Paediatric and neonatal sepsis and inflammation.

Sepsis has a huge impact on global mortality and has been declared as a priority by the World Health organisation the WHO.1 Children have a high incidence of sepsis especially in the neonatal with an estimated 3 million babies affected worldwide and mortality ranges from 11 to 19%.2 In addition, long-term neurodevelopmental outcomes are affected but this is largely unquantified. However, challenges remain in the early recognition, diagnosis and standardised management of sepsis. This series on Sepsis and inflammation in children reviews the conundrums of diagnostic criteria, biomarkers, management and future strategies to improve outcomes.

Carbon dioxide levels in neonates: what are safe parameters?

There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5-7 kPa was inferred following systematic review.

Altered inflammasome activation in neonatal encephalopathy persists in childhood.

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1ß, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1ß and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1ß gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention.

Paediatric Head Injury and Traumatic Brain Injury.

Aim To determine prevalence of head injury presenting to paediatric emergency departments (PEDs) and characterise by demographics, triage category, disposition neuroimaging or re-attendance. Methods Presentations in 2014 and 2015, with diagnoses of head injury, intracranial bleed, skull fracture including single or re-attendances within 28 days post head injury to all national PEDs, were analysed. Demographics, triage score, imaging rate, admission, mechanisms and representation rate were recorded. Results Head injury was diagnosed in 13,392 of 224,860 (5.9%), median (IQR) age 3.9 (1.4 - 8.3) years. Regionally 3% of children <5 years attend each year. The total admitted/transferred was 10.8% (n=1460). Neuroimaging rate was 4.3% (n= 570). Falls predominated. Sport accounted for 12.2%. Conclusion One in twenty children PED presentations are head injury, over half in preschool children. A sizeable number were symptomatic reflected by admission, transfer, imaging or re-attendance. Observational management was favoured over imaging reflected in the higher admission versus imaging rate.

Children's Palliative Care; the identified Learning Needs of Paediatricians.

Aim To determine baseline learning needs of Paediatricians in Ireland when caring for children with palliative care needs. Methods A questionnaire based online survey was conducted. Results One hundred and fourteen paediatricians responded to the survey, the majority were Specialist Registrars but almost half were consultant paediatricians (46% n=52). Most had never had formal education in the paediatric palliative care (57% n=48). Areas of future training that were ranked as important or highly important (percentage of respondents) included: pain management (98% n=81), management of the dying child (96% n=80), palliative care resources (95%n=79), advanced care planning (95% n=79) and communication skills (86% n=71). Those surveyed were asked to comment on the challenges of recent clinical interactions, on analysis three overarching themes emerged; best interests of the child, inadequate training and confidence and co-ordinating care. Conclusion This survey highlights the learning needs of paediatricians and will inform the development of meaningful education sessions for doctors.

Neonatal brain injury and systemic inflammation: modulation by activated protein C ex vivo.

Infection and inflammation can be antecedents of neonatal encephalopathy (NE) and increase the risk of neurological sequelae. Activated protein C (APC) has anti-coagulant and anti-inflammatory effects and provides neuroprotection in brain and spinal cord injury. We examined neutrophil and monocyte responses to lipopolysaccharide (LPS) in infants with NE compared with healthy adult and neonatal controls, and also studied the effect of APC. Whole blood was incubated with LPS and APC and Toll-like receptor (TLR)-4 (LPS recognition), CD11b expression (activation) and intracellular reactive oxygen intermediate (ROI; function) release from neutrophils and monocytes was examined by flow cytometry serially from days 1 to 7. We found a significant increase in neutrophil ROI in infants with NE on day 3 following LPS compared to neonatal controls and this augmented response was reduced significantly by APC. Neutrophil and monocyte CD11b expression was increased significantly on day 1 in infants with NE compared to neonatal controls. LPS-induced neutrophil TLR-4 expression was increased significantly in infants with NE on days 3 and 7 and was reduced by APC. LPS-induced monocyte TLR-4 was increased significantly in infants with NE on day 7. Neutrophil and monocyte activation and production of ROIs may mediate tissue damage in infants with NE. APC modified LPS responses in infants with NE. APC may reduce the inflammatory responses in NE and may ameliorate multi-organ dysfunction. Further study of the immunomodulatory effects of protein C may be warranted using mutant forms with decreased bleeding potential.

Biomarkers of acute kidney injury in neonatal encephalopathy.

Acute kidney injury (AKI) is a common complication of neonatal encephalopathy (NE). The accurate diagnosis of neonatal AKI, irrespective of the cause, relies on suboptimal methods such as identification of rising serum creatinine, decreased urinary output and glomerular filtration rate. Studies of AKI biomarkers in adults and children have shown that biomarkers can improve the early diagnosis of AKI. Hypoxia-ischaemia is the proposed aetiological basis of AKI in both NE and cardiopulmonary bypass (CPB). However, there is a paucity of studies examining the role of AKI biomarkers specifically in NE. Urinary cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18, kidney injury molecule-1, liver-type fatty acid-binding protein, serum CysC and serum NGAL all show good ability to predict early AKI in a heterogeneous critically ill neonatal population including infants post-CPB. Moreover, serum and urinary NGAL and urinary CysC are early predictors of AKI secondary to NE. These findings are promising and open up the possibility of biomarkers playing a significant role in the early diagnosis and treatment of NE-related AKI. There is an urgent need to explore the role of AKI biomarkers in infants with NE as establishing the diagnosis of AKI earlier may allow more timely intervention with potential for improving long-term outcome.

Cardiac biomarkers in neonatal hypoxic ischaemia.

