Prevalence of hearing impairment in neonatal encephalopathy due to hypoxia-ischemia: a systematic review and meta-analysis.

BACKGROUND: This systematic review was undertaken to estimate the overall prevalence of hearing impairment in survivors of neonatal HIE. METHODS: PubMed, EMBASE, CINAHL, EMCARE and Cochrane databases, mednar (gray literature) were searched till January 2023. Randomized controlled trials and observational studies were included. The main outcome was estimation of overall prevalence of hearing impairment in survivors of HIE. RESULTS: A total of 71studies (5821 infants assessed for hearing impairment) were included of which 56 were from high income countries (HIC) and 15 from low- or middle-income countries (LMIC). Overall prevalence rate of hearing impairment in cooled infants was 5% (95% CI: 3-6%, n = 4868) and 3% (95% CI: 1-6%, n = 953) in non-cooled HIE infants. The prevalence rate in cooled HIE infants in LMICs was 7% (95% CI: 2-15%) and in HICs was 4% (95% CI: 3-5%). The prevalence rate in non-cooled HIE infants in LMICs was 8% (95% CI: 2-17%) and HICs was 2% (95% CI: 0-4%). CONCLUSIONS: These results would be useful for counseling parents, and in acting as benchmark when comparing institutional data, and while monitoring future RCTs testing new interventions in HIE. There is a need for more data from LMICs and standardization of reporting hearing impairment. IMPACT: The overall prevalence rate of hearing impairment in cooled infants with HIE was 5% (95% CI: 3-6%) and 3% (95% CI: 1-6%) in the non-cooled infants. The prevalence rate in cooled HIE infants in LMICs was 7% (95% CI: 2-15%) and in HICs was 4% (95% CI: 3-5%). The prevalence rate in non-cooled HIE infants in LMICs was 8% (95% CI: 2-17%) and HICs was 2% (95% CI: 0-4%). These results would be useful for counseling parents, and in acting as benchmark when comparing institutional data, and while monitoring future RCTs testing new interventions in HIE.

Topical glyceryl trinitrate to increase radial artery diameter in neonates: study protocol for a randomized controlled trial.

BACKGROUND: Newborn infants admitted to the neonatal intensive care unit require arterial cannulation for hemodynamic monitoring and blood sampling. Arterial access is achieved through catheterization of umbilical or peripheral arteries. Peripheral artery cannulation is performed in critically ill newborns, but artery localization and cannulation is often challenging and unsuccessful. Therefore, increasing the internal diameter and preventing vasospasm are important for successful peripheral artery cannulation in neonates. Topical glyceryl trinitrate has the potential to increase cannulation success by relaxing arterial smooth muscles and thus increasing the internal diameter. We aim to conduct a pilot randomized controlled trial to evaluate the efficacy and safety of topycal glyceryl trinitrate in increasing the diameter of the radial artery in neonates. METHODS/DESIGN: This study will be a single-center, observer-blind, randomized, placebo-controlled trial conducted in the neonatal intensive care unit of Perth Children's Hospital, Western Australia. A total of 60 infants born at >34 weeks of gestation who are admitted for elective surgery or medical reasons and for whom a peripheral arterial line is needed for sampling or blood pressure monitoring will be recruited after informed parental consent is obtained. The primary outcome will be the change in radial arterial diameter from baseline to postintervention. Secondary outcomes will be the absolute and percentage change from baseline in the radial arterial diameter in both limbs and safety (hypotension and methemoglobinemia). DISCUSSION: This will be the first randomized controlled trial evaluating the use of topical glyceryl trinitrate to facilitate peripheral artery cannulation in neonates. If our pilot randomized controlled trial confirms the benefits of glyceryl trinitrate patches, it will pave the way for large multicenter randomized controlled trials in this field.

