The Impact of Time to Initiate Therapeutic Hypothermia on Short-Term Neurological Outcomes in Neonates with Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Therapeutic hypothermia is the standard treatment for neonates with hypoxic-ischemic encephalopathy. Preclinical evidence indicates that the time to initiate therapeutic hypothermia correlates with its therapeutic success. This study aims to explore whether there is a correlation between the early initiation of therapeutic hypothermia and improved short-term neurological outcomes in cooled asphyxiated newborns. METHODS: A retrospective analysis was conducted, involving 68 neonates from two different neonatal intensive care units. The impact of time to initiate treatment, time to reach the target temperature, and time between initiation and target temperature was correlated with short-term outcomes on MRI. RESULTS: We did not find a significant difference between outcomes regarding the time to start treatment and the time to achieve the target temperature. Interestingly, neonates with a poor outcome were treated on average earlier than neonates with a favorable outcome but required more time to reach the target temperature. Additionally, the study results did not support the hypothesis that a shorter time to initiate treatment would lead to shorter times to achieve the target temperature. CONCLUSION: Based on our findings, it is recommended to prioritize a thorough evaluation of neonatal encephalopathy before initiating therapeutic hypothermia. Early initiation of treatment should be balanced with the time required for precise assessment to ensure better outcomes.

Multi-centre randomised trial of invasive and less invasive surfactant delivery methods showed similar spirometry results at 5-9 years of age.

AIM: We explored whether subnormal forced expiratory volume within 1 s (FEV1 ) at 5-9 years of age was lower in children born preterm who received less invasive surfactant administration (LISA) rather than surfactant via an endotracheal tube. METHODS: The multi-centre, randomised Nonintubated Surfactant Application trial enrolled 211 preterm infants born at 23-26 weeks of gestation from 13 level III neonatal intensive care units from April 2009 to March 2012. They received surfactant via LISA (n = 107) or after conventional endotracheal intubation (n = 104). The follow-up assessments were carried out by a single team blinded to the group assignments. The main outcome was FEV1 < 80% of predicted values. RESULTS: Spirometry was successful in 102/121 children. The other children died or were lost to follow-up. Median FEV1 was 93% (interquartile range 80%-113%) of predicted values in the LISA group and 86% (interquartile range 77-102%) in the control group (p = 0.685). Rates of FEV1 < 80% were 11/57 (19%) and 15/45 (33%), respectively, which was an absolute risk reduction of 14% (95% confidence interval -3.1% to 31.2%, p = 0.235). There were no differences in other outcome measures. CONCLUSION: The proportion of children aged 5-9 years with subnormal FEV1 was not significantly different between the groups.

Thin-catheter Surfactant Application for Respiratory Distress Syndrome in Spontaneously Breathing Preterm Infants: A Meta-analysis of Randomized Clinical Trials.

BACKGROUND: Surfactant application by a thin catheter represented by the term less invasive surfactant administration (LISA) for respiratory distress syndrome in spontaneously breathing preterm infants was developed as an alternative to endotracheal intubation. METHODS: We conducted a meta-analysis to assess the effects of LISA when compared to the socalled intubation-surfactant-extubation (INSURE) and the standard endotracheal intubation and mechanical ventilation (MV). The primary outcome was the composite incidence of death or bronchopulmonary dysplasia at a postmenstrual age of 36 weeks. The secondary outcome was the composite incidence of seven other severe adverse events. On 06 October 2021, we searched randomized clinical trials (RCTs) in PubMed, the Cochrane Library, ClinicalTrials.gov, and the ICTRP Registry. RESULTS: We included 18 RCTs. The pooled data on the primary outcome favored LISA when compared to either INSURE (risk ratio 0.67; 95% CI, 0.51 to 0.88) or MV (risk ratio 0.78; 95% CI, 0.61 to 0.99). The pooled data on the second outcome also favored LISA when compared to INSURE (risk ratio 0.75; 95% CI, 0.60 to 0.94) and MV (risk ratio 0.73; 95% CI, 0.55 to 0.96). CONCLUSION: The findings showed that surfactant application by non-intubation respiratory support and the use of a thin catheter may decrease the composite risk of death or bronchopulmonary dysplasia. The included data support the view that LISA should be considered the preferred treatment option in eligible infants.

