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Advanced optical neuromonitoring of cerebral hemodynamics with hybrid diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) methods holds promise for non-invasive characterization of brain health in critically ill patients. However, the methods' fiber-coupled patient interfaces (probes) are challenging to apply in emergent clinical scenarios that require rapid and reproducible attachment to the head. To address this challenge, we developed a novel chassis-based optical probe design for DOS/DCS measurements and validated its measurement accuracy and reproducibility against conventional, manually held measurements of cerebral hemodynamics in pediatric swine (n = 20). The chassis-based probe design comprises a detachable fiber housing which snaps into a 3D-printed, circumferential chassis piece that is secured to the skin. To validate its reproducibility, eight measurement repetitions of cerebral tissue blood flow index (BFI), oxygen saturation (StO2), and oxy-, deoxy- and total hemoglobin concentration were acquired at the same demarcated measurement location for each pig. The probe was detached after each measurement. Of the eight measurements, four were acquired by placing the probe into a secured chassis, and four were visually aligned and manually held. We compared the absolute value and intra-subject coefficient of variation (CV) of chassis versus manual measurements. No significant differences were observed in either absolute value or CV between chassis and manual measurements (p > 0.05). However, the CV for BFI (mean ± SD: manual, 19.5% ± 9.6; chassis, 19.0% ± 10.8) was significantly higher than StO2 (manual, 5.8% ± 6.7; chassis, 6.6% ± 7.1) regardless of measurement methodology (p<0.001). The chassis-based DOS/DCS probe design facilitated rapid probe attachment/re-attachment and demonstrated comparable accuracy and reproducibility to conventional, manual alignment. In the future, this design may be adapted for clinical applications to allow for non-invasive monitoring of cerebral health during pediatric critical care.
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Circulación Cerebrovascular , Fibras Ópticas , Animales , Porcinos , Circulación Cerebrovascular/fisiología , Reproducibilidad de los Resultados , Análisis Espectral/métodos , Análisis Espectral/instrumentación , Encéfalo/fisiología , Diseño de Equipo , Hemodinámica , Hemoglobinas/análisis , Oxígeno/metabolismo , Oxígeno/análisisRESUMEN
An acute loss of smell emerged as a striking symptom present in roughly half of the people infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in the early phases of the COVID-19 pandemic. In most COVID-19 patients, olfaction recovers over the course of a few weeks. However, a lasting partial or complete loss of smell, often associated with distorted olfactory perceptions termed parosmia, has emerged as a widespread problem impacting at least 5%-10% of those who experience anosmia due to COVID-19. Our inability to offer effective therapies to this hyposmic or anosmic population, comprising millions of patients, highlights an enormous unmet need for the medical system. Here, we summarize the current understanding of the pathobiology causing acute olfactory loss due to SARS-CoV-2 infection, focusing on how the virus interacts with the peripheral olfactory system, a major site of viral infection. We also explore the problem of long-COVID olfactory dysfunction, which may accompany other persistent systemic disorders collectively termed postacute sequelae of COVID-19. Specifically, we discuss an emerging model focused on unresolved immune cell activity driving ongoing dysfunction. Finally, we review current and future therapeutic approaches aimed at restoring olfactory function.
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The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity-evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.
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Linaje de la Célula , Estesioneuroblastoma Olfatorio , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Animales , Ratones , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Humanos , Estesioneuroblastoma Olfatorio/genética , Estesioneuroblastoma Olfatorio/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Microambiente Tumoral , Neoplasias Nasales/genética , Neoplasias Nasales/patología , Mucosa Olfatoria/patología , Mucosa Olfatoria/metabolismo , Modelos Animales de Enfermedad , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
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.
