Prenatal Brain Maturation is Delayed in Neonates with Congenital Diaphragmatic Hernia.

OBJECTIVE: To assess brain development in fetuses with congenital diaphragmatic hernia (CDH) using a fetal Total Maturation Score (fTMS). STUDY DESIGN: This is a retrospective cohort study using data from a single-center clinical registry. Neonates with an antenatal diagnosis of CDH between 2014 and 2020 and prenatal brain magnetic resonance imaging (MRI) (n = 48) were included. We compared our study sample with historical healthy controls (n = 48). The relationship between fTMS and gestational age (GA), as well as the association between fTMS and key prenatal variables and placental pathologic findings, were evaluated. RESULTS: Compared with healthy controls, neonates with CDH had a significant delay in fTMS (P value <.001). Within the CDH cohort, there was no significant difference in fTMS based on CDH severity, intrathoracic liver position, right vs left CDH, sex, presence of abnormal echocardiogram findings, treatment with extracorporeal membrane oxygenation (ECMO), or in-hospital mortality. Placentas of neonates with CDH had a high proportion of fetal vascular malperfusion (56%) and chronic inflammation (67%), and relatively large placentas had a protective effect on prenatal brain maturation (P value = .025). CONCLUSIONS: Prenatal brain maturation in neonates with CDH is delayed. Placental pathology may influence fetal brain development. The etiology and clinical impact of prenatal brain immaturity in neonates with CDH warrant further investigation.

Unique model of chronic hypoxia in fetal lambs demonstrates abnormal contrast-enhanced ultrasound brain perfusion.

BACKGROUND: Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD. METHODS: Fifteen fetal lambs [hypoxic animals (n = 9) and normoxic controls (n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained. RESULTS: Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF (p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami (p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027). CONCLUSION: Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes. IMPACT: This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values. These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences. To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model. The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.

Predictors of the inability to achieve full oral feeding in postoperative infants with CHD.

OBJECTIVES: Poor oral feeding is a known contributor to growth challenges in neonates with complex CHD who require early surgery. Almost 60% of these infants do not achieve full oral feeding by hospital discharge. This study's objective was to identify predictors of the inability to achieve full oral feeding by discharge in neonates with complex CHD following surgical intervention with cardiopulmonary bypass. STUDY DESIGN: A retrospective analysis of a prospective study of 192 full-term neonates with complex CHD was performed. A stepwise selection logistic regression model was developed to predict oral feeding status at hospital discharge. Univariate subgroup analysis was performed with groups determined based on a CHD classification system. RESULTS: 58% of neonates (112/192) failed to achieve full oral feeding by hospital discharge. A logistic regression model identified duration of deep hypothermic circulatory arrest and reintubation as predictors of the inability to achieve full oral feeding. Among neonates who achieved full oral feeding by discharge (42%), only 7.5% did so after postoperative day 10. Brain maturation, brain injury, and preoperative oral feeding were not predictors of full postoperative oral feeding. CONCLUSIONS: Many infants with CHD fail to achieve full oral feeding by time of hospital discharge. Longer duration of deep hypothermic circulatory arrest and increased number of intubations were predictive of poor feeding after surgery. Prolonging hospitalisation solely to achieve full oral feeding after postoperative day ten is of limited utility; earlier discharge should be promoted to avoid negative impacts on neonatal neurodevelopment as unintended consequences of lengthy hospitalisations.

Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.

Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO2) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO2 was higher in hyperoxia animals throughout CPB (p < 0.001). There were no differences in cortical glycerol concentration between groups (p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals (p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration (p = 0.48), protein carbonyls (p = 0.74), or reactive oxygen species generation (p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.

Oral feeding dysfunction in post-operative infants with CHDs: a scoping review.

