Early human brain development: insights into macroscale connectome wiring.

BACKGROUND: Early brain development is closely dictated by distinct neurobiological principles. Here, we aimed to map early trajectories of structural brain wiring in the neonatal brain. METHODS: We investigated structural connectome development in 44 newborns, including 23 preterm infants and 21 full-term neonates scanned between 29 and 45 postmenstrual weeks. Diffusion-weighted imaging data were combined with cortical segmentations derived from T2 data to construct neonatal connectome maps. RESULTS: Projection fibers interconnecting primary cortices and deep gray matter structures were noted to mature faster than connections between higher-order association cortices (fractional anisotropy (FA) F = 58.9, p < 0.001, radial diffusivity (RD) F = 28.8, p < 0.001). Neonatal FA-values resembled adult FA-values more than RD, while RD approximated the adult brain faster (F = 358.4, p < 0.001). Maturational trajectories of RD in neonatal white matter pathways revealed substantial overlap with what is known about the sequence of subcortical white matter myelination from histopathological mappings as recorded by early neuroanatomists (mean RD 68 regions r = 0.45, p = 0.008). CONCLUSION: Employing postnatal neuroimaging we reveal that early maturational trajectories of white matter pathways display discriminative developmental features of the neonatal brain network. These findings provide valuable insight into the early stages of structural connectome development.

Effect of general anesthesia on neonatal aEEG-A cohort study of patients with non-cardiac congenital anomalies.

INTRODUCTION: The aim of the current study was to determine the effect of general anesthesia on neonatal brain activity using amplitude-integrated EEG (aEEG). METHODS: A prospective cohort study of neonates (January 2013-December 2015), who underwent major neonatal surgery for non-cardiac congenital anomalies. Anesthesia was administered at the discretion of the anesthetist. aEEG monitoring was started six hours preoperatively until 24 hours after surgery. Analysis of classes of aEEG background patterns, ranging from continuous normal voltage to flat trace in six classes, and quantitative EEG-measures, using spontaneous activity transients (SATs) and interSATintervals (ISI), was performed. RESULTS: In total, 111 neonates were included (36 preterm/75 full-term), age at time of surgery was (median (range) 2 (0-32) days. During anesthesia depression of brain activity was seen, with background patterns ranging from flat trace to discontinuous normal voltage. In most patients brain activity was two background pattern classes lower during anesthesia. After cessation of anesthesia, recovery to preoperative brain activity occurred within 24 hours in 86% of the preterm and 96% of the term infants. Gestational age and the dose of sevoflurane were significantly associated with SAT-rate (F(2,68) = 9.288, p < 0.001) and ISI- durations during surgery (F(3,71) = 12.96, p < 0.001). Background pattern and quantitative EEG-values were not associated with brain lesions (χ2(4) = 2.086, ns). CONCLUSION: aEEG shows a variable reduction of brain activity in response to anesthesia in neonates with noncardiac congenital anomalies, with fast recovery after cessation of anesthesia. This reduction is related to gestational age and the dose of sevoflurane. The aEEG offers the opportunity to monitor the depth of anesthesia in the neonate.

Neonatal Surgery for Noncardiac Congenital Anomalies: Neonates at Risk of Brain Injury.

OBJECTIVE: To evaluate the incidence of brain injury after neonatal surgery for noncardiac congenital anomalies using magnetic resonance imaging (MRI). STUDY DESIGN: An MRI was obtained in 101 infants at 7 days [range: 1-115] after neonatal surgery for major noncardiac congenital anomalies. Brain injury was assessed using T1, T2, diffusion weighted imaging, and susceptibility-weighted imaging. RESULTS: Thirty-two preterm infants (<37 weeks of gestation) and 69 full-term infants were included. MRI abnormalities were found in 24 (75%) preterm and 40 (58%) full-term infants. Parenchymal lesions were noted in 23 preterm (72%) and 29 full-term infants (42%). These consisted of punctate white matter lesions (n = 45), punctate cerebellar lesions (n = 17), thalamic infarction (n = 5), and periventricular hemorrhagic infarction (n = 4). Nonparenchymal abnormalities were found in 9 (28%) preterm and 26 (38%) full-term infants. These included supra- and infratentorial subdural hemorrhages (n = 30), intraventricular hemorrhage grade II (n = 7), and asymptomatic sinovenous thrombosis (n = 1). A combination of parenchymal lesions was present in 21 infants. Of infants who had an MRI within 10 days after surgery, punctate white matter lesions were visible on diffusion weighted imaging in 22 (61%), suggestive of recent ischemic origin. Type of congenital anomaly and prematurity were most predictive of brain injury. CONCLUSIONS: Infants who have neonatal surgery for noncardiac congenital anomalies are at risk of brain injury, potentially accounting for the neurodevelopmental delay frequently observed in this population. Further research is warranted into potential mechanisms of brain injury and its timing of onset. Long-term neurodevelopmental follow-up is needed in this vulnerable population.