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Animales Recién Nacidos , Puente Cardiopulmonar , Mitocondrias , Oxígeno , Especies Reactivas de Oxígeno , Animales , Porcinos , Puente Cardiopulmonar/efectos adversos , Puente Cardiopulmonar/métodos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Oxígeno/metabolismo , Consumo de Oxígeno , Ácido Láctico/metabolismo , Ácido Láctico/sangre , Estrés Oxidativo , Corteza Cerebral/metabolismo , Ácido Pirúvico/metabolismo , Hiperoxia/metabolismoRESUMEN
Despite improvements in survival after illnesses requiring extracorporeal life support, cerebral injury continues to hinder successful outcomes. Cerebral autoregulation (CA) is an innate protective mechanism that maintains constant cerebral blood flow in the face of varying systemic blood pressure. However, it is impaired in certain disease states and, potentially, following initiation of extracorporeal circulatory support. In this review, we first discuss patient-related factors pertaining to venovenous and venoarterial extracorporeal membrane oxygenation (ECMO) and their potential role in CA impairment. Next, we examine factors intrinsic to ECMO that may affect CA, such as cannulation, changes in pulsatility, the inflammatory and adaptive immune response, intracranial hemorrhage, and ischemic stroke, in addition to ECMO management factors, such as oxygenation, ventilation, flow rates, and blood pressure management. We highlight potential mechanisms that lead to disruption of CA in both pediatric and adult populations, the challenges of measuring CA in these patients, and potential associations with neurological outcome. Altogether, we discuss individualized CA monitoring as a potential target for improving neurological outcomes in extracorporeal life support.
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Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50-80% mortality prior to reaching medical care. Despite aggressive supportive care and targeted temperature management (TTM), half of adults do not live to hospital discharge and nearly one-third of survivors have significant neurologic injury. The current treatment approach following cardiac arrest resuscitation consists primarily of supportive care and possible TTM. While these current treatments are commonly used, mortality remains high, and survivors often develop lasting neurologic and cardiac sequela well after resuscitation. Hence, there is a critical need for further therapeutic development of adjunctive therapies. While select therapeutics have been experimentally investigated, one promising agent that has shown benefit is CO. While CO has traditionally been thought of as a cellular poison, there is both experimental and clinical evidence that demonstrate benefit and safety in ischemia with lower doses related to improved cardiac/neurologic outcomes. While CO is well known for its poisonous effects, CO is a generated physiologically in cells through the breakdown of heme oxygenase (HO) enzymes and has potent antioxidant and anti-inflammatory activities. While CO has been studied in myocardial infarction itself, the role of CO in cardiac arrest and post-arrest care as a therapeutic is less defined. Currently, the standard of care for post-arrest patients consists primarily of supportive care and TTM. Despite current standard of care, the neurological prognosis following cardiac arrest and return of spontaneous circulation (ROSC) remains poor with patients often left with severe disability due to brain injury primarily affecting the cortex and hippocampus. Thus, investigations of novel therapies to mitigate post-arrest injury are clearly warranted. The primary objective of this proposed study is to combine our expertise in swine models of CO and cardiac arrest for future investigations on the cellular protective effects of low dose CO. We will combine our innovative multi-modal diagnostic platform to assess cerebral metabolism and changes in mitochondrial function in swine that undergo cardiac arrest with therapeutic application of CO.
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Monóxido de Carbono , Modelos Animales de Enfermedad , Animales , Porcinos , Monóxido de Carbono/farmacología , Monóxido de Carbono/metabolismo , Paro Cardíaco/terapia , Paro Cardíaco Extrahospitalario/terapia , Masculino , Reanimación Cardiopulmonar/métodosRESUMEN
Objectives: We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB. Methods: Twenty piglets (mean weight 4.4 ± 0.5 kg) underwent 3â h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24â h (n = 5 per group). Markers of brain tissue damage (glycerol) and bioenergetic dysfunction (lactate to pyruvate ratio) were continuously measured in cerebral microdialysate samples. Control animals (n = 3, mean weight 4.1 ± 1.2 kg) did not undergo cannulation or CPB. Brain tissue was extracted immediately after euthanasia to obtain ex-vivo cortical mitochondrial respiration and frequency of cortical microglial nodules (indicative of cerebral microinfarctions) via neuropathology. Results: Both the lactate to pyruvate ratio (P < .0001) and glycerol levels (P = .01) increased in cerebral microdialysate within 8â h after CPB. At 24â h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P = .046). The presence of microglial nodules increased throughout the study period (24â h) (P = .01, R2 = 0.9). Conclusion: CPB results in impaired cerebral bioenergetics that persist for at least 24â h. During this period of bioenergetic impairment, there may be increased susceptibility to secondary injury related to alterations in metabolic delivery or demand, such as hypoglycemia, seizures, and decreased cerebral blood flow.