Fluid Supply and Feeding Practices in Cooled Asphyxiated Newborns.

Therapeutic hypothermia (TH) for 72 h is the standard treatment to reduce neurological deficits in term newborns with hypoxic-ischemic encephalopathy. There is a large variability regarding nutritional supply during TH treatment in asphyxiated newborns. We performed a retrospective multicentre study in four level I (highest level of care in Germany) NICUs, including 135 asphyxiated term newborns undergoing TH. We analyzed enteral and parenteral nutritional supply during and after TH. We correlated nutritional supply with risk factors for encephalopathy, pH, Sarnat score, mechanical ventilation, seizures, and sedation. A total of 120 of 135 neonates received enteral nutritional supply within the first 24 h, and the majority of children were fully enterally fed within the first 10 days. The grade of encephalopathy and mechanical ventilation had a significant influence on the amount of enteral fluids (p = 0.01), whereas the pH and appearance of seizures did not affect the amount of nutritional supply significantly. Furthermore, we did not observe any correlation between enteral intake and abdominal complications such as necrotizing enterocolitis. We observed a large variability of feeding regimes in the four participating NICUs. Early enteral feeding among newborns undergoing TH was performed in each NICU and was well tolerated without increased rates of complications.

Mechanical Ventilation, Partial Pressure of Carbon Dioxide, Increased Fraction of Inspired Oxygen and the Increased Risk for Adverse Short-Term Outcomes in Cooled Asphyxiated Newborns.

Neonates treated with therapeutic hypothermia (TH) following perinatal asphyxia (PA) suffer a considerable rate of disability and mortality. Several risk factors associated with adverse outcomes have been identified. Mechanical ventilation might increase the risk for hyperoxia and hypocapnia in cooled newborns. We carried out a retrospective study in 71 asphyxiated cooled newborns. We analyzed the association of ventilation status and adverse short-term outcomes and investigated the effect of the former on pCO2 and oxygen delivery before, during and after TH. Death, abnormal findings on magnetic resonance imaging, and pathological amplitude-integrated electroencephalography traces were used to define short-term outcomes. The need for mechanical ventilation was significantly higher in the newborns with adverse outcomes (38% vs. 5.6%, p = 0.001). Compared to spontaneously breathing neonates, intubated newborns suffered from significantly more severe asphyxia, had significantly lower levels of mean minimum pCO2 over the first 6 and 72 h of life (HOL) (p = 0.03 and p = 0.01, respectively) and increased supply of inspired oxygen, which was, in turn, significantly higher in the newborns with adverse outcomes (p < 0.01). Intubated newborns with adverse short-term outcomes had lower levels of pCO2 over the first 36 HOL. In conclusion, need for mechanical ventilation was significantly higher in newborns with more severe asphyxia. In ventilated newborns, level of encephalopathy, lower pCO2 levels, and increased oxygen supplementation were significantly higher in the adverse short-term outcomes group. Ventilatory parameters need to be carefully monitored in cooled asphyxiated newborns.

Association of Routinely Measured Proinflammatory Biomarkers With Abnormal MRI Findings in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.

Background: The neuroprotective treatment effect of therapeutic hypothermia (TH) following perinatal asphyxia may be negatively influenced by neonatal sepsis and concomitant inflammation. We aimed to correlate routinely used blood biomarkers for perinatal sepsis in cooled asphyxiated newborns with MRI findings. Methods: Perinatal data was retrospectively collected from 67 cooled asphyxiated newborns. Levels of C-reactive protein (CRP), white blood cells and platelets were analyzed before, during and after TH. Interleukin-6 blood levels were analyzed before initiation of TH. Magnetic resonance imaging (MRI) on postnatal day 5-7 was used defining short-term outcome. Adverse outcome was defined as death or adverse MRI findings. Amplitude-integrated electroencephalography (aEEG) was additionally analyzed and correlated with short-term MRI outcome. Results: Forty-nine newborns had favorable short-term MRI outcome. Perinatal data referring to perinatal sepsis did not differ significantly between groups. IL-6 levels before initiation of TH and CRP levels on day three and after TH were significantly higher in newborns with adverse short-term MRI outcome. Males with adverse short-term MRI outcome had significantly increased CRP values at the end of the cooling phase. aEEG strongly correlated with short-term MRI outcome. Conclusion: Routinely used blood biomarkers may be helpful early identifying newborns at high risk of unfavorable outcome and in need of close neurodevelopmental follow-up.

