during the COVID-19 pandemic: a Danish nationwide cohort study.

BACKGROUND: The incidence of respiratory syncytial virus (RSV) increased in several countries after the relaxation of COVID-19 restrictions. We aimed to investigate the age-related risk of RSV-associated hospital admissions and need for mechanical ventilation during the RSV resurgence in summer and autumn 2021 compared with the four RSV seasons preceding the COVID-19 pandemic. We also aimed to describe the clinical complications necessitating mechanical ventilation. METHODS: This population-based cohort study included patients aged 0-17 years admitted to hospital with RSV in Denmark during the RSV resurgence in summer and autumn 2021, and the four pre-COVID-19 RSV seasons (2016-17, 2017-18, 2018-19, and 2019-20). We retrieved data on RSV-associated hospital admissions from the Danish National Patient Registry and demographic and clinical details of children who received mechanical ventilation through prospective real-time data collection in 2021-22 and retrospective data collection for the 2016-17 to 2019-20 RSV seasons from all eight paediatric and neonatal intensive care units in Denmark. Risk factors for severe RSV disease were as defined as age younger than 3 months or severe comorbidities. We calculated the risk of RSV-associated hospital admissions per 100 000 population in each RSV season from week 21 to week 20 of the following year. We also calculated the risk rate of receiving mechanical ventilation per 100 000 population and 1000 RSV-associated hospital admissions during each RSV season from week 21 to week 20 of the following year. We calculated risk ratios (RRs) for hospital admission and mechanical ventilation by dividing the risk rate of hospital admission and mechanical ventilation in 2021-22 by annual mean risk rates in the four pre-COVID-19 RSV epidemics (2016-17 to 2019-20). We compared RRs using Fisher's exact test. We compared complications leading to intubation between children with and without risk factors for severe RSV disease. The study is registered at ClinicalTrials.gov, NCT05186597. FINDINGS: Among 310 423 Danish children aged younger than 5 years, the mean number of RSV-associated hospital admissions increased from 1477 (SD 226) in the 2016-17 to 2019-20 RSV seasons to 3000 in the 2021-22 RSV season (RR 2·0 [95% CI 1·9-2·1]). 54 children with RSV received mechanical ventilation in 2021-22 compared with 15-28 annually in the 2016-17 to 2019-20 RSV seasons (2·3 [1·6-3·3]). The highest increase in hospital admissions and need for mechanical ventilation occurred among children aged 24-59 months (4·1 [3·6-4·7] for hospital admission; 4·6 [1·7-12·6] for mechanical ventilation). Among children admitted to hospital, the risk of mechanical ventilation was similar in 2021-22 and the four pre-COVID-19 seasons (risk rate 14·3 per 1000 RSV-associated hospital admissions [95% CI 10·4-19·3] vs 12·9 [10·1-16·1]; RR 1·1 [95% CI 0·8-1·6]). Across all RSV seasons studied, among children younger than 3 months or those with severe comorbidities, respiratory failure due to bronchiolitis led to mechanical ventilation in 69 (79%) of 87 children. Of 46 children with no risk factors for severe RSV, 40 (87%) received mechanical ventilation due to additional complications, including neurological (n=16; 35%), cardiac (n=1; 2%), and pulmonary complications (n=23; 50%; eg, wheeze responsive to bronchodilator therapy, severe bacterial co-infections, and pneumothorax). INTERPRETATION: In Denmark, RSV disease did not seem to be more severe for the individual child during the RSV resurgence in 2021 following relaxation of COVID-19 restrictions. However, hospital admissions were higher among older children, possibly due to a postponed first RSV infection or no recent reinfection. Older children without risk factors for severe RSV disease had atypical complications that led to intubation. If new RSV-preventive interventions for healthy infants delay first RSV infection, a higher number of older children might be admitted to hospital due to atypical clinical phenotypes, rather than classical bronchiolitis. FUNDING: National Ministry of Higher Education and Science and the Innovation Fund Denmark.

The Patent Ductus Arteriosus in Extremely Preterm Neonates Is More than a Hemodynamic Challenge: New Molecular Insights.