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Animales Recién Nacidos , Puente Cardiopulmonar , Metabolismo Energético , Mitocondrias , Animales , Puente Cardiopulmonar/efectos adversos , Porcinos , Metabolismo Energético/fisiología , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Encéfalo/metabolismo , Ácido Láctico/metabolismo , Ácido Láctico/sangre , Ácido Láctico/análisis , Ácido Pirúvico/metabolismo , Glicerol/metabolismoRESUMEN
INTRODUCTION: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). One of the glaring gaps is the lack of rigorous experimental models that may recapitulate survivors of acute CO poisoning in the early phase. The primary objective of this preliminary study is to use our advanced swine platform of acute CO poisoning to develop a clinically relevant survivor model to perform behavioral assessment and MRI imaging that will allow future development of biomarkers and therapeutics. METHODS: Four swine (10 kg) were divided into two groups: control (n = 2) and CO (n = 2). The CO group received CO at 2000 ppm for over 120 min followed by 30 min of re-oxygenation at room air for one swine and 150 min followed by 30 min of re-oxygenation for another swine. The two swine in the sham group received room air for 150 min. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. Following exposures, all surviving animals were observed for a 24-h period with neurobehavioral assessment and imaging. At the end of the 24-h period, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration. RESULTS: While a preliminary ongoing study, animals in the CO group showed alterations in cerebral metabolism and cellular function in the acute exposure phase with possible sustained mitochondrial changes 24 h after the CO exposure ended. CONCLUSIONS: This preliminary research further establishes a large animal swine model investigating survivors of CO poisoning to measure translational metrics relevant to clinical medicine that includes a basic neurobehavioral assessment and post exposure cellular measures.
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Intoxicación por Monóxido de Carbono , Animales , Porcinos , Intoxicación por Monóxido de Carbono/terapia , Mitocondrias/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Imagen por Resonancia Magnética , Monóxido de Carbono/toxicidad , Monóxido de Carbono/metabolismoRESUMEN
Background: Infants with complex congenital heart disease (CHD) require life-saving corrective/palliative heart surgery in the first weeks of life. These infants are at risk for brain injury and poor neurodevelopmental outcomes. Cerebral microhemorrhages (CMH) are frequently seen after neonatal bypass heart surgery, but it remains unknown if CMH are a benign finding or constitute injury. Herein, we investigate the risk factors for developing CMH and their clinical significance. Methods: 192 infants with CHD undergoing corrective cardiac surgery with cardiopulmonary bypass (CPB) at a single institution were prospectively evaluated with pre-(n = 183) and/or postoperative (n = 162) brain magnetic resonance imaging (MRI). CMH severity was scored based on total number of microhemorrhages. Antenatal, perioperative, and postoperative candidate risk factors for CMH and neurodevelopmental (ND) outcomes were analyzed. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley-III Scales of Infants and Toddler Development in a subset of patients (n = 82). Linear regression was used to analyze associations between risk factors or ND outcomes and presence/number of CMH. Results: The most common CHD subtypes were hypoplastic left heart syndrome (HLHS) (37%) and transposition of the great arteries (TGA) (33%). Forty-two infants (23%) had CMH present on MRI before surgery and 137 infants (85%) post-surgery. No parameters evaluated were significant risk factors for preoperative CMH. In multivariate analysis, cardiopulmonary bypass (CPB) duration (p < 0.0001), use of extracorporeal membrane oxygenation (ECMO) support (p < 0.0005), postoperative seizure(s) (p < 0.03), and lower birth weight (p < 0.03) were associated with new or worsened CMH postoperatively. Higher CMH number was associated with lower scores on motor (p < 0.03) testing at 18 months. Conclusion: CMH is a common imaging finding in infants with CHD with increased prevalence and severity after CPB and adverse impact on neurodevelopmental outcomes starting at a young age. Longer duration of CPB and need for postoperative ECMO were the most significant risk factors for developing CMH. However, presence of CMH on preoperative scans indicates non-surgical risk factors that are yet to be identified. Neuroprotective strategies to mitigate risk factors for CMH may improve neurodevelopmental outcomes in this vulnerable population.