Topical glyceryl trinitrate to increase radial artery diameter in neonates: study protocol for a randomized controlled trial / Trinitrato de glicerilo tópico para aumentar o diâmetro da artéria radial em recém-nascidos: protocolo de estudo de um ensaio clínico randomizado

ABSTRACT Background: Newborn infants admitted to the neonatal intensive care unit require arterial cannulation for hemodynamic monitoring and blood sampling. Arterial access is achieved through catheterization of umbilical or peripheral arteries. Peripheral artery cannulation is performed in critically ill newborns, but artery localization and cannulation is often challenging and unsuccessful. Therefore, increasing the internal diameter and preventing vasospasm are important for successful peripheral artery cannulation in neonates. Topical glyceryl trinitrate has the potential to increase cannulation success by relaxing arterial smooth muscles and thus increasing the internal diameter. We aim to conduct a pilot randomized controlled trial to evaluate the efficacy and safety of topycal glyceryl trinitrate in increasing the diameter of the radial artery in neonates. Methods/Design: This study will be a single-center, observer-blind, randomized, placebo-controlled trial conducted in the neonatal intensive care unit of Perth Children's Hospital, Western Australia. A total of 60 infants born at >34 weeks of gestation who are admitted for elective surgery or medical reasons and for whom a peripheral arterial line is needed for sampling or blood pressure monitoring will be recruited after informed parental consent is obtained. The primary outcome will be the change in radial arterial diameter from baseline to postintervention. Secondary outcomes will be the absolute and percentage change from baseline in the radial arterial diameter in both limbs and safety (hypotension and methemoglobinemia). Discussion: This will be the first randomized controlled trial evaluating the use of topical glyceryl trinitrate to facilitate peripheral artery cannulation in neonates. If our pilot randomized controlled trial confirms the benefits of glyceryl trinitrate patches, it will pave the way for large multicenter randomized controlled trials in this field.

RESUMO Histórico: Os recém-nascidos internados na unidade de terapia intensiva neonatal necessitam de canulação arterial para monitoramento hemodinâmico e coleta de sangue. O acesso arterial é obtido por meio de cateterização das artérias umbilicais ou periféricas. A canulação da artéria periférica é realizada em recém-nascidos em estado grave, mas a localização e a canulação da artéria são, muitas vezes, desafiadoras e sem sucesso. Assim, o aumento do diâmetro interno e a prevenção do vasoespasmo são importantes para o sucesso da canulação da artéria periférica em recém-nascidos. O trinitrato de glicerilo tópico tem o potencial de aumentar o sucesso da canulação ao relaxar a musculatura lisa arterial e, dessa forma, aumentar o diâmetro interno. Nosso objetivo é realizar um ensaio piloto controlado e randomizado para avaliar a eficácia e segurança do trinitrato de glicerilo tópico no aumento do diâmetro da artéria radial em recém-nascidos. Métodos/Desenho: Este estudo será um estudo de centro único, cego para o observador, randomizado, controlado por placebo, conduzido na unidade de terapia intensiva neonatal do Perth Children's Hospital, Austrália Ocidental. Serão recrutados 60 bebês nascidos com mais de 34 semanas de gestação, internados para cirurgia eletiva ou por razões médicas e para os quais é necessária a colocação de um acesso arterial periférico para coleta de amostras ou monitoramento da pressão arterial, após a obtenção do consentimento informado dos pais. O desfecho primário será a mudança no diâmetro arterial radial basal e pós-intervenção. Os desfechos secundários serão a alteração absoluta e percentual basal no diâmetro arterial radial em ambos os membros e a segurança (hipotensão e metemoglobinemia). Discussão: Este será o primeiro estudo controlado e randomizado a avaliar o uso de trinitrato de glicerilo tópico para facilitar a canulação da artéria periférica em recém-nascidos. Se nosso estudo-piloto randomizado e controlado confirmar os benefícios dos adesivos de trinitrato de glicerilo, ele abrirá caminho para grandes estudos multicêntricos randomizados e controlados nesse campo.

Utility of the Ages and Stages Questionnaire to Identify Developmental Delay in Children Aged 12 to 60 Months: A Systematic Review and Meta-analysis.