Post-operative oral feeding difficulties in neonates and infants with CHD is common. While pre-operative oral feeding may be normal, oral feeding challenges manifest in the post-operative period without a clearly defined aetiology. The objective of this scoping review was to examine post-operative oral feeding in full-term neonates and infants with a CHD. Electronic databases query (1 January 1975-31 May 2021), hand-search of the reference lists of included studies, contact with experts, and review of relevant conferences were performed to identify quantitative studies evaluating post-operative oral feeding in full-term neonates and infants with a CHD. Associations with additional quantitative variables in these studies were also examined. Twenty-five studies met inclusion criteria. Eighty per cent were cohort studies that utilised retrospective chart review from a single institution. The primary variable of interest in all studies was oral feeding status upon discharge from neonatal hospitalisation. The most common risk factors evaluated with poor feeding at time of discharge were birth weight (36% of included studies), gestational age (44%), duration of post-operative intubation (48%), cardiac diagnosis (40%), and presence of genetic syndrome or chromosomal anomaly (36%). The most common health-related outcomes evaluated were length of hospital stay (40%) and length of ICU stay (16%). Only the health-related outcomes of length of hospital stay and length of ICU stay were consistently significantly associated with poor post-operative oral feeding across studies in this review. A clear aetiology of poor post-operative oral feeding remains unknown.

Radiographic and histologic characterisation of white matter injury in a sheep model of CHD.

Nearly one in five children with CHD is born with white matter injury that can be recognised on postnatal MRI by the presence of T1 hyperintense lesions. This pattern of white matter injury is known to portend poor neurodevelopmental outcomes, but the exact aetiology and histologic characterisation of these lesions have never been described. A fetal sheep was cannulated at gestational age 110 days onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid environment for 14.5 days. The fetus was supported under hypoxic conditions (mean oxygen delivery 16 ml/kg/day) to simulate the in utero conditions of CHD. At necropsy, the brain was fixed, imaged with MRI, and then stained to histologically identify areas of injury. Under hypoxemic in utero conditions, the fetus developed a T1 hyperintense lesion in its right frontal lobe. Histologically, this lesion was characterised by microvascular proliferation and astrocytosis without gliosis. These findings may provide valuable insight into the aetiology of white matter injury in neonates with CHD.

Neurologic complications of infective endocarditis in children.

OBJECTIVES: To define the frequency and characteristics of acute neurologic complications in children hospitalised with infective endocarditis and to identify risk factors for neurologic complications. STUDY DESIGN: Retrospective cohort study of children aged 0-18 years hospitalised at a tertiary children's hospital from 1 January, 2008 to 31 December, 2017 with infective endocarditis. RESULTS: Sixty-eight children met Duke criteria for infective endocarditis (43 definite and 25 possible). Twenty-three (34%) had identified neurologic complications, including intracranial haemorrhage (25%, 17/68) and ischaemic stroke (25%, 17/68). Neurologic symptoms began a median of 4.5 days after infective endocarditis symptom onset (interquartile range 1, 25 days), though five children were asymptomatic and diagnosed on screening neuroimaging only. Overall, only 56% (38/68) underwent neuroimaging during acute hospitalisation, so additional asymptomatic neurologic complications may have been missed. Children with identified neurologic complications compared to those without were older (48 versus 22% ≥ 13 years old, p = 0.031), more often had definite rather than possible infective endocarditis (96 versus 47%, p < 0.001), mobile vegetations >10mm (30 versus 11%, p = 0.048), and vegetations with the potential for systemic embolisation (65 versus 29%, p = 0.004). Six children died (9%), all of whom had neurologic complications. CONCLUSIONS: Neurologic complications of infective endocarditis were common (34%) and associated with mortality. The true frequency of neurologic complications was likely higher because asymptomatic cases may have been missed without screening neuroimaging. Moving forward, we advocate that all children with infective endocarditis have neurologic consultation, examination, and screening neuroimaging. Additional prospective studies are needed to determine whether early identification of neurologic abnormalities may direct management and ultimately reduce neurologic morbidity and overall mortality.

Effects of circulatory arrest and cardiopulmonary bypass on cerebral autoregulation in neonatal swine.