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Cardiopulmonary bypass (CPB) provides cerebral oxygenation and blood flow (CBF) during neonatal congenital heart surgery, but the impacts of CPB on brain oxygen supply and metabolic demands are generally unknown. To elucidate this physiology, we used diffuse correlation spectroscopy and frequency-domain diffuse optical spectroscopy to continuously measure CBF, oxygen extraction fraction (OEF), and oxygen metabolism (CMRO2) in 27 neonatal swine before, during, and up to 24 h after CPB. Concurrently, we sampled cerebral microdialysis biomarkers of metabolic distress (lactate-pyruvate ratio) and injury (glycerol). We applied a novel theoretical approach to correct for hematocrit variation during optical quantification of CBF in vivo. Without correction, a mean (95% CI) +53% (42, 63) increase in hematocrit resulted in a physiologically improbable +58% (27, 90) increase in CMRO2 relative to baseline at CPB initiation; following correction, CMRO2 did not differ from baseline at this timepoint. After CPB initiation, OEF increased but CBF and CMRO2 decreased with CPB time; these temporal trends persisted for 0-8 h following CPB and coincided with a 48% (7, 90) elevation of glycerol. The temporal trends and glycerol elevation resolved by 8-24 h. The hematocrit correction improved quantification of cerebral physiologic trends that precede and coincide with neurological injury following CPB.
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Adult neurogenesis occurs in the mammalian olfactory epithelium to maintain populations of neurons that are vulnerable to injury yet essential for olfaction. Multipotent olfactory basal stem cells are activated by damage, although mechanisms regulating lineage decisions are not understood. Using mouse lesion models, we focused on defining the role of Polycomb repressive complexes (PRCs) in olfactory neurogenesis. PRC2 has a well-established role in developing tissues, orchestrating transcriptional programs via chromatin modification. PRC2 proteins are expressed in olfactory globose basal cells (GBCs) and nascent neurons. Conditional PRC2 loss perturbs lesion-induced neuron production, accompanied by altered histone modifications and misexpression of lineage-specific transcription factors in GBCs. De-repression of Sox9 in PRC2-mutant GBCs is accompanied by increased Bowman's gland production, defining an unrecognized role for PRC2 in regulating gland versus neuron cell fate. Our findings support a model for PRC2-dependent mechanisms promoting sensory neuronal differentiation in an adult neurogenic niche.
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Complejo Represivo Polycomb 2 , Olfato , Ratones , Animales , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Neurogénesis/fisiología , Diferenciación Celular/fisiología , Mucosa Olfatoria , Complejo Represivo Polycomb 1 , Mamíferos/metabolismoRESUMEN
The olfactory mucosa, lining a portion of the nasal cavity, houses the primary olfactory sensory neurons responsible for odor transduction, along with supporting cell populations. Tremendous advances have come from studying the peripheral olfactory system in animal models, especially the mouse. However, acquired human olfactory disorders lack effective therapies, and many of these conditions involve pathology in the olfactory mucosa. Thus, the ability to obtain human olfactory biopsy samples from subjects with olfactory dysfunction, or controls, may be of value. Here, we describe established techniques for collecting olfactory tissue from human subjects and preparing samples for downstream assays such as immunohistochemistry, flow cytometry, single-cell RNA-sequencing, or chromatin studies.