Clinical management and knowledge of neonatal hypoglycaemia in Germany: A national survey of midwives and nurses.

AIM: Despite being a common metabolic condition, the detection and care of neonatal hypoglycaemia in Germany largely depends on the infant's health-care provider, rather than a national protocol. Therefore, this study aimed to evaluate midwives' and nurses' knowledge and management of neonatal hypoglycaemia and to determine the need for national guidelines. METHODS: An anonymous online survey was developed and completed by 127 perinatal nurses and midwives. Descriptive statistics, Mann-Whitney-U, χ2 and Fisher's exact tests were used to summarise and analyse the results. RESULTS: In total, 82% of respondents indicated using guidelines but routine blood glucose screening for neonates at risk for hypoglycaemia was rarely reported (44%). A blood glucose concentration of 2.5 mmol/L (45 mg/dL) was considered the treatment threshold by 52% of the respondents. However, the responses to clinical scenarios showed distinct differences regarding the management of neonatal hypoglycaemia. Finally, 49% of respondents reported insufficient knowledge regarding neonatal hypoglycaemia and 77% indicated that they would advocate the implication of enhanced national guidelines. CONCLUSIONS: There is considerable variation in knowledge about the prevention, screening and management of neonatal hypoglycaemia among nurses and midwives in Germany. Enhanced guidelines and education of health-care professionals are urgently needed to provide the best possible care to all hypoglycaemic newborns.

Establishment of a sustainable newborn TSH-screening program in the People's Democratic Republic of Laos.

BACKGROUND: Neonatal screening programs have been established and are in use in most countries worldwide. Laos belongs to the few countries which still have not established any kind of newborn screening. METHODS: Basis for the current screening was an initial pilot project between 2008 and 2010. Then 11.362 samples of newborn infants were screened, samples were weekly air-shipped to a German screening laboratory. During the current project TSH-measurements take place at the laboratory of the largest delivery hospital in Laos, the Mother & Newborn Hospital in Vientiane. RESULTS: Teaching regarding taking samples and doing measurements started in January 2019, until end of July 2020 altogether 3214 samples were measured. None of the samples was above the predefined cutoff of 20µU/l. CONCLUSIONS: Newborn screening for congenital hypothyroidism with measurements of samples within Laos is feasible. Plausibility control is achieved by regular checks of screening results sent by email to Germany. The most challenging task is to cover all newborns born at participating hospitals and finally to expand the screening beyond the capital to other areas in the country.

Visual Perception, Fine Motor, and Visual-Motor Skills in Very Preterm and Term-Born Children before School Entry-Observational Cohort Study.

Very preterm children (<32 weeks gestation at birth; VP) are at risk of developmental difficulties. Specific functional difficulties and delays in visual perception, fine motor, and visual-motor skills have received little research attention, although they are critical for daily life and school readiness. Our aim was to assess these skills in a contemporary cohort of 60 VP and 60 matched term-born children before school entry. We administered the Movement Assessment Battery for Children (M-ABC-2) and the Developmental Test of Visual Perception (DTVP-2). Linear and logistic regressions were run to test group differences in performance and rates of developmental delay in visual perception, fine motor, and visual-motor skills. Very preterm children had lower scores than term-born children in visual perception (ß = -0.25; p = 0.006), fine motor (ß = -0.44; p < 0.001), and visual-motor tasks (ß = -0.46; p < 0.001). The rate of developmental delay (<-1 SD) was higher among VP in visual perception (odds ratio (OR) = 3.4; 95% confidence interval (CI 1.1-10.6)), fine motor (OR = 6.2 (2.4-16.0)), and visual-motor skills (OR = 13.4 (4.1-43.9)) than in term-born controls. VP children are at increased risk for clinically relevant developmental delays in visual perception, fine motor, and visual-motor skills. Following up VP children until preschool age may facilitate early identification and timely intervention.

Two-year outcome data suggest that less invasive surfactant administration (LISA) is safe. Results from the follow-up of the randomized controlled AMV (avoid mechanical ventilation) study.