BACKGROUND: Cerebral autoregulation mechanisms help maintain adequate cerebral blood flow (CBF) despite changes in cerebral perfusion pressure. Impairment of cerebral autoregulation, during and after cardiopulmonary bypass (CPB), may increase risk of neurologic injury in neonates undergoing surgery. In this study, alterations of cerebral autoregulation were assessed in a neonatal swine model probing four perfusion strategies. METHODS: Neonatal swine (n = 25) were randomized to continuous deep hypothermic cardiopulmonary bypass (DH-CPB, n = 7), deep hypothermic circulatory arrest (DHCA, n = 7), selective cerebral perfusion (SCP, n = 7) at deep hypothermia, or normothermic cardiopulmonary bypass (control, n = 4). The correlation coefficient (LDx) between laser Doppler measurements of CBF and mean arterial blood pressure was computed at initiation and conclusion of CPB. Alterations in cerebral autoregulation were assessed by the change between initial and final LDx measurements. RESULTS: Cerebral autoregulation became more impaired (LDx increased) in piglets that underwent DH-CPB (initial LDx: median 0.15, IQR [0.03, 0.26]; final: 0.45, [0.27, 0.74]; p = 0.02). LDx was not altered in those undergoing DHCA (p > 0.99) or SCP (p = 0.13). These differences were not explained by other risk factors. CONCLUSIONS: In a validated swine model of cardiac surgery, DH-CPB had a significant effect on cerebral autoregulation, whereas DHCA and SCP did not. IMPACT: Approximately half of the patients who survive neonatal heart surgery with cardiopulmonary bypass (CPB) experience neurodevelopmental delays. This preclinical investigation takes steps to elucidate and isolate potential perioperative risk factors of neurologic injury, such as impairment of cerebral autoregulation, associated with cardiac surgical procedures involving CPB. We demonstrate a method to characterize cerebral autoregulation during CPB pump flow changes in a neonatal swine model of cardiac surgery. Cerebral autoregulation was not altered in piglets that underwent deep hypothermic circulatory arrest (DHCA) or selective cerebral perfusion (SCP), but it was altered in piglets that underwent deep hypothermic CBP.

Chronic foetal hypoxaemia does not cause elevation of serum markers of brain injury.

OBJECTIVES: The objective of this study was to investigate changes in serum biomarkers of acute brain injury, including white matter and astrocyte injury during chronic foetal hypoxaemia. We have previously shown histopathological changes in myelination and neuronal density in fetuses with chronic foetal hypoxaemia at a level consistent with CHD. METHODS: Mid-gestation foetal sheep (110 ± 3 days gestation) were cannulated and attached to a pumpless, low-resistance oxygenator circuit, and incubated in a sterile fluid environment mimicking the intrauterine environment. Fetuses were maintained with an oxygen delivery of 20-25 ml/kg/min (normoxemia) or 14-16 ml/kg/min (hypoxaemia). Myelin Basic Protein and Glial Fibrillary Acidic Protein serum levels in the two groups were assessed by ELISA at baseline and at 7, 14, and 21 days of support. RESULTS: Based on overlapping 95% confidence intervals, there were no statistically significant differences in either Myelin Basic Protein or Glial Fibrillary Acidic Protein serum levels between the normoxemic and hypoxemic groups, at any time point. No statistically significant correlations were observed between oxygen delivery and levels of Myelin Basic Protein and Glial Fibrillary Acidic Protein. CONCLUSION: Chronic foetal hypoxaemia during mid-gestation is not associated with elevated serum levels of acute white matter (Myelin Basic Protein) or astrocyte injury (Glial Fibrillary Acidic Protein), in this model. In conjunction with our previously reported findings, our data support the hypothesis that the brain dysmaturity with impaired myelination found in fetuses with chronic hypoxaemia is caused by disruption of normal developmental pathways rather than by direct cellular injury.

Optical Detection of Intracranial Pressure and Perfusion Changes in Neonates With Hydrocephalus.

OBJECTIVE: To demonstrate that a novel noninvasive index of intracranial pressure (ICP) derived from diffuse optics-based techniques is associated with intracranial hypertension. STUDY DESIGN: We compared noninvasive and invasive ICP measurements in infants with hydrocephalus. Infants born term and preterm were eligible for inclusion if clinically determined to require cerebrospinal fluid (CSF) diversion. Ventricular size was assessed preoperatively via ultrasound measurement of the fronto-occipital (FOR) and frontotemporal (FTHR) horn ratios. Invasive ICP was obtained at the time of surgical intervention with a manometer. Intracranial hypertension was defined as invasive ICP ≥15 mmHg. Diffuse optical measurements of cerebral perfusion, oxygen extraction, and noninvasive ICP were performed preoperatively, intraoperatively, and postoperatively. Optical and ultrasound measures were compared with invasive ICP measurements, and their change in values after CSF diversion were obtained. RESULTS: We included 39 infants, 23 with intracranial hypertension. No group difference in ventricular size was found by FOR (P = .93) or FTHR (P = .76). Infants with intracranial hypertension had significantly higher noninvasive ICP (P = .02) and oxygen extraction fraction (OEF) (P = .01) compared with infants without intracranial hypertension. Increased cerebral blood flow (P = .005) and improved OEF (P < .001) after CSF diversion were observed only in infants with intracranial hypertension. CONCLUSIONS: Noninvasive diffuse optical measures (including a noninvasive ICP index) were associated with intracranial hypertension. The findings suggest that impaired perfusion from intracranial hypertension was independent of ventricular size. Hemodynamic evidence of the benefits of CSF diversion was seen in infants with intracranial hypertension. Noninvasive optical techniques hold promise for aiding the assessment of CSF diversion timing.

Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature.

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

Variability in atlas registration of optical intrinsic signal imaging and its effect on functional connectivity analysis.

To compare neuroimaging data between subjects, images from individual sessions need to be aligned to a common reference or "atlas." Atlas registration of optical intrinsic signal imaging of mice, for example, is commonly performed using affine transforms with parameters determined by manual selection of canonical skull landmarks. Errors introduced by such procedures have not previously been investigated. We quantify the variability that arises from this process and consequent errors from misalignment that affect interpretation of functional neuroimaging data. We propose an improved method, using separately acquired high-resolution images and demonstrate improvements in variability and alignment using this method.

Early Evaluation and the Effect of Socioeconomic Factors on Neurodevelopment in Infants with Tetralogy of Fallot.

Neurodevelopmental sequelae are prevalent among patients with congenital heart defects (CHD). In a study of infants and children with repaired tetralogy of Fallot (TOF), we sought to identify those at risk for abnormal neurodevelopment and to test associations between socioeconomic and medical factors with neurodevelopment deficits. Single-center retrospective observational study of patients with repaired TOF that were evaluated at the institution's Cardiac Kids Developmental Follow-up Program (CKDP) between 2012 and 2018. Main outcomes included neurodevelopmental test scores from the Bayley Infant Neurodevelopmental Screener (BINS), Peabody Developmental Motor Scale (PDMS), and Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Mixed effects linear regression and marginal logistic regression models tested relationships between patient characteristics and outcomes. Sub-analyses were conducted to test correlations between initial and later neurodevelopment tests. In total, 49 patients were included, predominantly male (n = 33) and white (n = 28), first evaluated at a median age of 4.5 months. Forty-three percent of patients (n = 16) had deficits in the BINS, the earliest screening test. Several socioeconomic parameters and measures of disease complexity were associated with neurodevelopment, independently of genetic syndrome. Early BINS and PDMS performed in infancy were associated with Bayley-III scores performed after 1 year of age. Early screening identifies TOF patients at risk for abnormal neurodevelopment. Socioeconomic factors and disease complexity are associated with abnormal neurodevelopment and should be taken into account in the risk stratification and follow-up of these patients. Early evaluation with BINS and PDMS is suggested for detection of early deficits.

Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest: A Scientific Statement From the American Heart Association.

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine, and nursing to review existing neurological prognostication studies, the practice of neurological prognostication, and withdrawal of life-sustaining treatment. The writing group determined that the overall quality of existing neurological prognostication studies is low. As a consequence, the degree of confidence in the predictors and the subsequent outcomes is also low. Therefore, the writing group suggests that neurological prognostication parameters need to be approached as index tests based on relevant neurological functions that are directly related to the functional outcome and contribute to the quality of life of cardiac arrest survivors. Suggestions to improve the quality of adult and pediatric neurological prognostication studies are provided.

A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.

OBJECTIVE: To compare the safety and efficacy of phenobarbital and levetiracetam in a cohort of neonates with seizures following cardiac surgery. METHODS: We performed a retrospective single-center study of consecutive neonates with electrographically confirmed seizures managed with antiseizure medication after cardiac surgery from June 15, 2012 to December 31, 2018. We compared the safety and efficacy of phenobarbital and levetiracetam as first-line therapy. RESULTS: First-line therapy was phenobarbital in 31 neonates and levetiracetam in 22 neonates. Phenobarbital was associated with more adverse events (P = .006). Eight neonates (14%) experienced an adverse event related to phenobarbital use, including seven with hypotension and one with respiratory depression. No adverse events were reported with levetiracetam use. The cessation of electrographic seizures was similar in both groups, including 18 neonates (58%) with seizure cessation after phenobarbital and 12 neonates (55%) with seizure cessation after levetiracetam (P = 1.0). The combined cessation rates of phenobarbital and levetiracetam when used as first- or second-line therapy were 58% and 47%, respectively (P = .47). SIGNIFICANCE: Phenobarbital was associated with more adverse events than levetiracetam, and the two drugs were equally but incompletely effective in treating electrographically confirmed seizures in neonates following cardiac surgery. Given its more acceptable safety profile and potential noninferiority, levetiracetam may be a reasonable option for first-line therapy for treatment of seizures in this population. Further prospective studies are needed to confirm these results.