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Bioensayo , Olfato , Humanos , Animales , Ratones , Biopsia , Cromatina , Citometría de FlujoRESUMEN
Monitoring physiological waveforms, specifically hemodynamic variables (e.g., blood pressure waveforms) and end-tidal CO2 (EtCO2), during pediatric cardiopulmonary resuscitation (CPR) has been demonstrated to improve survival rates and outcomes when compared to standard depth-guided CPR. However, waveform guidance has largely been based on thresholds for single parameters and therefore does not leverage all the information contained in multimodal data. We hypothesize that the combination of multimodal physiological features improves the prediction of the return of spontaneous circulation (ROSC), the clinical indicator of short-term CPR success. We used machine learning algorithms to evaluate features extracted from eight low-resolution (4 samples per minute) physiological waveforms to predict ROSC. The waveforms were acquired from the 2nd to 10th minute of CPR in pediatric swine models of cardiac arrest (N = 89, 8-12 kg). The waveforms were divided into segments with increasing length (both forward and backward) for feature extraction, and machine learning algorithms were trained for ROSC prediction. For the full CPR period (2nd to 10th minute), the area under the receiver operating characteristics curve (AUC) was 0.93 (95% CI: 0.87-0.99) for the multivariate model, 0.70 (0.55-0.85) for EtCO2 and 0.80 (0.67-0.93) for coronary perfusion pressure. The best prediction performances were achieved when the period from the 6th to the 10th minute was included. Poor predictions were observed for some individual waveforms, e.g., right atrial pressure. In conclusion, multimodal waveform features carry relevant information for ROSC prediction. Using multimodal waveform features in CPR guidance has the potential to improve resuscitation success and reduce mortality.
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Reanimación Cardiopulmonar , Paro Cardíaco , Humanos , Animales , Porcinos , Niño , Retorno de la Circulación Espontánea , Paro Cardíaco/terapia , Hemodinámica , Presión SanguíneaRESUMEN
Background: Surgical procedures involving the aortic arch present unique challenges to maintaining cerebral perfusion, and optimal neuroprotective strategies to prevent neurological injury during such high-risk procedures are not completely understood. The use of antegrade cerebral perfusion (ACP) has gained favor as a neuroprotective strategy over deep hypothermic circulatory arrest (DHCA) due to the ability to selectively perfuse the brain. Despite this theoretical advantage over DHCA, there has not been conclusive evidence that ACP is superior to DHCA. One potential reason for this is the incomplete understanding of ideal ACP flow rates to prevent both ischemia from underflowing and hyperemia and cerebral edema from overflowing. Critically, there are no continuous, noninvasive measurements of cerebral blood flow (CBF) and cerebral oxygenation (StO2) to guide ACP flow rates and help develop standard clinical practices. The purpose of this study is to demonstrate the feasibility of using noninvasive, diffuse optical spectroscopy measurements of CBF and cerebral oxygenation during the conduct of ACP in human neonates undergoing the Norwood procedure. Methods: Four neonates prenatally diagnosed with hypoplastic left heart syndrome (HLHS) or a similar variant underwent the Norwood procedure with continuous intraoperative monitoring of CBF and cerebral oxygen saturation (StO2) using two non-invasive optical techniques, namely diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy (FD-DOS). Changes in CBF and StO2 due to ACP were calculated by comparing these parameters during a stable 5â min period of ACP to the last 5â min of full-body CPB immediately prior to ACP initiation. Flow rates for ACP were left to the discretion of the surgeon and ranged from 30 to 50â ml/kg/min, and all subjects were cooled to 18°C prior to initiation of ACP. Results: During ACP, the continuous optical monitoring demonstrated a median (IQR) percent change in CBF of -43.4% (38.6) and a median (IQR) absolute change in StO2 of -3.6% (12.3) compared to a baseline period during full-body cardiopulmonary bypass (CPB). The four subjects demonstrated varying responses in StO2 due to ACP. ACP flow rates of 30 and 40â ml/kg/min (n = 3) were associated with decreased CBF during ACP compared to full-body CPB. Conversely, one subject with a higher flow6Di rate of 50â ml/kg/min demonstrated increased CBF and StO2 during ACP. Conclusions: This feasibility study demonstrates that novel diffuse optical technologies can be utilized for improved neuromonitoring in neonates undergoing cardiac surgery where ACP is utilized. Future studies are needed to correlate these findings with neurological outcomes to inform best practices during ACP in these high-risk neonates.