Less invasive surfactant administration (LISA) is a method to deliver surfactant to spontaneously breathing premature infants via a thin catheter. Here we report the two-year outcome from the AMV (avoid mechanical ventilation) study, the first randomized controlled trial on this mode of surfactant delivery. No statistically significant differences in weight, length or neurodevelopmental outcome (Bayley II scores) were found between the LISA intervention group (n = 95) and the control group (n = 84) that received standard treatment.Conclusion: No differences in outcome were observed at 2 years. LISA seems safe in that aspect. What is Known: • LISA is a method that is in increasing use for surfactant delivery to spontaneously breathing infants. LISA reduces the need for mechanical ventilation. What is New: • Outcome data at 2 years from the first randomized study with LISA raise no safety concerns in comparison to a group of infants that received standard treatment.

Immediate and Sustained Effect of Neonatal Teaching in a Perinatal Setting in Urban Laos.

OBJECTIVE: This study aimed to quantify knowledge on neonatal topics among obstetricians and pediatricians participating in a perinatal teaching program aimed at reducing neonatal mortality in Laos. STUDY DESIGN: Obstetricians and pediatricians from Vientiane and the surrounding areas participated in a 1-week teaching program in obstetric and neonatal topics and responded to pre- and posttests questionnaires to quantify their knowledge. RESULTS: Although questions were predominantly related to neonatal topics, obstetricians performed significantly better than pediatricians during the pretest. Both groups increased their knowledge significantly as quantified by the results of the posttest. CONCLUSION: The teaching program was effective in improving knowledge on perinatal mortality related topics of the participants. These results may be related to the fact that most of the obstetricians had participated in a structured teaching program previously, whereas the pediatricians did not. We thus speculate that there is a sustained effect of even a 1-week teaching program in neonatology even several years after the initial teaching.

Quantification of fetal steroids in nails of neonates to quantify prenatal stress and growth restriction.

This study assesses the impact of prenatal stress and intrauterine growth restriction (IUGR) on the dehydroepiandrosterone (DHEA) and dehydroepiandrosteronesulfate (DHEAS) concentrations in nails of newborns. Nail samples were gained from 56 newborn infants. The concentration of DHEA and DHEAS was measured by liquid chromatography/tandem mass spectrometry. Prenatal stress was assessed by the Prenatal Distress Questionnaire and by the Life Experience Survey. Prenatal stress was not associated with infant nail DHEA or DHEAS concentrations. The concentration of DHEA and DHEAS was decreased in infants with IUGR (DHEA: p = 0.037, DHEAS p < 0.01). Nail-DHEAS increased with gestational age (p < 0.01). In this study prenatal life event stress or pregnancy specific stress do not correlate with higher DHEA or DHEAS concentrations in nails of newborns. Concentration of DHEAS is rather affected by length of gestation. Our approach is an easily applicable method to assess intrauterine life with the potential to give insights in the activity of fetal hormone systems and mechanism underlying fetal programming.

Favourable Outcome in Two Pregnancies in a Patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency.

In patients with 3-hydroxy-3-methylglutaryl(HMG)-CoA lyase deficiency (OMIM 246450), five pregnancies have been described worldwide, which were either terminated or resulted in severe metabolic sequelae during pregnancy or delivery. Here, we report on a patient with HMG-CoA lyase deficiency, who underwent two uncomplicated pregnancies. The 19-year-old patient was admitted because of recurrent vomiting and nausea. Diagnostics revealed pregnancy at week 8 of gestation. Metabolic analyses revealed normal lactate and blood glucose levels and normal acid-base status. Urine organic acid analysis showed an elevated excretion of 3-CH3-glutaric acid, 2,3-CH3-glutaconic acid, and 3-CH3-3-OH-glutaric acid. Oral treatment with carnitine and glucose wes administered intravenously during the period of nausea and vomiting. After clinical recovery, a diet with 0.89 g/kg of protein/d and 38 kcal/kg body weight/d was given. Meals were taken every 3 h. Additionally, 70 g of starch was given at midnight to maintain normoglycemia at night time. Peripartum, a complete parenteral nutrition, was delivered through a central venous catheter. The patient delivered a healthy male infant by Caesarean section at week 38 of gestation (Apgar 9/10/10) and remained metabolically stable throughout the peripartum period. Postpartum nutrition was gradually changed from parenteral to oral diet. Two years later, the patient became pregnant again and presented with hyperemesis gravidarum. With metabolic monitoring and treatment as before no decompensation occurred. At week 38 of gestation, she delivered a healthy female infant by elective Caesarian section (Apgar 9/10/10). This case report describes the metabolic and obstetric management of two pregnancies in a patient with HMG-CoA lyase deficiency with favorable outcome without metabolic complications.