Noninvasive optical measurement of microvascular cerebral hemodynamics and autoregulation in the neonatal ECMO patient.

BACKGROUND: Extra-corporeal membrane oxygenation (ECMO) is a life-saving intervention for severe respiratory and cardiac diseases. However, 50% of survivors have abnormal neurologic exams. Current ECMO management is guided by systemic metrics, which may poorly predict cerebral perfusion. Continuous optical monitoring of cerebral hemodynamics during ECMO holds potential to detect risk factors of brain injury such as impaired cerebrovascular autoregulation (CA). METHODS: We conducted daily measurements of microvascular cerebral blood flow (CBF), oxygen saturation, and total hemoglobin concentration using diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy in nine neonates. We characterize CA utilizing the correlation coefficient (DCSx) between CBF and mean arterial blood pressure (MAP) during ECMO pump flow changes. RESULTS: Average MAP and pump flow levels were weakly correlated with CBF and were not correlated with cerebral oxygen saturation. CA integrity varied between individuals and with time. Systemic measurements of MAP, pulse pressure, and left cardiac dysfunction were not predictive of impaired CA. CONCLUSIONS: Our pilot results suggest that systemic measures alone cannot distinguish impaired CA from intact CA during ECMO. Furthermore, optical neuromonitoring could help determine patient-specific ECMO pump flows for optimal CA integrity, thereby reducing risk of secondary brain injury. IMPACT: Cerebral blood flow and oxygenation are not well predicted by systemic proxies such as ECMO pump flow or blood pressure. Continuous, quantitative, bedside monitoring of cerebral blood flow and oxygenation with optical tools enables new insight into the adequacy of cerebral perfusion during ECMO. A demonstration of hybrid diffuse optical and correlation spectroscopies to continuously measure cerebral blood oxygen saturation and flow in patients on ECMO, enabling assessment of cerebral autoregulation. An observation of poor correlation of cerebral blood flow and oxygenation with systemic mean arterial pressure and ECMO pump flow, suggesting that clinical decision making guided by target values for these surrogates may not be neuroprotective. ~50% of ECMO survivors have long-term neurological deficiencies; continuous monitoring of brain health throughout therapy may reduce these tragically common sequelae through brain-focused adjustment of ECMO parameters.

Epinephrine's effects on cerebrovascular and systemic hemodynamics during cardiopulmonary resuscitation.

BACKGROUND: Despite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first. METHODS: One-month-old piglets (n = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10-20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO2]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first. RESULTS: With the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures (p < 0.001). The effects of epinephrine on CBF and cerebral tissue oxygenation decreased with subsequent doses. By the fifth dose of epinephrine, there were no demonstrable increases in CBF of cerebral tissue oxygenation. Invasive and noninvasive CBF measurements were highly correlated during asphyxia (slope effect 1.3, p < 0.001) and CPR (slope effect 0.20, p < 0.001). CONCLUSIONS: This model suggests that epinephrine increases CBF and cerebral tissue oxygenation, but that effects wane following the third dose. Noninvasive measurements of neurological health parameters hold promise for developing and directing resuscitation strategies.

Cardiopulmonary Resuscitation in Infants and Children With Cardiac Disease: A Scientific Statement From the American Heart Association.

Cardiac arrest occurs at a higher rate in children with heart disease than in healthy children. Pediatric basic life support and advanced life support guidelines focus on delivering high-quality resuscitation in children with normal hearts. The complexity and variability in pediatric heart disease pose unique challenges during resuscitation. A writing group appointed by the American Heart Association reviewed the literature addressing resuscitation in children with heart disease. MEDLINE and Google Scholar databases were searched from 1966 to 2015, cross-referencing pediatric heart disease with pertinent resuscitation search terms. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. The recommendations in this statement concur with the critical components of the 2015 American Heart Association pediatric basic life support and pediatric advanced life support guidelines and are meant to serve as a resuscitation supplement. This statement is meant for caregivers of children with heart disease in the prehospital and in-hospital settings. Understanding the anatomy and physiology of the high-risk pediatric cardiac population will promote early recognition and treatment of decompensation to prevent cardiac arrest, increase survival from cardiac arrest by providing high-quality resuscitations, and improve outcomes with postresuscitation care.