Complications to preterm birth are numerous, including the presence of a patent ductus arteriosus (PDA). The biological understanding of the PDA is sparse and treatment remains controversial. Herein, we speculate whether the PDA is more than a cardiovascular imbalance, and may be a marker in response to immature core molecular and physiological processes driven by biological systems, such as inflammation. To achieve a new biological understanding of the PDA, we performed echocardiography and collected plasma samples on day 3 of life in 53 consecutively born neonates with a gestational age at birth below 28 completed weeks. The proteome of these samples was analyzed by mass spectrometry (nanoLC-MS/MS) and immunoassay of 17 cytokines and chemokines. We found differences in 21 proteins and 8 cytokines between neonates with a large PDA (>1.5 mm) compared to neonates without a PDA. Amongst others, we found increased levels of angiotensinogen, periostin, pro-inflammatory associations, including interleukin (IL)-1ß and IL-8, and anti-inflammatory associations, including IL-1RA and IL-10. Levels of complement factors C8 and carboxypeptidases were decreased. Our findings associate the PDA with the renin-angiotensin-aldosterone system and immune- and complement systems, indicating that PDA goes beyond the persistence of a fetal circulatory connection of the great vessels.

Increased inflammatory markers in adult patients born with an atrial septal defect.

Patients with atrial septal defect (ASD) have higher mortality and higher risk of atrial fibrillation, heart failure, pneumonia, and stroke than the general population even if the ASD closes spontaneously in childhood. The reason for the long-term complications remains unknown. Since many of the complications can be linked up with alterations in inflammatory response, we speculate that inflammation may contribute to the association between ASD and morbidity and mortality. We investigated inflammatory activity in adults with an ASD compared with controls. We included 126 adults with an unrepaired ASD. A group of healthy controls were recruited as comparison group (n = 23). Serum samples were analyzed for 92 inflammation-related protein biomarkers using a proximity extension assay. A pathway enrichment analysis was performed using Reactome database. Out of 92 biomarkers, 73 were eligible for data analysis. Increased levels of 14 (19%) biomarkers were found in patients with open ASD and 24 (33%) biomarkers in patients with spontaneously closed defects compared with controls (p < 0.05). Multiple inflammatory pathways showed stronger enrichment in both patient groups when compared with controls. In conclusion, inflammatory activity is altered in adult patients with an unrepaired ASD compared with healthy controls. The increased inflammatory burden of patients with an unrepaired ASD may contribute to the development of morbidities.

Cardiovascular biomarkers in the evaluation of patent ductus arteriosus in very preterm neonates: A cohort study.

BACKGROUND: The evaluation of the patent ductus arteriosus (PDA) in the very premature neonate is a challenge. Echocardiography provides an interpretation of the hemodynamic condition. It is however, only a snapshot. Biomarkers may represent a physiological response to the hemodynamic alterations brought on by the PDA and may add to the identification of the clinical significant PDA. AIM: To investigate the association between mid regional proadrenomodulin (MR-proADM), N-terminal pro b-type natriuretic peptide (NT-proBNP), mid regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro endothelin-1 (CT-proET1) and copeptin and echocardiographic measures of PDA. STUDY DESIGN: Cohort study with echocardiography performed on day 3 and 6. Blood samples from day 3. SUBJECT: 139 consecutive neonates born at a gestational age <32 weeks. OUTCOME MEASURES: The main outcomes were presence of a PDA day 3 and 6, PDA diameter, left atrium to aorta ratio (LA:Ao-ratio), and descending aorta diastolic flow (DADF). RESULTS: Adjusted plasma levels of all investigated biomarkers, except CT-proET1, were found to be associated with both PDA diameter and LA:Ao-ratio, and also the presence of a large PDA. CT-proET1 and copeptin was found to be associated with abnormal DADF. Using pre-specified cut-off values NT-proBNP and MR-proANP day 3 seemed to be of value in identifying a large PDA day 3 and 6 in very preterm neonates. CONCLUSION: Among the investigated biomarkers NT-proBNP and MR-proANP performed best in relation to echocardiographic markers of PDA severity in very preterm neonates.

Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation: A Randomized Clinical Trial.

