A systematic review of immune-based interventions for perinatal neuroprotection: closing the gap between animal studies and human trials.

BACKGROUND: Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential. METHODS: We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690). RESULTS: Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias. CONCLUSION: Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation.

Individualized vancomycin dosing in infants: prospective evaluation of an online dose calculator.

BACKGROUND: Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level. METHODS: This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration. RESULTS: A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC0-24) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity. CONCLUSION: Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC0-24, respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions.

Ganaxolone versus Phenobarbital for Neonatal Seizure Management.

OBJECTIVE: Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia. METHODS: Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology. RESULTS: Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus. INTERPRETATION: Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.

Short-course intravenous antibiotics for young infants with urinary tract infection.

OBJECTIVE: Shorter courses of intravenous antibiotics for young infants with urinary tract infection (UTI) have myriad advantages. As practice shifts toward shorter intravenous treatment courses, this study aimed to determine the safety of early intravenous-to-oral antibiotic switch and identify risk factors for bacteraemia with UTI. METHODS: Retrospective audit of infants aged ≤90 days with a positive urine culture at a quaternary paediatric hospital over 4 years (2016-2020). Data were collected from the hospital electronic medical record and laboratory information system. Short-course intravenous antibiotic duration was defined as <48 hours for non-bacteraemic UTI and <7 days for bacteraemic UTI. Multivariate analysis was used to determine patient factors predicting bacteraemia. RESULTS: Among 427 infants with non-bacteraemic UTI, 257 (60.2%) were treated for <48 hours. Clinicians prescribed shorter intravenous courses to infants who were female, aged >30 days, afebrile and those without bacteraemia or cerebrospinal fluid pleocytosis. Treatment failure (30-day UTI recurrence) occurred in 6/451 (1.3%) infants. All had non-bacteraemic UTI and one received <48 hours of intravenous antibiotics. None had serious complications (bacteraemia, meningitis, death). Follow-up audiology occurred in 21/31 (68%) infants with cerebrospinal fluid pleocytosis, and one had sensorineural hearing loss. Bacteraemia occurred in 24/451 (5.3%) infants, with 10 receiving <7 days intravenous antibiotics with no treatment failure. Fever and pyelonephritis were independent predictors of bacteraemia. CONCLUSION: Short-course intravenous antibiotics for <48 hours for young infants with non-bacteraemic UTI should be considered, provided meningitis has been excluded. Treatment failure and serious complications were rare in young infants with UTI.

Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T 1-w/T 2-w Ratio.

BACKGROUND AND OBJECTIVES: To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term equivalent and 7 and 13 years of age based on the ratio of T 1- and T 2-weighted MRI (T 1-w/T 2-w), including (1) whether longitudinal changes differ between birth groups or sexes, (2) associations with perinatal risk factors in VP children, and (3) relationships with neurodevelopmental outcomes at 13 years. METHODS: Prospective longitudinal cohort study of VP (born <30 weeks' gestation or <1,250 g) and FT infants born between 2001 and 2004 and followed up at term equivalent and 7 and 13 years of age, including MRI studies and neurodevelopmental assessments. T 1-w/T 2-w images were parcellated into 48 white matter regions of interest. RESULTS: Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had useable T 1-w/T 2-w data from at least one timepoint. T 1-w/T 2-w values increased between term equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age, and postnatal infection were associated with reduced regional T 1-w/T 2-w values in childhood and adolescence. Increased T 1-w/T 2-w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T 1-w/T 2-w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T 1-w/T 2-w values at 7 years were associated with poorer mathematics performance. DISCUSSION: VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T 1-w/T 2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T 1-w/T 2-w ratio at 13 years appeared to be associated with better motor and working memory function and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning, and mathematics performance.

Preventing harm: A balance measure for improving the detection of fetal growth restriction.

BACKGROUND: Increasing the detection of fetal growth restriction (FGR), while reducing stillbirth, also leads to unnecessary early intervention, and associated morbidity, for normally grown babies who are incorrectly suspected of FGR. AIMS: We sought to design a balance measure that addresses the specificity of FGR detection. METHODS: A retrospective cohort study on all singleton births ≥32 weeks gestation in 2016 and 2017 in Victoria. We compared two balance measures for the detection of FGR, defined as the proportion of all babies iatrogenically delivered before 39 weeks gestation for suspected FGR that had a birthweight ≥10th centile (balance measure 1) or ≥25th centile (balance measure 2). Hospital level performance on each balance measure was derived and compared to an existing performance measure for severe FGR detection in Victoria. RESULTS: Of the 38 hospitals analysed, 12 (32%) had a favourable performance on an existing indicator of FGR detection, seven (18%) hospitals had a favourable performance on balance measure 1, and 15 (39%) had a favourable performance on balance measure 2. There was a moderate correlation between hospital performance on the existing indicator and on balance measure 1 (r = 0.447, P = 0.005) but not balance measure 2 (r = -0.063, P = 0.71). There was no difference in perinatal mortality between high performing hospitals and low performing hospitals. CONCLUSION: Introducing a balance measure into routine reporting may bring greater awareness to the unintended harm associated with increased detection of FGR.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Continuous Versus Intermittent Vancomycin Infusions in Infants: A Randomized Controlled Trial.