UNLABELLED: Following a perinatal hypoxic-ischaemic insult, term infants commonly develop cardiovascular dysfunction. Troponin-T, troponin-I and brain natriuretic peptide are sensitive indicators of myocardial compromise. The long-term effects of cardiovascular dysfunction on neurodevelopmental outcome following perinatal hypoxic ischaemia remain controversial. Follow-up studies are warranted to ensure optimal cardiac function in adulthood. CONCLUSION: Cardiac biomarkers may improve the diagnosis of myocardial injury, help guide management, estimate mortality risk and may also aid in longterm neurodevelopmental outcome prediction following neonatal hypoxic-ischaemia.

Digital fetal scalp stimulation (dFSS) versus fetal blood sampling (FBS) to assess fetal wellbeing in labour-a multi-centre randomised controlled trial: Fetal Intrapartum Randomised Scalp Stimulation Trial (FIRSST NCT05306756).

BACKGROUND: Cardiotocography (CTG) is a screening test used to detect fetal hypoxia in labour. It has a high false positive rate resulting in many potentially unnecessary caesarean sections. Fetal blood sampling (FBS) is a second-line test of the acid-base status of the fetus. It is used to provide either reassurance that it is safe for labour to continue or objective evidence of compromise so that delivery can be expedited. Digital fetal scalp stimulation (dFSS) to elicit a fetal heart rate acceleration is an alternative less invasive second-line test of fetal wellbeing. This study aims to provide robust evidence on the role of these two second-line tests in assessing fetal wellbeing and potentially preventing operative delivery. METHODS: A multi-centre parallel group randomised controlled trial (RCT) is planned in four maternity centres in Ireland. The study aims to recruit 2500 nulliparous women with a term (≥37+0 weeks) singleton pregnancy who require a second-line test of fetal wellbeing in labour due to an abnormal CTG. Women will be allocated randomly to dFSS or FBS on a 1:1 ratio. The primary outcome is caesarean section. With 1250 women in each arm, the study will have 90% power to detect a difference of 5-6%, at a two-sided alpha significance level of 5%, assuming a caesarean section rate of at least 20% in the dFSS group. DISCUSSION: If the proposed study shows evidence that dFSS is a safe, reliable and effective alternative to FBS, this would have ground-breaking implications for labour management worldwide. It could potentially lead to a reduction in invasive procedures and emergency caesarean sections. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306756. Registered on 31 March 2022. The trial commenced enrolment on 10 May 2022. Ethical committee approval has been granted by the Research Ethics Committee (REC) of each hospital: Dublin/CWIUH REC: 12.06.2019; Cork/UCC REC: 29.11.2019; Galway/NUIG REC: 06.09.2019; Limerick/UL REC: 30.09.2019.

Neonatal encephalopathy: Etiologies other than hypoxic-ischemic encephalopathy.

Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed.

Elevated iron indices in preterm infants: association with male gender.

Elevated iron indices may be underrecognized in preterm infants. Sixty growing, stable preterm infants < 1500 g studied had elevated iron indices, which was especially elevated in male infants. Careful evaluation of iron indices is essential to prevent potential organ injury and unnecessary iron supplementation.

Congenital diaphragmatic hernia: neonatal outcomes following referral to a paediatric surgical centre.

Congenital diaphragmatic hernia (CDH) is a rare malformation observed in approximately 1 in 3000 live births. Estimates of postnatal survival range from 50 to 70% despite advances in neonatal care. Antenatal diagnosis is associated with termination of pregnancy in 25-50% pregnancy internationally which may not be reflective of the Irish population. We aimed to evaluate the mortality of infants with CDH who survived to admission in a tertiary referral paediatric hospital between 1996 and 2007. The Hospital In-Patient Enquiry system was used to determine the number of neonatal referrals for CDH to OLHSC between 1996 and 2007. Mortality, sex distribution, length of patient stay and the number of cases per year were examined. 141 neonates with CDH were over 12 years with approximately 12 referrals per annum of which 82 (58%) were male and 59 (42%) female. The average length of stay in the hospital was 33 (range 0-364) days. Overall 71% of the patients survived to discharge. In the first epoch (1996-2001) survival was 63% compared with 78% in the later epoch (2002-7). The overall survival for neonates with CDH presenting to OLCHC during the 12 year-period was 71% although this improved to 78% in recent epoch. Further study of associated congenital anomalies, number of terminations of pregnancy, complexity of the diaphragmatic defect and degree of pulmonary hypertension are required to compare this population with other international centres.

Maternal and neonatal lipopolysaccharide and Fas responses are altered by antenatal risk factors for sepsis.

The diagnosis of neonatal sepsis is difficult, resulting in unnecessary treatment to minimize morbidity and mortality. We hypothesized that exposure to antenatal risk factors for sepsis alters the perinatal neutrophil phenotype. The study setting was a tertiary referral university-affiliated maternity and neonatal hospital. Neutrophils from adults, normal neonates, neonates with antenatal sepsis risk factors and their respective maternal samples were incubated alone, with agonistic Fas antibody or with lipopolysaccharide (LPS). Surface receptor CD11b expression and the percentage apoptosis (persistent inflammatory response) were assessed using flow cytometry. Both mothers and asymptomatic neonates exposed to maternal sepsis risk factors had increased spontaneous neutrophil apoptosis compared to their respective controls. Infants with sepsis were LPS and Fas hyporesponsive. Maternal neutrophils had a delay in apoptosis in all groups with enhanced LPS and Fas responses associated with neonatal sepsis. CD11b expression was not altered significantly between groups. Maternal neutrophil function is altered in neonatal sepsis and may have a diagnostic role. Neonatal sepsis was associated with LPS hyporesponsiveness, potentially increasing susceptibility to infection.