Importance: Nasal continuous positive airway pressure (nCPAP) is a well-established treatment of respiratory distress syndrome in preterm infants. Suboptimal weaning from nCPAP may be associated with lung injury, pulmonary morbidity, and infant weight gain. To our knowledge, the best weaning strategy from nCPAP is unknown. Objective: To compare the effect of sudden wean and pressure wean from nCPAP in very preterm infants. Design, Setting, and Participants: A randomized, clinical, open-label, multicenter trial was conducted at 6 neonatal intensive care units in Denmark from September 2012 to December 2016 and included infants born before 32 weeks of gestation. Interventions: Sudden wean with discontinuation of nCPAP without a prior reduction in pressure. Pressure wean with gradual pressure reduction prior to the discontinuation of nCPAP. Main Outcome and Measures: The primary outcome was weight gain velocity from randomization to postmenstrual age 40 weeks. Secondary outcomes included other measures of growth, nCPAP and the duration of oxygen supplementation, postmenstrual age at successful wean and at discharge, successful wean at the first attempt, the number of attempts to wean, and the length of the hospital stay. Prespecified subgroup analyses by gestational age were performed. Results: Of the 372 randomized infants, 185 (49.7%) were randomized to sudden wean and 187 infants (50.3%) to pressure wean. A total of 177 infants in both groups completed the trial (median gestational age for sudden and pressure wean, 30 weeks [interquartile range, 29-31]; male: sudden wean, 89 [50%]; pressure wean, 96 [54%]). There was no difference in mean [SD] weight gain velocity from randomization to 40 weeks postmenstrual age between the 2 groups (22 [6] g/kg/day). No difference was found in any of the secondary outcomes. More infants born before 28 weeks of gestation were successfully weaned from nCPAP during the first attempt in the pressure wean group compared with the sudden wean group (risk difference, 31%; 95% CI, 13%-50%), but there was no difference in the duration of nCPAP and oxygen supplementation. Conclusions and Relevance: Overall, we found no difference in weight gain velocity or any of the secondary outcomes between very preterm infants who were randomized to sudden wean or pressure wean from nCPAP. However, among infants born before 28 weeks' gestation, infants from the pressure wean group were more often successfully weaned during the first attempt without a longer total duration of nCPAP treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01721629.

Urinary Neutrophil Gelatinase-associated Lipocalin in the evaluation of Patent Ductus Arteriosus and AKI in Very Preterm Neonates: a cohort study.

BACKGROUND: A patent ductus arteriosus (PDA) is frequently found in very preterm neonates and is associated with increased risk of morbidity and mortality. A shunt across a PDA can result in an unfavorable distribution of the cardiac output and may in turn result in poor renal perfusion. Urinary Neutrophil Gelatinase-associated Lipocalin (U-NGAL) is a marker of renal ischemia and may add to the evaluation of PDA. Our primary aim was to investigate if U-NGAL is associated with PDA in very preterm neonates. Secondary, to investigate whether U-NGAL and PDA are associated with AKI and renal dysfunction evaluated by fractional excretion of sodium (FENa) and urine albumin in a cohort of very preterm neonates. METHODS: A cohort of 146 neonates born at a gestational age less than 32 weeks were consecutively examined with echocardiography for PDA and serum sodium, and urine albumin and sodium were measured on postnatal day 3 and U-NGAL and serum creatinine day 3 and 6. AKI was defined according to modified neonatal Acute Kidney Injury Network (AKIN) criteria. The association between U-NGAL and PDA was investigated. And secondly we investigated if PDA and U-NGAL was associated with AKI and renal dysfunction. RESULTS: U-NGAL was not associated with a PDA day 3 when adjusted for gestational age and gender. A PDA day 3 was not associated with AKI when adjusted for gestational age and gender; however, it was associated with urine albumin. U-NGAL was not associated with AKI, but was found to be associated with urine albumin and FENa. CONCLUSIONS: Based on our study U-NGAL is not considered useful as a diagnostic marker to identify very preterm neonates with a PDA causing hemodynamic changes resulting in early renal morbidity. The interpretation of NGAL in preterm neonates remains to be fully elucidated.

N-Terminal Pro-B Type Natriuretic Peptide as a Marker of Bronchopulmonary Dysplasia or Death in Very Preterm Neonates: A Cohort Study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) has been suggested as a marker that may predict BPD within a few days after birth. OBJECTIVES: To investigate the association between NT-proBNP day three and bronchopulmonary dysplasia (BPD) or death and further to assess the impact of patent ductus arteriosus (PDA) on this association in neonates born before 32 gestational weeks. METHODS: A cohort study of 183 neonates born before 32 gestational weeks consecutively admitted to the Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. On day three plasma samples were collected and echocardiography carried out. NT-proBNP was measured by routine immunoassays. The combined outcome BPD or death was assessed at 36 weeks of postmenstrual age. Receiver operator characteristic (ROC) analysis was performed to determine the discrimination ability of NT-proBNP by the natural log continuous measure to recognize BPD or death. The association of BPD or death was assessed in relation to natural log NT-proBNP levels day three. RESULTS: The risk of BPD or death increased 1.7-fold with one unit increase of natural log NT-proBNP day three when adjusted for gestational age at birth (OR = 1.7, 95% CI 1.3; 2.3). The association was found both in neonates with and without a PDA. Adjusting for GA, PDA diameter, LA:Ao-ratio, or early onset sepsis did not change the estimate. CONCLUSION: We found NT-proBNP to be associated with BPD or death in very preterm neonates. This association was not only explained by the PDA. We speculate that NT-proBNP may help the identification of neonates at risk of BPD as early as postnatal day three.

Predictors for an unsuccessful INtubation-SURfactant-Extubation procedure: a cohort study.

