Bronchiolitis: evidence-based management in high-risk infants in the intensive care setting.

AIM: Systematically review the management of infants with severe bronchiolitis in a paediatric intensive care unit (PICU) setting with a focus on high-risk infants to identify gaps in evidence-based knowledge. METHODS: This systematic review utilised Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) to examine the literature on the PICU management of bronchiolitis in infants <24 months old. Three databases, Embase, PubMed and Medline, were searched and higher levels of evidence I, II and III were included. RESULTS: There were 455 papers reviewed and 26 met the inclusion criteria. Furthermore, 19 of these studied respiratory interventions such as positive airway pressure and oxygen delivery. The remaining 7 examined: erythropoietin, caffeine, dexamethasone, protein supplementation, ribavirin, respiratory syncytial virus immune globulin, or diuretic therapy. Of the 26 studies, 20 excluded infants with high-risk conditions. Therapies showing favourable outcomes included Heliox, prophylactic dexamethasone pre-extubation, protein supplementation, and diuretic use. CONCLUSIONS: Clinical trials for bronchiolitis management frequently exclude high-risk children. Innovative study design in the future may improve access to clinical trials for the management of bronchiolitis in high-risk infants in a PICU setting. IMPACT: Clinical trials for bronchiolitis management frequently exclude high-risk children. We review the evidence base for the management of an under-investigated patient demographic in the setting of acute bronchiolitis. Randomised controlled trials are needed to determine the efficacy of management strategies for bronchiolitis in high-risk infants in a paediatric intensive care setting.

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Diuretics use in the management of bronchopulmonary dysplasia in preterm infants: A systematic review.

AIM: Bronchopulmonary dysplasia (BPD), a respiratory complication associated with neonatal prematurity, presents opportunities for pharmacological intervention due to its contributing risk factors. Despite diuretics' controversial usage in BPD treatment and varying institutional practices, this review aims to consolidate evidence from clinical trials regarding diuretic use in BPD. METHODS: We conducted a systematic review following PRISMA guidelines, searching EMBASE, Medline, Web of Science and CINAHL databases (PROSPERO 2022: CRD42022328292). Covidence facilitated screening and data extraction, followed by analysis and formatting in Microsoft Excel. RESULTS: Among 430 screened records, 13 were included for analysis. Three studies assessed spironolactone and chlorothiazide combinations, two studied spironolactone and hydrochlorothiazide, while eight examined furosemide. All studies evaluated drug effects on dynamic pulmonary compliance and pulmonary resistance, serving as comparative measures in our review. CONCLUSION: Diuretics' effectiveness in treating bronchopulmonary dysplasia remains uncertain. The limited number of identified randomised controlled trials (RCTs) hampers high-level evidence-based conclusions when applying the Population, Intervention, Comparison, Outcome (PICO) approach. Conducting large prospective studies of good quality could provide more definitive insights, but the rarity of outcomes and eligible patients poses challenges. Further research, primarily focusing on RCTs assessing diuretics' safety and efficacy in this population, is warranted.

Neuroprotective therapies in the NICU in term infants: present and future.

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

Causes and Terminology in Neonatal Encephalopathy: What is in a Name? Neonatal Encephalopathy, Hypoxic-ischemic Encephalopathy or Perinatal Asphyxia.

Neurologic depression in term/near-term neonates (neonatal encephalopathy, NE) is uncommon with modern obstetric care. Asphyxial birth, with or without co-factors, accounts for a minority of NE, while maldevelopment (congenital malformations, growth aberrations, genetic, metabolic and placental abnormalities) plays an enlarging role in identifying etiologic subgroups of NE. The terms NE and hypoxic-ischemic encephalopathy (HIE) have not been employed uniformly, hampering research and clinical care. The authors propose the term NE as an early working-diagnosis, to be supplemented by a diagnosis of NE due to HIE or to other factors, as a final diagnosis once workup is complete.

Neonatal encephalopathy multiorgan scoring systems: systematic review.

Introduction: Neonatal encephalopathy (NE) is a condition with multifactorial etiology that causes multiorgan injury to neonates. The severity of multiorgan dysfunction (MOD) in NE varies, with therapeutic hypothermia (TH) as the standard of care. The aim is to identify current approaches used to assess and determine an optimum scoring system for MOD in NE. Methods: The systematic review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search was conducted using PubMed, EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Scopus, and CINAHL for studies of scoring systems for MOD in NE. Results: The search yielded 628 articles of which 12 studies were included for data extraction and analysis. Five studies found a positive correlation between the severity of NE and MOD. There was significant heterogeneity across the scoring systems, including the eligibility criteria for participants, the methods assessing specific organ systems, the length of follow-up, and adverse outcomes. The neurological, hepatic, cardiovascular, respiratory, hematological, and renal systems were included in most studies while the gastrointestinal system was only in three studies. The definitions for hepatic, renal, and respiratory systems dysfunction were most consistent while the cardiovascular system varied the most. Discussion: A NE multiorgan scoring system should ideally include the renal, hepatic, respiratory, neurological, hematological, and cardiovascular systems. Despite the heterogeneity between the studies, these provide potential candidates for the standardization of MOD scoring systems in NE. Validation is needed for the parameters with adequate length of follow-up beyond the neonatal period. Additionally, the evaluation of MOD may be affected by TH considering its multiorgan effects.