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Background: Pediatric neurological injury and disease is a critical public health issue due to increasing rates of survival from primary injuries (e.g., cardiac arrest, traumatic brain injury) and a lack of monitoring technologies and therapeutics for the treatment of secondary neurological injury. Translational, preclinical research facilitates the development of solutions to address this growing issue but is hindered by a lack of available data frameworks and standards for the management, processing, and analysis of multimodal data sets. Methods: Here, we present a generalizable data framework that was implemented for large animal research at the Children's Hospital of Philadelphia to address this technological gap. The presented framework culminates in an interactive dashboard for exploratory analysis and filtered data set download. Results: Compared with existing clinical and preclinical data management solutions, the presented framework accommodates heterogeneous data types (single measure, repeated measures, time series, and imaging), integrates data sets across various experimental models, and facilitates dynamic visualization of integrated data sets. We present a use case of this framework for predictive model development for intra-arrest prediction of cardiopulmonary resuscitation outcome. Conclusions: The described preclinical data framework may serve as a template to aid in data management efforts in other translational research labs that generate heterogeneous data sets and require a dynamic platform that can easily evolve alongside their research.
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In this study, we used diffuse optics to address the need for non-invasive, continuous monitoring of cerebral physiology following traumatic brain injury (TBI). We combined frequency-domain and broadband diffuse optical spectroscopy with diffuse correlation spectroscopy to monitor cerebral oxygen metabolism, cerebral blood volume, and cerebral water content in an established adult swine-model of impact TBI. Cerebral physiology was monitored before and after TBI (up to 14 days post injury). Overall, our results suggest that non-invasive optical monitoring can assess cerebral physiologic impairments post-TBI, including an initial reduction in oxygen metabolism, development of cerebral hemorrhage/hematoma, and brain swelling.
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Background Infants with congenital heart disease (CHD) are at risk for white matter injury (WMI) before neonatal heart surgery. Better knowledge of the causes of preoperative WMI may provide insights into interventions that improve neurodevelopmental outcomes in these patients. Methods and Results A prospective single-center study of preoperative WMI in neonates with CHD recorded data on primary cardiac diagnosis, maternal-fetal environment (MFE), delivery type, subject anthropometrics, and preoperative care. Total maturation score and WMI were assessed, and stepwise logistic regression modeling selected risk factors for WMI. Among subjects with severe CHD (n=183) who received a preoperative brain magnetic resonance imaging, WMI occurred in 40 (21.9%) patients. WMI prevalence (21.4%-22.1%) and mean volumes (119.7-160.4 mm3) were similar across CHD diagnoses. Stepwise logistic regression selected impaired MFE (odds ratio [OR], 2.85 [95% CI, 1.29-6.30]), male sex (OR, 2.27 [95% CI, 1.03-5.36]), and older age at surgery/magnetic resonance imaging (OR, 1.20 per day [95% CI, 1.03-1.41]) as risk factors for preoperative WMI and higher total maturation score values (OR, 0.65 per unit increase [95% CI, 0.43-0.95]) as protective. A quarter (24.6%; n=45) of subjects had ≥1 components of impaired MFE (gestational diabetes [n=12; 6.6%], gestational hypertension [n=11; 6.0%], preeclampsia [n=2; 1.1%], tobacco use [n=9; 4.9%], hypothyroidism [n=6; 3.3%], and other [n=16; 8.7%]). In a subset of 138 subjects, an exploratory analysis of additional MFE-related factors disclosed other potential risk factors for WMI. Conclusions This study is the first to identify impaired MFE as an important risk factor for preoperative WMI. Vulnerability to preoperative WMI was shared across CHD diagnoses.