Brain Oxygenation During Thoracoscopic Repair of Long Gap Esophageal Atresia.

BACKGROUND: Elongation and repair of long gap esophageal atresia (LGEA) can be performed thoracoscopically, even directly after birth. The effect of thoracoscopic CO2-insufflation on cerebral oxygenation (rScO2) during the consecutive thoracoscopic procedures in repair of LGEA was evaluated. METHODS: Prospective case series of five infants, with in total 16 repetitive thoracoscopic procedures. A CO2-pneumothorax was installed with a pressure of maximum 5 mmHg and flow of 1 L/min. Parameters influencing rScO2 were monitored. For analysis 10 time periods of 10' during surgery and in the perioperative period were selected. RESULTS: Median gestational age was 35+3 [range 33+4 to 39+6] weeks; postnatal age at time of first procedure 4 [2-53] days and time of insufflation 127[22-425] min. Median rScO2 varied between 55 and 90%. Transient outliers in cerebral oxygenation were observed in three patients. In Patient 2 oxygenation values below 55% occurred during a low MABP and Hb < 6 mmol/L. The rScO2 increased after erythrocytes transfusion. Patient 5 also showed a rScO2 of 50% with a Hb <6 mmol/L during all procedures, except for a substantial increase during a high paCO2 of 60 mmHg. Patient 4 had a rScO2 > 85% during the first procedure with a concomitant high FiO2 > 45%. All parameters recovered during the surgical course. CONCLUSIONS: This prospective case series of NIRS during consecutive thoracoscopic repair of LGEA showed that cerebral oxygenation remained stable. Transient outliers in rScO2 occurred during changes in hemodynamic or respiratory parameters and normalized after interventions of the anesthesiologist. This study underlines the importance of perioperative neuromonitoring and the close collaboration between pediatric surgeon, anesthesiologist and neonatologist.

A survey of the dose of inhalational agents used to maintain anaesthesia in infants.

BACKGROUND: Various animal studies suggest that currently used anaesthetics are toxic to the developing brain. Many reviews advise that the total anaesthetic drug exposure should be reduced but the dose usually used in clinical practice has not been clearly elucidated. OBJECTIVES: To provide an overview of the dose ranges currently used in clinical practice during the maintenance phase of anaesthesia in infants undergoing anaesthesia for noncardiac surgery and diagnostic procedures. DESIGN: A two-centre mixed prospective (London) and retrospective (Utrecht) observational cohort study. SETTING: Two independent tertiary paediatric referral centres in March and November 2013; Great Ormond Street Hospital (GOSH), London, United Kingdom and Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), The Netherlands. PATIENTS: A total of 76 infants were included in the analysis, 38 infants from each hospital. METHODS: Patients from GOSH were matched by procedure, age and weight with patients from the UMCU. The end-tidal concentrations of the inhalational agents were investigated from anaesthetic charts during the maintenance phase and corrected for the age-specific minimal alveolar concentration (MAC), expressed as a percentage from the MAC (%MAC). RESULTS: Three different types of inhalational anaesthetics were used: sevoflurane, desflurane, isoflurane. The mean %MAC was 0.85. No significant differences in %MAC were found between GOSH and the UMCU (P = 0.329); the mean %MAC in GOSH was 0.87 and in the UMCU was 0.82. There was a significant increase in the %MAC in relation to age (slope = 0.036 MAC month, P < 0.001). Of all patients, 75% had an end-tidal concentration lower than 1 MAC. There was no significant effect of the use of analgesia on the end-tidal concentration of inhalational anaesthetics (P = 0.366). CONCLUSION: The concentration of inhalational anaesthetics in %MAC increased with age and was lowest in neonates. Most young infants received inhalational anaesthetics at a concentration below 1 MAC, which accords with current guidance to minimise anaesthetic drug exposure but may have unintended consequences.