Importance: The Ages and Stages Questionnaire (ASQ) is a commonly used developmental screening tool, but its utility is debated. Objectives: To conduct a a systematic review and meta-analysis to evaluate ASQ's utility as a screening or diagnostic tool to identify developmental delay in children aged 12-60 months. Data Sources: Medline, EMBASE, CINAHL, PsycINFO, and Mednar were searched from inception until December 2021. Study Selection: Studies meeting both criteria were included. ASQ was performed at age 12 to 60 months or where the median age at ASQ was at least 12 months and formal developmental assessments were done within 2 months of ASQ. Data Extraction and Synthesis: True positive, false positive, false negative, and true negatives from individual studies were extracted. Meta-analysis was conducted with Stata version 16.1. Risk of bias was assessed using the QUADAS-2 tool. Certainty of evidence (COE) was assessed using GRADE guidelines. Main Outcomes and Measures: Ability of ASQ scores more than 2 SDs below the mean in more than 1 domain (ASQ-2SD) to identify any developmental delay or severe delay. Based on generally accepted interpretation of likelihood ratio (LR) values, a positive LR (PLR) more than 5 and a negative LR (NLR) of 0.2 or less were considered necessary to rule in or rule out developmental delay, respectively, with at least moderate probability. Results: Initial search yielded 5777 citations of which 43 were included in the review. Of them, 36 were included in the meta-analysis. The pooled sensitivity, specificity, PLR, and NLR are as follows: ASQ-2SD to predict any delay in 1 or more domain (n = 16), 0.77 (95% CI, 0.64-0.86), 0.81 (95% CI, 0.75-0.86), 4.10 (95% CI, 3.17-5.30), and 0.28 (95% CI, 0.18-0.44); ASQ-2SD to predict severe delay in 1 or more domain (n = 15), 0.84 (95% CI, 0.75-0.90), 0.77 (95% CI, 0.71-0.82), 3.72 (95% CI, 2.98-4.64), and 0.20 (95% CI, 0.13-0.32); ASQ-2SD motor domain to predict motor delay (n = 7), 0.41 (95% CI, 0.26-0.57), 0.94 (95% CI, 0.87-0.97), 6.5 (95% CI, 3.8-11.1), and 0.63 (95% CI, 0.50-0.81); and ASQ-2SD cognitive domain to predict cognitive delay (n = 2), 0.44 (95% CI, 0.24-0.65), 0.93 (95% CI, 0.81-0.95), 6.4 (95% CI, 2.4-16.8), and 0.61 (95% CI, 0.43-0.86). The COE was low/very low. Conclusions and Relevance: If a child aged 12 to 60 months passes all ASQ domains, there is a moderate probability that they do not have severe developmental delay (low COE). If a child aged 12-60 months fails the motor or cognitive domain of ASQ, there is a moderate probability that they have some motor or cognitive delay, respectively (very low COE). Trial Registration: PROSPERO (CRD42021268543).

Local nitroglycerin to facilitate peripheral arterial cannulation in children: systematic review and meta-analysis.

BACKGROUND: Neonates and children admitted to intensive care units require peripheral arterial cannulation to monitor their blood pressures and for blood sampling, but many times it is unsuccessful. OBJECTIVE: To conduct a systematic review and meta-analysis to evaluate the efficacy and safety of local nitroglycerin (NTG) to facilitate peripheral artery cannulation in neonates and children. REVIEW METHODS: PubMed, EMBASE, CINAHL, Emcare and Cochrane library were searched till August 2021. Grey literature was searched through Mednar. Data were extracted by two reviewers independently using a prespecified form and the risk of bias was assessed. Meta-analysis was conducted using a random-effects model. The I2 statistic was used to quantify statistical heterogeneity. Certainty of evidence was assessed using the criteria of inconsistency, imprecision, indirectness, publication bias and size of effect as per the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. RESULTS: Two randomised controlled trials (RCTs) were included in this meta-analysis (n=153). One was conducted in children 2-8 years of age and the other was in children <2 years. Both trials found increased success rates with the use of local NTG. Pooling of the two studies found that the first-attempt success rate was significantly higher in the NTG group (risk difference: 0.44, 95% CI 0.05 to 0.83; I2=89%). Overall procedure time was significantly lower in the NTG group (mean difference: -100.28 s, 95% CI -136.74 to -63.82; I2=0%). No major complications secondary to the use of NTG were noted. The GRADE of evidence was very low. CONCLUSION: Local NTG may be useful in facilitating peripheral arterial cannulation in children. Adequately powered RCTs are needed to confirm these findings.

Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial.

Importance: Seizures in the neonatal period are associated with increased mortality and morbidity. Bedside amplitude-integrated electroencephalography (aEEG) has facilitated the detection of electrographic seizures; however, whether these seizures should be treated remains uncertain. Objective: To determine if the active management of electrographic and clinical seizures in encephalopathic term or near-term neonates improves survival free of severe disability at 2 years of age compared with only treating clinically detected seizures. Design, Setting, and Participants: This randomized clinical trial was conducted in tertiary newborn intensive care units recruited from 2012 to 2016 and followed up until 2 years of age. Participants included neonates with encephalopathy at 35 weeks' gestation or more and younger than 48 hours old. Data analysis was completed in April 2021. Interventions: Randomization was to an electrographic seizure group (ESG) in which seizures detected on aEEG were treated in addition to clinical seizures or a clinical seizure group (CSG) in which only seizures detected clinically were treated. Main Outcomes and Measures: Primary outcome was death or severe disability at 2 years, defined as scores in any developmental domain more than 2 SD below the Australian mean assessed with Bayley Scales of Neonate and Toddler Development, 3rd ed (BSID-III), or the presence of cerebral palsy, blindness, or deafness. Secondary outcomes included magnetic resonance imaging brain injury score at 5 to 14 days, time to full suck feeds, and individual domain scores on BSID-III at 2 years. Results: Of 212 randomized neonates, the mean (SD) gestational age was 39.2 (1.7) weeks and 122 (58%) were male; 152 (72%) had moderate to severe hypoxic-ischemic encephalopathy (HIE) and 147 (84%) had electrographic seizures. A total of 86 neonates were included in the ESG group and 86 were included in the CSG group. Ten of 86 (9%) neonates in the ESG and 4 of 86 (4%) in the CSG died before the 2-year assessment. The odds of the primary outcome were not significantly different in the ESG group compared with the CSG group (ESG, 38 of 86 [44%] vs CSG, 27 of 86 [31%]; odds ratio [OR], 1.83; 95% CI, 0.96 to 3.49; P = .14). There was also no significant difference in those with HIE (OR, 1.77; 95% CI, 0.84 to 3.73; P = .26). There was evidence that cognitive outcomes were worse in the ESG (mean [SD] scores, ESG: 97.4 [17.7] vs CSG: 103.8 [17.3]; mean difference, -6.5 [95% CI, -1.2 to -11.8]; P = .01). There was little evidence of a difference in secondary outcomes, including time to suck feeds, seizure burden, or brain injury score. Conclusions and Relevance: Treating electrographic and clinical seizures with currently used anticonvulsants did not significantly reduce the rate of death or disability at 2 years in a heterogeneous group of neonates with seizures. Trial Registration: http://anzctr.org.au Identifier: ACTRN12611000327987.

Early neurodevelopmental outcomes of congenital gastrointestinal surgical conditions: a single-centre retrospective study.

BACKGROUND: Evidence is emerging that surgery in the neonatal period is associated with increased risk of suboptimal neurodevelopmental outcomes (SNDO). The aim of this study was to describe neurodevelopmental outcomes (at 1 year) of neonatal surgery for congenital gastrointestinal surgical conditions (CGSC) and to explore risk factors. METHODS: Retrospective study (2005-2014) of infants born ≥34 weeks gestation with CGSC and admitted to the surgical neonatal intensive care unit of Perth Children's Hospital, Western Australia. Clinical details and 1-year developmental outcomes based on Griffiths Mental Developmental Assessment Scales were collated from the database and by reviewing the medical records of study infants. SNDO was defined as one or more of the following: a general quotient less than 88 (ie, >1 SD below mean), cerebral palsy, blindness or sensorineural deafness. Univariable and multivariable logistic regression analyses were carried out to explore risk factors for SNDO. A total of 413 infants were included, of which 13 died. Median gestation was 37.6 weeks (IQR: 36.4-39.1). Information on developmental outcomes was available from 262 out of 400 survivors. A total of 43/262 (16.4%) had SNDO. On univariable analysis, lower z scores for birth weight, prolonged duration of antibiotics, increased episodes of general anaesthesia and prolonged duration of hospital stay were associated with SNDO. On multivariable analysis, lower z scores for birth weight and prolonged hospital stay were associated with increased risk of SNDO. CONCLUSIONS: Late preterm and term infants undergoing neonatal surgery for CGSC may be at risk for SNDO. Studies with longer duration of follow-up are needed to further evaluate the role of potentially modifiable risk factors on their neurodevelopmental outcomes.