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Lesiones Encefálicas , Procedimientos Quirúrgicos Cardíacos , Cardiopatías Congénitas , Sustancia Blanca , Recién Nacido , Lactante , Embarazo , Femenino , Humanos , Masculino , Estudios Prospectivos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/patología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/métodos , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/epidemiología , Lesiones Encefálicas/etiología , Imagen por Resonancia Magnética/métodos , Factores de RiesgoRESUMEN
Timely detection and monitoring of acute brain injury in children is essential to mitigate causes of injury and prevent secondary insults. Increasing survival in critically ill children has emphasized the importance of neuroprotective management strategies for long-term quality of life. In emergent and critical care settings, traditional neuroimaging modalities, such as computed tomography and magnetic resonance imaging (MRI), remain frontline diagnostic techniques to detect acute brain injury. Although detection of structural and anatomical abnormalities remains crucial, advanced MRI sequences assessing functional alterations in cerebral physiology provide unique diagnostic utility. Head ultrasound has emerged as a portable neuroimaging modality for point-of-care diagnosis via assessments of anatomical and perfusion abnormalities. Application of electroencephalography and near-infrared spectroscopy provides the opportunity for real-time detection and goal-directed management of neurological abnormalities at the bedside. In this review, we describe recent technological advancements in these neurodiagnostic modalities and elaborate on their current and potential utility in the detection and management of acute brain injury.
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Lesiones Encefálicas , Calidad de Vida , Humanos , Niño , Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/terapia , Neuroimagen/métodos , Imagen por Resonancia Magnética , Electroencefalografía , EncéfaloRESUMEN
Objectives: Recent research suggests that increased cerebral oxygen use during surgical intervention for neonates with congenital heart disease may play a role in the development of postoperative white matter injury. The objective of this study is to determine whether increased cerebral electrical activity correlates with greater decrease of cerebral oxygen saturation during deep hypothermic circulatory arrest. Methods: Neonates with critical congenital heart disease requiring surgical intervention during the first week of life were studied. All subjects had continuous neuromonitoring with electroencephalography and an optical probe (to quantify cerebral oxygen saturation) during cardiac surgical repair that involved the use of cardiopulmonary bypass and deep hypothermic circulatory arrest. A simple linear regression was used to investigate the association between electroencephalography metrics before the deep hypothermic circulatory arrest period and the change in cerebral oxygen saturation during the deep hypothermic circulatory arrest period. Results: Sixteen neonates had both neuromonitoring modalities attached during surgical repair. Cerebral oxygen saturation data from 5 subjects were excluded due to poor data quality, yielding a total sample of 11 neonates. A simple linear regression model found that the presence of electroencephalography activity at the end of cooling is positively associated with the decrease in cerebral oxygen saturation that occurs during deep hypothermic circulatory arrest (P < .05). Conclusions: Electroencephalography characteristics within 5 minutes before the initiation of deep hypothermic circulatory arrest may be useful in predicting the decrease in cerebral oxygen saturation that occurs during deep hypothermic circulatory arrest. Electroencephalography may be an important tool for guiding cooling and the initiation of circulatory arrest to potentially decrease the prevalence of new white matter injury in neonates with critical congenital heart disease.