Neurodevelopmental Outcomes After Neonatal Surgery for Major Noncardiac Anomalies.

CONTEXT: Increasing concerns have been raised about the incidence of neurodevelopmental delay in children with noncardiac congenital anomalies (NCCA) requiring neonatal surgery. OBJECTIVE: This study aimed to determine the incidence and potential risk factors for developmental delay after neonatal surgery for major NCCA. DATA SOURCES: A systematic search in PubMed, Embase and the Cochrane Library was performed through March 2015. STUDY SELECTION: Original research articles on standardized cognitive or motor skills tests. DATA EXTRACTION: Data on neurodevelopmental outcome, the Bayley Scales of Infant Development, and risk factors for delay were extracted. RESULTS: In total, 23 eligible studies were included, reporting on 895 children. Meta-analysis was performed with data of 511 children, assessed by the Bayley Scales of Infant Development at 12 and 24 months of age. Delay in cognitive development was reported in a median of 23% (3%-56%). Meta-analysis showed a cognitive score of 0.5 SD below the population average (Mental Development Index 92 ± 13, mean ± SD; P < .001). Motor development was delayed in 25% (0%-77%). Meta-analysis showed a motor score of 0.6 SD below average (Psychomotor Development Index 91 ± 14; P < .001). Several of these studies report risk factors for psychomotor delay, including low birth weight, a higher number of congenital anomalies, duration of hospital admission, and repeated surgery. LIMITATIONS: All data were retrieved from studies with small sample sizes and various congenital anomalies using different neurodevelopmental assessment tools. CONCLUSIONS: Cognitive and motor developmental delay was found in 23% of patients with NCCA. Meta-analysis showed that the mean neurodevelopmental outcome scores were 0.5 SD below the normative score of the healthy population.

Neonatal brain oxygenation during thoracoscopic correction of esophageal atresia.

BACKGROUND: Little is known about the effects of carbon dioxide (CO2) insufflation on cerebral oxygenation during thoracoscopy in neonates. Near-infrared spectroscopy can measure perioperative brain oxygenation [regional cerebral oxygen saturation (rScO2)]. AIMS: To evaluate the effects of CO2 insufflation on rScO2 during thoracoscopic esophageal atresia (EA) repair. METHODS: This is an observational study during thoracoscopic EA repair with 5 mmHg CO2 insufflation pressure. Mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), partial pressure of arterial carbon dioxide (paCO2), pH, and rScO2 were monitored in 15 neonates at seven time points: baseline (T0), after anesthesia induction (T1), after CO2-insufflation (T2), before CO2-exsufflation (T3), and postoperatively at 6 (T4), 12 (T5), and 24 h (T6). RESULTS: MABP remained stable. SaO2 decreased from T0 to T2 [97 ± 3-90 ± 6 % (p < 0.01)]. PaCO2 increased from T0 to T2 [41 ± 6-54 ± 15 mmHg (p < 0.01)]. pH decreased from T0 to T2 [7.33 ± 0.04-7.25 ± 0.11 (p < 0.05)]. All parameters recovered during the surgical course. Mean rScO2 was significantly higher at T1 compared to T2 [77 ± 10-73 ± 7 % (p < 0.05)]. Mean rScO2 levels never dropped below a safety threshold of 55 %. CONCLUSION: The impact of neonatal thoracoscopic repair of EA with insufflation of CO2 at 5 mmHg was studied. Intrathoracic CO2 insufflation caused a reversible decrease in SaO2 and pH and an increase in paCO2. The rScO2 was higher at anesthesia induction but remained stable and within normal limits during and after the CO2 pneumothorax, which suggest no hampering of cerebral oxygenation by the thoracoscopic intervention. Future studies will focus on the long-term effects of this surgery on the developing brain.