Hemodynamic-Directed Cardiopulmonary Resuscitation Improves Neurologic Outcomes and Mitochondrial Function in the Heart and Brain.

OBJECTIVES: Less than half of the thousands of children who suffer in-hospital cardiac arrests annually survive, and neurologic injury is common among survivors. Hemodynamic-directed cardiopulmonary resuscitation improves short-term survival, but its impact on longer term survival and mitochondrial respiration-a potential neurotherapeutic target-remains unknown. The primary objectives of this study were to compare rates of 24-hour survival with favorable neurologic outcome after cardiac arrest treated with hemodynamic-directed cardiopulmonary resuscitation versus standard depth-guided cardiopulmonary resuscitation and to compare brain and heart mitochondrial respiration between groups 24 hours after resuscitation. DESIGN: Randomized preclinical large animal trial. SETTING: A large animal resuscitation laboratory at a large academic children's hospital. SUBJECTS: Twenty-eight 4-week-old female piglets (8-11 kg). INTERVENTIONS: Twenty-two swine underwent 7 minutes of asphyxia followed by ventricular fibrillation and randomized treatment with either hemodynamic-directed cardiopulmonary resuscitation (n = 10; compression depth titrated to aortic systolic pressure of 90 mm Hg, vasopressors titrated to coronary perfusion pressure ≥ 20 mm Hg) or depth-guided cardiopulmonary resuscitation (n = 12; depth 1/3 chest diameter, epinephrine every 4 min). Six animals (sham group) underwent anesthesia and instrumentation without cardiac arrest. The primary outcomes were favorable neurologic outcome (swine Cerebral Performance Category ≤ 2) and mitochondrial maximal oxidative phosphorylation utilizing substrate for complex I and complex II (OXPHOSCI+CII) in the cerebral cortex and hippocampus. MEASUREMENTS AND MAIN RESULTS: Favorable neurologic outcome was more likely with hemodynamic-directed cardiopulmonary resuscitation (7/10) than depth-guided cardiopulmonary resuscitation (1/12; p = 0.006). Hemodynamic-directed cardiopulmonary resuscitation resulted in higher intra-arrest coronary perfusion pressure, aortic pressures, and brain tissue oxygenation. Hemodynamic-directed cardiopulmonary resuscitation resulted in higher OXPHOSCI+CII (pmol oxygen/s × mg/citrate synthase) in the cortex (6.00 ± 0.28 vs 3.88 ± 0.43; p < 0.05) and hippocampus (6.26 ± 0.67 vs 3.55 ± 0.65; p < 0.05) and higher complex I respiration (pmol oxygen/s × mg) in the right (20.62 ± 1.06 vs 15.88 ± 0.81; p < 0.05) and left ventricles (20.14 ± 1.40 vs 14.17 ± 1.53; p < 0.05). CONCLUSIONS: In a model of asphyxia-associated pediatric cardiac arrest, hemodynamic-directed cardiopulmonary resuscitation increases rates of 24-hour survival with favorable neurologic outcome, intra-arrest hemodynamics, and cerebral and myocardial mitochondrial respiration.

X-linked Charcot-Marie-Tooth Disease Presenting with Stuttering Stroke-like Symptoms.

X-linked Charcot-Marie-Tooth disease (CMTX1) is the second most common form of Charcot-Marie-Tooth disease (CMT). It is caused by a mutation in the gap junction ß 1 (GJB1) gene, which encodes for connexin-32. In addition to the peripheral neuropathy and foot deformities observed in classic CMT, central nervous system symptoms and magnetic resonance imaging (MRI) signal abnormalities in the brain have been reported in patients with CMTX1. Here we describe two cases of adolescent males who presented with stuttering neurologic deficits that were initially suggestive of acute ischemic stroke and were ultimately diagnosed with genetically confirmed CMTX1. Both patients had evidence of T2 hyperintensity and decreased diffusion on MRI in the centrum semiovale, posterior corona radiata, posterior periventricular white matter, and corpus callosum. Though rare, these cases illustrate the importance of comprehensive neurologic history, physical examination, and appropriate diagnostic evaluation.