Neonatal Mortality and Morbidity in Regional Provincial Hospitals in the People's Democratic Republic of Laos.

OBJECTIVE: The aim of this study was to identify the causes and incidences of neonatal diseases and deaths in five provincial hospitals in People's Democratic Republic of Laos retrospectively for the years 2010-12. METHODS: Data of neonatal patients were collected before a 3-year-training program for medical and nursing staff involved in the care of newborn infants in the provincial and associated district hospitals. RESULTS: In the years 2010-12, a total of 1673 neonatal patients were treated in the provincial hospitals. The reasons of treatment were as follows: 48% infections, 17% complications of prematurity, 14% intrapartum-related complications and 9% other, not categorized diseases. The average mortality rate in all hospitals was 6.5%. The main causes of death were complications because of prematurity, infectious diseases and asphyxia. CONCLUSION: These data could be the basis for any teaching program aimed at reducing neonatal mortality. Furthermore, they enable an evaluation of the ongoing teaching program.

Congenital Adrenal Hyperplasia with Non-functional Mutations in Both Alleles in a Clinically Unaffected Infant.

BACKGROUND: Results in neonatal screening programs aiming at detection of congenital adrenal hyperplasia (CAH) can only report elevated levels of 17-hydroxy-progesterone (17-OHP), without being able to differentiate presence or absence of salt loss. AIM: To predict presence or absence of salt loss in newborn infants with CAH. METHODS: The first specimen of suspected CAH in samples sent from People's Democratic Republic of Laos (Lao PDR) was investigated for known mutations in CAH associated with salt loss. RESULTS: Molecular genetic diagnosis revealed mutations associated with loss of function in both alleles; however, the infant was clinically unaffected even without any corticosteroid substitution therapy. CONCLUSIONS: Although molecular genetic methods can theoretically predict loss of function in CAH, our infant was clinically unaffected even without therapy at 6 years of age. We speculate that in CAH, remaining enzyme activity can be sufficiently high, despite the presence of loss of function mutations, which do not affect infants clinically.

Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial.

IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614.

Continuous infusion of clonidine in ventilated newborns and infants: a randomized controlled trial.

OBJECTIVES: To assess the influence of an infusion of clonidine 1 µg/kg/hr on fentanyl and midazolam requirement in ventilated newborns and infants. DESIGN: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.com/ISRCTN77772144. SETTING: Twenty-eight level 3 German PICUs/neonatal ICUs. PATIENTS: Ventilated newborns and infants: stratum I (1-28 d), stratum II, (29-120 d), and stratum III (121 d to 2 yr). INTERVENTIONS: Patients received clonidine 1 µg/kg/hr or placebo on day 4 after intubation. Fentanyl and midazolam were adjusted to achieve a defined level of analgesia and sedation according to Hartwig score. MEASUREMENTS AND MAIN RESULTS: Two hundred nineteen infants were randomized; 212 received study medication, 69.7% were ventilated in the postoperative care and 30.3% for other reasons. Primary endpoint: consumption of fentanyl and midazolam in the 72 hours following the onset of study medication (main observation period) in the overall study population. The confirmatory analysis of the overall population showed no difference in the consumption of fentanyl and midazolam. Explorative age-stratified analysis demonstrated that in stratum I (n = 112) the clonidine group had a significantly lower consumption of fentanyl (clonidine: 2.1 ± 1.8 µg/kg/hr, placebo: 3.2 ± 3.1 µg/kg/hr; p = 0.032) and midazolam (clonidine: 113.0 ± 100.1 µg/kg/hr, placebo: 180.2 ± 204.0 µg/kg/hr; p = 0.030). Strata II (n = 43) and III (n = 46) showed no statistical difference. Sedation and withdrawal-scores were significantly lower in the clonidine group of stratum I (p < 0.001). Frequency of severe adverse events did not differ between groups. CONCLUSIONS: Clonidine 1 µg/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.