BACKGROUND: The INtubation-SURfactant-Extubation (INSURE) is a procedure that is increasingly being used to treat the respiratory distress syndrome in preterm infants. The objective of this study was to identify predictors for an unsuccessful INSURE procedure. METHODS: The neonates included were less than 32 weeks' gestation, treated with surfactant in the neonatal intensive care unit, and born 1998-2010. INSURE was defined as surfactant administration during intubation for less than 2 hours without the need for mechanical ventilation. INSURE success was defined as no re-intubation within 72 hours after INSURE, and INSURE failure was defined as re-intubation within 72 hours after INSURE. An unsuccessful INSURE procedure was either INSURE failure or mechanical ventilation for more than 24 hours immediately after surfactant administration. All predictors were defined a priori and were present before surfactant administration. Multivariate logistic regression was performed. RESULTS: In total, 322 neonates were included: 31% (n = 100) had INSURE success, 10% (n = 33) had INSURE failure, 49% (n = 158) needed mechanical ventilation for more than 24 hours, and the remaining 10% (n = 31) needed mechanical ventilation for less than 24 hours. Predictors for INSURE failure were low gestational age and hemoglobin below 8.5 mmol/l. Predictors for mechanical ventilation for more than 24 hours were low gestational age, Apgar at 5 minutes below 7, oxygen need above 50%, CO2 pressure above 7 kPa (~53 mmHg), pH below 7.3, lactate above 2.5 mmol/l, need for inotropes, and surfactant administration shortly after birth, whereas preeclampsia reduced the risk. CONCLUSIONS: We identified specific predictors associated with an unsuccessful INSURE procedure. Keeping high-risk neonates with one or several predictors intubated and treated with mechanical ventilation after surfactant may prevent a re-intubation procedure.

Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3.

OBJECTIVE: To assess the association between a patent ductus arteriosus (PDA) on day 3 of life and severe morbidity and mortality. DESIGN: Cohort study. SETTING: Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. PATIENTS: All neonates with a gestational age less than 32 weeks admitted from 2010 to 2012. INTERVENTIONS: All neonates (n=183) were routinely screened with echocardiography for PDA on day 3 of life. Information on baseline characteristics and outcome was collected by structured coding sheets and medical records. MAIN OUTCOME MEASURES: The association among PDA diameter and pulmonary haemorrhage, intraventricular haemorrhage (IVH), necrotising enterocolitis, bronchopulmonary dysplasia (BPD), death, and the composite outcome of death or severe morbidity was assessed. RESULTS: In neonates, born prior to 28 gestational weeks, a PDA on day 3 of life was associated with a threefold increase in odds of death or severe morbidity compared with neonates without PDA (OR=3.4; CI 1.1 to 11). The odds were highest in neonates with a large PDA (diameter ≥1.5 mm). Neonates with a large PDA were also found to have increased odds of IVH (OR 4.2; CI 1.3 to 14) and BPD (OR 3.7; CI 1.0 to 14) compared with neonates with no PDA. CONCLUSIONS: In neonates born with a gestational age below 28 weeks the presence of a PDA on day 3 of life was associated with adverse outcome; this association was even more pronounced with a large PDA. Thus, early echocardiography may facilitate the identification of neonates suitable for a targeted approach to intervention in future randomised controlled trials.

Necrotizing enterocolitis after red blood cell transfusion in preterm infants with patent ductus arteriosus: a case series.

AIM: Both patent ductus arteriosus (PDA) and packed red blood cell (PRBC) transfusion are risk factors for necrotizing enterocolitis (NEC). The combination of PDA and PRBC transfusion may have a synergistic effect on the intestinal circulation. METHODS: We present four cases of NEC in very low birth weight (VLBW) infants within 14 h after PRBC transfusion. RESULTS: All infants were growing on full enteral feeding, and they all had a PDA. CONCLUSION: We are concerned that the simultaneous presence of a PDA and PRBC transfusion in VLBW infants may place the infant at even greater risk of NEC than each of these factors alone.

[Traumatic duodenal perforation in a 16 month-old girl]. / Perforation af duodenum efter banalt traume hos en 16 måneder gammel pige.

Duodenal injury following a blunt abdominal trauma is a rare condition. It poses a diagnostic challenge since symptoms are often subtle in the beginning and the trauma may initially remain undisclosed. We present a case of a 16 month-old girl, who was admitted to hospital due to critical illness after a tumble the day before. An explorative laparotomy revealed a perforation of the duodenum. This case demonstrates the importance of thoroughly evaluating anamnesis information and emphasises the need of considering a variety of potential diagnoses when assessing the critically ill child.