BACKGROUND: In adults, continuous infusions of vancomycin (CIV) are associated with earlier attainment of target drug concentrations, require fewer blood samples for monitoring, and may reduce drug toxicity. We aimed to determine, in young infants, if CIV or intermittent infusions of vancomycin (IIV) better achieves target vancomycin concentrations at the first steady-state level and to compare the frequency of drug-related adverse effects. METHODS: In a multicenter randomized controlled trial in 2 tertiary neonatal units over a 40-month period, young infants aged 0 to 90 days requiring vancomycin therapy for at least 48 hours were randomly assigned to CIV and IIV. RESULTS: Of 111 infants randomized, 104 were included in the intention-to-treat analysis. Baseline characteristics were similar for both groups. The proportion of infants achieving target concentrations at the first steady-state level was higher for CIV compared with IIV (45 in 53 [85%] vs 21 in 51 [41%]; P < .001). Fewer dose adjustments were required in the CIV group (median 0; range 0-1) compared with the IIV group (median 1; range 0-3; P < .001). The mean daily dose required to achieve target concentrations was lower with CIV compared with IIV (40.6 [SD 10.7] vs 60.6 [SD 53.0] mg/kg per day, respectively; P = .01). No drug-related adverse effects occurred in either group. CONCLUSIONS: In young infants, CIV is associated with earlier and improved attainment of target concentrations compared with IIV. Lower total daily doses are required to achieve target levels with CIV. There is no difference in the rate of drug-related adverse effects.

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.

BACKGROUND: In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. METHODS: In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI -2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. INTERPRETATION: Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population. FUNDING: US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment-National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.

Protocol for a randomised controlled trial of continuous infusions of vancomycin to improve the attainment of target vancomycin levels in young infants: The VANC trial.

INTRODUCTION: Vancomycin is frequently used in the treatment of late-onset sepsis in young infants and is routinely administered as intermittent infusions (IIV); however, existing IIV dosing guidelines achieve target vancomycin levels in less than half of infants. Continuous infusions of vancomycin (CIV) are an attractive alternative as adult studies report a higher attainment of target vancomycin levels, simpler drug monitoring and fewer drug side effects. METHODS: This is a multicentre, randomised controlled trial in which 200 young infants (aged 0-90 days) requiring vancomycin will be randomised to CIV or IIV for a duration determined by the treating clinician. Vancomycin levels will be measured immediately after the first dose in both arms. Trough and peak levels will be determined in the IIV arm and steady-state levels 18-30 hours after commencement of infusion will be measured in the CIV arm. Full blood count, urea and electrolytes, and C reactive protein level will be monitored throughout treatment. For all Gram-positive bacteria isolated from blood culture, a vancomycin Etest will be done to determine the minimum inhibitory concentration of the bacterium. ANALYSIS: Primary outcome: the proportion of infants with levels within target range at their first steady-state concentration. SECONDARY OUTCOMES: (1) the proportion of drug-related adverse effects; (2) the time to achieve target levels in the blood; (3) the pharmacodynamics of vancomycin (using non-linear mixed effect modelling). ETHICS AND DISSEMINATION: The study has been approved by The Royal Children's Hospital Melbourne Human Research Ethics Committee (HREC) (No. 34030) and the South Eastern Sydney Local Health District HREC (SSA 16/G/335). Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02210169.

Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study.

BACKGROUND: The GAS study is an international RCT to evaluate neurodevelopmental outcome comparing general plus regional anesthesia versus regional anesthesia alone in 722 neonates and infants who had inguinal hernia repair up to 60 weeks of postmenstrual age. This paper comprises a secondary descriptive analysis of hernias, aspects of surgery and outcomes. METHODS: The incidence of unilateral and bilateral hernias, side preponderance, predictive factors for bilateral hernias and surgical approaches were collated. Follow-up outcome data were examined at 2 years. RESULTS: Of 711 eligible patients, there were 679 with hernia data showing that 321 hernias were right-sided, 190 left and 168 bilateral. Male to female ratio was 5:1. Of those with unilateral hernias, 25.8% underwent contralateral exploration and in these cases a patent processus vaginalis was found in 68.9%. Bilateral hernias were more common in younger and female patients. At 2 years there was a recurrence rate of 0.99% and in 2.7% of patients a hernia was evident on the contralateral side (metachrony), and this was unrelated to the anesthesia technique. CONCLUSIONS: Bilateral hernias are associated with lower gestational age at birth and female gender. There was a low incidence of complications and the anesthesia technique did not affect surgical outcome. LEVEL OF EVIDENCE: Level 1 evidence from prospective treatment study.