Inter-rater reliability of amplitude-integrated EEG for the detection of neonatal seizures.

BACKGROUND: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for seizure detection in neonates. However, data regarding inter-rater reliability among neonatologists for the use of aEEG for the detection of neonatal seizures is lacking. METHODS: Term and late-preterm infants at risk of seizures were monitored simultaneously with 24-h video-electroencephalography (vEEG) and aEEG. vEEG was interpreted by an experienced neurologist. Five neonatologists with experience in aEEG interpretation from four different neonatal units interpreted aEEG recordings independently. The Brennan and Prediger kappa coefficient and Intra-class Correlation Coefficients (ICC) were used to assess inter-rater reliability between the neonatologists. RESULTS: Thirty-five infants at risk of seizure with gestational age at birth 35-42 weeks were recruited for the study after informed parental consent. vEEG detected seizures in seven infants with a total of 169 individual seizure episodes. Neonatologists detected seizures in 10 to 15 infants on aEEG. The sensitivities for the detection of individual seizures by neonatologists ranged from 18% to 38%. The inter-rater reliability for detection of: individual seizure was "fair" (kappa = 0.37; 95% CI: 0.32-0.42), infant with seizure was "moderate" (kappa = 0.60; 95% CI: 0.44-0.75), duration of individual seizure (ICC: 0.22; 95% CI: 0.18-0.28) and total duration of seizures in an infant (ICC: 0.46; 95% CI: 0.30-0.63) was "poor". The neonatologists missed 77-90% of the duration of seizures. CONCLUSION: The inter-rater reliability of aEEG for the detection of neonatal seizures was suboptimal. Even when interpreted by experienced and trained clinicians, seizure detection with aEEG has limitations and can miss large number and duration of seizures.

Servo controlled versus manual cooling methods in neonates with hypoxic ischemic encephalopathy.

BACKGROUND: Therapeutic hypothermia is known to improve outcomes in neonates with hypoxic ischemic encephalopathy (HIE). There are no studies that have compared servo controlled cooling (SCC) versus manually controlled cooling (MCC) methods in HIE. AIM: To compare the outcomes of SCC versus MCC in neonates with HIE. METHODS AND OUTCOME MEASURES: Between Jan 2008 and May 2011, MCC with cool-gel packs was used to achieve rectal temperatures of 33.5 to 34.5°C in our units. Subsequently, we changed to SCC to achieve rectal temperatures of 33 to 34°C. 105 neonates received SCC whereas 95 received MCC. Retrospective study with multivariate analysis was conducted comparing thermoregulation (primary outcome) and neurodevelopmental outcomes of SCC versus MCC. RESULTS: In the SCC group, 72.3% had stage 2 or 3 HIE versus 77.9% in the MCC. The remaining had stage 1, but attending neonatologists decided to provide cooling. Prescribed rectal temperatures were achieved in 80.5% (5768/7168) instances in SCC versus 72.9% (4449/6108) in MCC (p<0.0001). There were no significant differences in the incidence of 'death or moderate-severe disability' [SCC 26/85 vs MCC 26/87, adjusted odds ratio: 1.29, 95% CI: 0.48, 3.42; p=0.614]. The results were similar after excluding stage 1 HIE [SCC 25/66 vs MCC 26/69, adjusted odds ratio: 1.01, 95% CI: 0.50, 2.02; p=0.981]. CONCLUSIONS: SCC resulted in better thermoregulation in neonates undergoing therapeutic hypothermia. There were no significant differences in neurodevelopmental outcomes, but the study was underpowered to answer this. Randomized trials are needed to fine-tune various aspects of TH in neonates with HIE.

Developmental outcomes in cerebrospinal fluid proven enteroviral meningitis in neonates > 32 weeks of gestation.