Outcomes of interventions in neonatal sepsis: A systematic review of qualitative research.

BACKGROUND: While a systematic review exists detailing neonatal sepsis outcomes from clinical trials, there remains an absence of a qualitative systematic review capturing the perspectives of key stakeholders. OBJECTIVES: Our aim is to identify outcomes from qualitative research on any intervention to prevent or improve the outcomes of neonatal sepsis that are important to parents, other family members, healthcare providers, policymakers, and researchers as a part of the development of a core outcome set (COS) for neonatal sepsis. SEARCH STRATEGY: A literature search was carried out using MEDLINE, EMBASE, CINAHL, and PsycInfo databases. SELECTION CRITERIA: Publications describing qualitative data relating to neonatal sepsis outcomes were included. DATA COLLECTION AND ANALYSIS: Drawing on the concepts of thematic synthesis, texts related to outcomes were coded and grouped. These outcomes were then mapped to the domain headings of an existing model. MAIN RESULTS: Out of 6777 records screened, six studies were included. Overall, 19 outcomes were extracted from the included studies. The most frequently reported outcomes were those in the domains related to parents, healthcare workers and individual organ systemas such as gastrointestinal system. The remaining outcomes were classified under the headings of general outcomes, miscellaneous outcomes, survival, and infection. CONCLUSIONS: The outcomes identified in this review are different from those reported in neonatal sepsis clinical trials, thus highlighting the importance of incorporating qualitative studies into COS development to encapsulate all relevant stakeholders' perspectives.

Biomarkers in retinopathy of prematurity: a systematic review and meta-analysis.

Aim: Retinopathy of prematurity is a significant global cause of childhood blindness. This study aims to identify serum biomarkers that are associated with the development of ROP. Methods: A systematic review and meta-analysis was conducted using PRISMA guidelines. Three databases were searched (Pubmed, Scopus and Web of Science) from 2003 to March 2023. Only studies investigating serum biomarker levels in preterm infants (<37 weeks gestation) were included. Results: Meta-analysis suggests that low serum IGF-1 levels have a strong association with the development of ROP [SMD (95% CI) of -.46 [-.63, -.30], p < .001]. Meta-analysis suggests that higher serum glucose levels were associated with the development of ROP [SMD (95% CI) of 1.25 [.94, 1.55], p < .001]. Meta-analysis suggests that thrombocytopenia is associated with the development of ROP [SMD (95% CI) of -.62 [-.86, -.37], p < .001]. Conclusion: Low levels of serum IGF-1, high levels of serum glucose and thrombocytopenia all appear to have the strongest association with the development of ROP out of the 63 biomarkers investigated in this review. These associations highlight their potential use as diagnostic biomarkers in ROP, though further research is needed to establish the exact relationship between these biomarkers and disease pathogenesis.

Thresholds for surfactant use in preterm neonates: a network meta-analysis.

OBJECTIVE: To perform a network meta-analysis of randomised controlled trials of different surfactant treatment strategies for respiratory distress syndrome (RDS) to assess if a certain fraction of inspired oxygen (FiO2) is optimal for selective surfactant therapy. DESIGN: Systematic review and network meta-analysis using Bayesian analysis of randomised trials of prophylactic versus selective surfactant for RDS. SETTING: Cochrane Central Register of Controlled Trials, MEDLINE, Embase and Science Citation Index Expanded. PATIENTS: Randomised trials including infants under 32 weeks of gestational age. INTERVENTIONS: Intratracheal surfactant, irrespective of type or dose. MAIN OUTCOME MEASURES: Our primary outcome was neonatal mortality, compared between groups treated with selective surfactant therapy at different thresholds of FiO2. Secondary outcomes included respiratory morbidity and major complications of prematurity. RESULTS: Of 4643 identified references, 14 studies involving 5298 participants were included. We found no statistically significant differences between 30%, 40% and 50% FiO2 thresholds. A sensitivity analysis of infants treated in the era of high antenatal steroid use and nasal continuous positive airway pressure as initial mode of respiratory support showed no difference in mortality, RDS or intraventricular haemorrhage alone but suggested an increase in the combined outcome of major morbidities in the 60% threshold. CONCLUSION: Our results do not show a clear benefit of surfactant treatment at any threshold of FiO2. The 60% threshold was suggestive of increased morbidity. There was no advantage seen with prophylactic treatment. Randomised trials of different thresholds for surfactant delivery are urgently needed to guide clinicians and provide robust evidence. PROSPERO REGISTRATION NUMBER: CRD42020166620.

Sex differences in neonatal brain injury and inflammation.

Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects.

Benefits and harms of interventions to improve anxiety, depression, and other mental health outcomes for autistic people: A systematic review and network meta-analysis of randomised controlled trials.