Early surgery and neurodevelopmental outcomes of children born extremely preterm.

OBJECTIVES: To (1) compare the neurodevelopmental outcomes at 8 years of age of children born extremely preterm (EP) who underwent surgical procedures during the course of their initial hospital admission with those who did not and (2) compare the outcomes across eras, from 1991 to 2005. DESIGN: Prospective observational cohort studies conducted over three different eras (1991-1992, 1997 and 2005). Surviving EP children, who required surgical intervention during the primary hospitalisation, were assessed for general intelligence (IQ) and neurosensory status at 8 years of age. Major neurosensory disability comprised any of moderate/severe cerebral palsy, IQ less than -2 SD relative to term controls, blindness or deafness. RESULTS: Overall, 29% (161/546) of survivors had surgery during the newborn period, with similar rates in each era. Follow-up rates at 8 years were high (91%; 499/546), and 17% (86/499) of survivors assessed had a major neurosensory disability. Rates of major neurosensory disability were substantially higher in the surgical group (33%; 52/158) compared with those who did not have surgery (10%; 34/341) (OR 4.28, 95% CI 2.61 to 7.03). Rates of disability in the surgical group did not improve over time. After adjustment for relevant confounders, no specific surgical procedure was associated with increased risk of disability. IMPLICATIONS AND RELEVANCE: Major neurosensory disability at 8 years was higher in children born EP who underwent surgery during their initial hospital admission compared with those who did not. The rates of major neurosensory disability in the surgical cohort are not improving over time.

Is selective echocardiography in duodenal atresia the future standard of care?

BACKGROUND: Duodenal atresia (DA) is associated with cardiac defects that may have perioperative care implications. Standard preoperative care includes echocardiography to identify such cardiac defects, but this dogma has been challenged. We aimed to assess selective and selective strategies for preoperative echocardiography in DA patients. METHODS: Single-center retrospective review of neonates with DA over a 16-year period was performed. Data included preoperative cardiovascular and respiratory examination, chest x-ray, and echocardiography. We compared the current nonselective versus selective strategies, limiting preoperative echocardiogram to those in whom: (1) cardiac or respiratory or chest x-ray examination was abnormal, or (2) cardiac or respiratory examination was abnormal. Sensitivity, specificity, positive and negative predictive values were compared with chi-square tests. RESULTS: Seventy-one of 109 (65%) consecutive neonates with DA underwent preoperative echocardiography according to a nonselective, physician-determined strategy. Forty of 71 (56%) patients had cardiac defects, including 16/40 (27%) major defects. Sixteen additional postoperative echocardiograms revealed 2 missed major defects. In the same cohort, selective strategies would have performed 17-24% fewer echocardiograms without significant detriment in performance. CONCLUSIONS: All strategies considered missed some major cardiac defects. A selective strategy, determining DA patients not requiring preoperative echocardiogram, could reduce the number of echocardiograms performed without compromising patient safety. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level II.

Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children.

OBJECTIVE: To determine the relationship between brain abnormalities on newborn magnetic resonance imaging (MRI) and neurodevelopmental impairment at 7 years of age in very preterm children. STUDY DESIGN: A total of 223 very preterm infants (<30 weeks of gestation or <1250 g) born at Melbourne's Royal Women's Hospital had a brain MRI scan at term equivalent age. Scans were scored using a standardized system that assessed structural abnormality of cerebral white matter, cortical gray matter, deep gray matter, and cerebellum. Children were assessed at 7 years on measures of general intelligence, motor functioning, academic achievement, and behavior. RESULTS: One hundred eighty-six very preterm children (83%) had both an MRI at term equivalent age and a 7-year follow-up assessment. Higher global brain, cerebral white matter, and deep gray matter abnormality scores were related to poorer intelligence quotient (IQ) (Ps < .01), spelling (Ps < .05), math computation (Ps < .01), and motor function (Ps < .001). Higher cerebellum abnormality scores were related to poorer IQ (P = .001), math computation (P = .018), and motor outcomes (P = .001). Perinatal, neonatal, and social confounders had little effect on the relationships between the MRI abnormality scores and outcomes. Moderate-severe global abnormality on newborn MRI was associated with a reduction in IQ (-6.9 points), math computation (-7.1 points), and motor (-1.9 points) scores independent of the other potential confounders. CONCLUSIONS: Structured evaluation of brain MRI at term equivalent is predictive of outcome at 7 years of age, independent of clinical and social factors.