Brain oxygenation during laparoscopic correction of hypertrophic pyloric stenosis.

BACKGROUND: Concern remains about the safety of carbon dioxide (CO2) pneumoperitoneum (PP) in young infants having surgery for pyloric stenosis via laparoscopy. Interests here mainly focus on possible jeopardized organ perfusion and in particular brain oxygenation with possible adverse neurodevelopmental outcomes. The aim of this study was to investigate the intraoperative effects of CO2 gas PP on cerebral oxygenation during laparoscopic surgery for hypertrophic pyloric stenosis in young infants. PATIENTS AND METHODS: In this single-center prospective observational study, we investigated brain oxygenation in 12 young infants receiving laparoscopic pyloromyotomy with CO2 PP, with a pressure of 8 mm Hg and a flow rate of 5 L/minute. Intraoperative hemodynamic parameters and transcranial near-infrared spectroscopy to assess regional cerebral oxygen saturation (rScO2) were monitored continuously during the whole procedure. Parameters were analyzed in four intervals: before insufflation (T0), during (start [T1] and end [T2]), and after cessation (T3) of the CO2 PP. RESULTS: Blood pressure and end-tidal CO2 (etCO2) increased during the procedure: mean arterial pressure, 35±5 mm Hg at T0 to 43±9 mm Hg at T2; etCO2, 35±4 mm Hg at T0 to 40±3 mm Hg at T3. The rScO2 remained stable throughout the whole anesthetic period. In none of the patients did the rScO2 drop below the safety threshold of 55% (rScO2, 68±14% at T0 to 71±9% at T3). CONCLUSIONS: Our results indicate that a laparoscopic procedure with a CO2 PP of 8 mm Hg can be performed under safe anesthetic conditions in the presence of gradually increasing blood pressure and etCO2 without altering regional brain oxygenation levels.

The effects of CO2-insufflation with 5 and 10 mmHg during thoracoscopy on cerebral oxygenation and hemodynamics in piglets: an animal experimental study.

OBJECTIVE: To evaluate the effect of CO2-insufflation with 5 and 10 mmHg on cerebral oxygenation and hemodynamics in neonates. BACKGROUND: An increasing percentage of surgical interventions in neonates are performed by minimal invasive techniques. Recently, concerns have been raised regarding a decrease of cerebral oxygenation in neonates during thoracoscopy as a result of CO2-insufflation. METHODS: This was an animal experimental study. Piglets were anesthetized, intubated, ventilated, and surgically prepared for CO2-insufflation. Insufflation was done with 5 or 10 mmHg CO2 during 1 h. Arterial saturation (SaO2), heart rate (HR), mean arterial blood pressure (MABP), and cerebral oxygenation (rScO2) were monitored. CFTOE, an estimator of cerebral oxygen extraction ((SaO2 - rScO2)/SaO2)), was calculated. Arterial blood gases were drawn every 15': pre (T0), during (T1-T4) and after CO2-insufflation (T5). RESULTS: Ten piglets (4 kg) were randomized for 5 (P5) and 10 (P10) mmHg CO2-insufflation. Two P10 piglets needed resuscitation after insufflation, none P5. Linear mixed-effect modeling of paCO2, pH, and SaO2 showed that values were dependent on time and time squared (p < 0.001) but were not different between the 5 and 10 mmHg groups. Analysis demonstrated significant changes over time in heart rate and MABP between the 5 and 10 mmHg groups, with a significant higher heart rate and lower blood pressure in the 10 mmHg group (p < 0.001). For rScO2 and cFTOE, no group differences could be demonstrated, but a significant effect of time was found: rScO2 increased and cFTOE decreased (p < 0.001). CONCLUSIONS: Insufflation of CO2 during thoracoscopy with 10 mmHg caused more severe hemodynamic instability and seems to be related with a decrease of cerebral perfusion as represented by a higher oxygen extraction. CO2-insufflation of 5 mmHg for thoracoscopy seems to have no adverse effects on cerebral oxygenation.