AIM: The aim of this study is to assess the short-term and long-term (1 year) outcomes of cerebrospinal fluid (CSF) confirmed enteroviral meningitis in neonates > 32 weeks of gestation. METHODS: A retrospective audit of neonates admitted between 1 July 2002 to 30 June 2012. RESULTS: Thirty-three neonates were diagnosed with enteroviral meningitis based on a positive CSF enteroviral PCR. Physical growth and neurodevelopmental outcomes at 1 year corrected for prematurity were available for 24 infants. All infants were alive at 1 year. The median weight, length and head circumference at 1 year were in the 72nd, 62nd and 78th centile and were comparable with the birth parameters. The mean general quotient (GQ) was 98.5 (SD 7.1) and was not significantly different from the population mean of 100.2 (P = 0.27). None of the infants had a GQ > 2SD below the population mean. Neurological recovery was complete in the 24 neonates assessed except one, who developed cerebral palsy, epilepsy and progressive hydrocephalus requiring ventriculoperitoneal shunt at 1 year. CONCLUSION: Neonatal enteroviral meningitis was associated with optimal growth and neurodevelopment in the majority of the infants at 1 year corrected for prematurity. Longer term studies are needed to better define developmental outcomes.

Outcomes of hypoxic ischaemic encephalopathy treated with therapeutic hypothermia using cool gel packs - experience from Western Australia.

UNLABELLED: Therapeutic hypothermia is the standard clinical practice for neonates with moderate to severe hypoxic ischaemic encephalopathy (HIE). AIM: To describe the two year neurodevelopmental outcomes of neonates who were routinely cooled using cool gel packs for HIE in Western Australia. METHODS: Retrospective study. Cases were identified from the neonatal databases. Information was collected from chart review. RESULTS: 65 infants received therapeutic hypothermia, of which 13 had mild, 35 moderate and 17 had severe HIE. There were no serious adverse effects attributable to cooling. All 13 infants with mild HIE survived, of whom developmental outcomes were available on nine; none had severe disability. Among 52 infants with moderate to severe HIE, there were nine deaths (17%) and developmental outcomes were available on 39; the incidence of severe disability was 23%. The risk of death or severe disability was 40% in infants with moderate to severe HIE. Physical growth was adequate at two years of age. CONCLUSIONS: Neonates undergoing therapeutic hypothermia with cool gel packs had both good survival rates and long term neurodevelopmental outcomes and met international benchmarks.

Is extubation associated with changes in ductal and pulmonary blood flow in extremely preterm neonates?

AIM: Early extubation is desirable in preterm neonates to minimise the risk of complications associated with prolonged intubation. The association of significant pulmonary haemorrhage (PH) with extubation in a cluster of very preterm infants instigated an assessment of ductal and pulmonary haemodynamic effects of early extubation. METHOD: This is a prospective observational study in 20 neonates (gestation <28 weeks) undergoing early extubation. Echocardiography was performed 5 min pre-extubation and 20 min post-extubation to continuous positive airway pressure. Normal cardiac anatomy was ascertained. Left pulmonary artery (LPA) and ductus arteriosus diameter and flows were recorded. Doppler spectral pattern of velocity was recorded over a minimum of four cycles. RESULTS: Median (range) gestation, birthweight and age at extubation were 26.5 (24.0-28.0) weeks, 932 (595-1260) g and 18 (6-51) h, respectively. There was no significant change in pulmonary flow post-extubation: ductal size: (pre--1.2 (0-3.3) mm, post--1.0 (0-3.5) mm); ductal flow: (pre--44 (0-515), post--49 (0-441) mL/kg/min); LPA diameter: (pre--2.4 (1.9-3.8) mm, post--2.6 (1.9-3.4) mm); LPA flow: (pre--112 (59-255), post--122 (58-188) mL/kg/min. There were 3 out of 20 infants who developed PH at the post-natal age of 2, 11 and 16 days after extubation. Ductal and LPA flow did not change significantly after extubation in infants with or without PH irrespective of the ductal status. CONCLUSIONS: Early extubation was not associated with a significant change from baseline in ductal and pulmonary flow in extremely preterm infants.