LAY ABSTRACT: Nearly three out of four autistic people experience mental health problems such as stress, anxiety or depression. The research already done does not guide us on how best to prevent or treat mental health problems for autistic people. Our aim was to look at the benefits and harms of different interventions on mental health outcomes in autistic people. We searched all the published randomised controlled trials (RCTs) about interventions for mental health conditions in autistic people until 17 October 2020. We also searched for RCTs that were not published in peer-reviewed journals. These were obtained from registers of clinical trials online. We then combined the information from all these trials using advanced statistical methods to analyse how good the interventions are. Seventy-one studies (3630 participants) provided information for this research. The studies reported how participants were responding to the intervention for only a short period of time. The trials did not report which interventions worked for people with intellectual disability. In people without intellectual disability, some forms of cognitive behavioural therapy and mindfulness therapy may be helpful. However, further research is necessary. Many trials used medications to target core features of autism rather than targeting mental health conditions, but these medications did not help autistic people. Until we have more evidence, treatment of mental health conditions in autistic people should follow the evidence available for non-autistic people. We plan to widely disseminate the findings to healthcare professionals through medical journals and conferences and contact other groups representing autistic people.

Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy.

INTRODUCTION: Melatonin has been suggested an adjunctive therapy in neonatal encephalopathy (NE). Melatonin reduces oxidative stress and neutrophil activation; however, the immunological effects in NE have not been studied. METHODS: Infants with NE and neonatal controls were prospectively recruited. Whole blood was sampled in the first week of life. Following endotoxin and or melatonin treatment, diurnal variation was measured by RT PCR for circadian rhythm genes (brain and Muscle Arnt-Like protein [BMAL1], circadian locomotor output cycles kaput [CLOCK], Nuclear Receptor Subfamily 1 Group D Member 2 [REV Erß], and cryptochrome circadian clock [CRY]). Neutrophil and monocyte cell surface markers of activation CD11b, reactive oxygen intermediates (ROIs), and Toll-like receptor (TLR)-4 were also examined by flow cytometry in matching samples. RESULTS: Serum and RNA samples from forty infants were included (controls n = 20; NE n = 20) over the first week of life. Melatonin reduced neutrophil CD11b and TLR-4 expression in response to LPS in infants with NE compared to controls. There were no differences in ROIs. BMAL1 and CLOCK baseline gene expression levels were similar. BMAL1 was significantly decreased with LPS stimulation in NE. There was no significant diurnal variation in melatonin, neutrophil, and monocyte function or circadian genes. CONCLUSIONS: Melatonin alters immune function ex vivo in infants with NE. Infants with NE have altered immune circadian responses following LPS stimulation, which have potential for modulation.

Protocol for the development of a core outcome set for neonatal sepsis (NESCOS).

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Evaluation of the Quick Wee method of inducing faster clean catch urine collection in pre-continent infants: a randomized controlled trial.

INTRODUCTION: The acquisition of non-contaminated urine samples in pre-continent infants remains a challenge. The Quick Wee method uses bladder stimulation to induce voiding. A previous randomized trial showed a higher rate of voiding within 5 minutes using this method. We evaluated this method in an Irish hospital providing secondary care. METHODS: A non-blinded, randomized, controlled trial was carried out. Eligible infants were between 1 and 12 months of age, who required urine sampling as part of clinical care. Participants were randomly allocated to receive the intervention (Quick Wee Method-supra-pubic stimulation with cold saline) or the control (usual care-clean catch with no bladder stimulation) for 5 min. Primary outcome was voiding of urine within 5 min. RESULTS: A total of 140 infants were included in this study (73 in intervention group; 67 in control group). Baseline characteristics were similar. 25% in the intervention group passed urine in the 5-min trial period compared with 18% in the control group [P = 0.4, absolute difference 7% (95% confidence interval: - 7% to + 20%)]. CONCLUSION: The Quick Wee method is a simple and inexpensive intervention that did not show a statistically significant increase in urine samples obtained in pre-continent infants.

Management of Acute Kidney Injury in Extremely Low Birth Weight Infants.

Acute kidney injury (AKI) is a common problem in the neonatal intensive care unit (NICU). Neonates born at <1,000 g (extremely low birth weight, ELBW) are at an increased risk of secondary associated comorbidities such as intrauterine growth restriction, prematurity, volume restriction, ischaemic injury, among others. Studies estimate up to 50% ELBW infants experience at least one episode of AKI during their NICU stay. Although no curative treatment for AKI currently exists, recognition is vital to reduce potential ongoing injury and mitigate long-term consequences of AKI. However, the definition of AKI is imperfect in this population and presents clinical challenges to correct identification, thus contributing to under recognition and reporting. Additionally, the absence of guidelines for the management of AKI in ELBW infants has led to variations in practice. This review summarizes AKI in the ELBW infant and includes suggestions such as close observation of daily fluid balance, review of medications to reduce nephrotoxic exposure, management of electrolytes, maximizing nutrition, and the use of diuretics and/or dialysis when appropriate.