Evaluation of Preoperative Amplitude-Integrated Electroencephalography (aEEG) Monitoring for Predicting Long-Term Neurodevelopmental Outcome Among Infants Undergoing Major Surgery in the Neonatal Period.

The authors aimed to evaluate preoperative amplitude-integrated electroencephalography (aEEG) patterns for predicting neurodevelopmental outcome among infants undergoing major surgery in the neonatal period. They retrospectively reviewed the preoperative aEEG data of 58 neonates who had undergone major neonatal surgery between 2006 and 2008. The authors classified aEEGs using a weighted background score. Neurodevelopmental outcome was assessed at 3 years of age using the Bayley Scales of Toddler and Infant Development III. Over a third of infants (36%) showed an abnormal aEEG background. Seizure activity was identified in 11 (19%) infants. The majority (68%) of infants had developmental delay, with no significant differences between cardiac and other surgery groups. Logistic regression found no statistically significant but some clinically important associations between aEEG background and neurodevelopmental outcome. Comorbidity was associated with worse outcomes. While the predictive utility of aEEG in this population remains unclear, the findings suggest that further research is warranted.

Perioperative risk factors for impaired neurodevelopment after cardiac surgery in early infancy.

OBJECTIVE: Historical cohort studies have reported adverse neurodevelopment following cardiac surgery during early infancy. Advances in surgical techniques and perioperative care have coincided with updating of neurodevelopmental assessment tools. We aimed to determine perioperative risk factors for impaired neurodevelopment at 2 years following surgery for congenital heart disease (CHD) in early infancy. DESIGN AND PATIENTS: We undertook a prospective longitudinal study of 153 full-term infants undergoing surgery for CHD before 2 months of age. Infants were excluded if they had a genetic syndrome associated with neurodevelopmental impairment. OUTCOME MEASURES: Predefined perioperative parameters were recorded and infants were classified according to cardiac anatomy. At 2 years, survivors were assessed using the Bayley Scales of Infant Development-III. RESULTS: At 2 years, 130 children (98% of survivors) were assessed. Mean cognitive, language and motor scores were 93.4±13.6, 93.6±16.1 and 96.8±12.5 respectively (100±15 norm). Twenty (13%) died and 12 (9%) survivors had severe impairment (score <70), mostly language (8%). The lowest scores were in infants born with single ventricle physiology with obstruction to the pulmonary circulation who required a neonatal systemic-to-pulmonary artery shunt. Additional risk factors for impairment included reduced gestational age, postoperative elevation of lactate or S100B and repeat cardiac surgery. CONCLUSIONS: In the modern era of infant cardiac surgery and perioperative care, children continue to demonstrate neurodevelopmental delays. The use of updated assessment tools has revealed early language dysfunction and relative sparing of motor function. Ongoing follow-up is critical in this high-risk population.

Structural connectivity relates to perinatal factors and functional impairment at 7years in children born very preterm.

OBJECTIVE: To use structural connectivity to (1) compare brain networks between typically and atypically developing (very preterm) children, (2) explore associations between potential perinatal developmental disturbances and brain networks, and (3) describe associations between brain networks and functional impairments in very preterm children. METHODS: 26 full-term and 107 very preterm 7-year-old children (born <30weeks' gestational age and/or <1250g) underwent T1- and diffusion-weighted imaging. Global white matter fibre networks were produced using 80 cortical and subcortical nodes, and edges were created using constrained spherical deconvolution-based tractography. Global graph theory metrics were analysed, and regional networks were identified using network-based statistics. Cognitive and motor function were assessed at 7years of age. RESULTS: Compared with full-term children, very preterm children had reduced density, lower global efficiency and higher local efficiency. Those with lower gestational age at birth, infection or higher neonatal brain abnormality score had reduced connectivity. Reduced connectivity within a widespread network was predictive of impaired IQ, while reduced connectivity within the right parietal and temporal lobes was associated with motor impairment in very preterm children. CONCLUSIONS: This study utilised an innovative structural connectivity pipeline to reveal that children born very preterm have less connected and less complex brain networks compared with typically developing term-born children. Adverse perinatal factors led to disturbances in white matter connectivity, which in turn are associated with impaired functional outcomes, highlighting novel structure-function relationships.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).