Early Impairment of Cerebral Bioenergetics After Cardiopulmonary Bypass in Neonatal Swine.

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 3 h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24 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 8 h after CPB. At 24 h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P = .046). The presence of microglial nodules increased throughout the study period (24 h) (P = .01, R2 = 0.9). Conclusion: CPB results in impaired cerebral bioenergetics that persist for at least 24 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.

The association of arterial blood pressure waveform-derived area duty cycle with intra-arrest hemodynamics and cardiac arrest outcomes.

AIM: Develop a novel, physiology-based measurement of duty cycle (Arterial Blood Pressure-Area Duty Cycle [ABP-ADC]) and evaluate the association of ABP-ADC with intra-arrest hemodynamics and patient outcomes. METHODS: This was a secondary retrospective study of prospectively collected data from the ICU-RESUS trial (NCT02837497). Invasive arterial waveform data were used to derive ABP-ADC. The primary exposure was ABP-ADC group (<30%; 30-35%; >35%). The primary outcome was systolic blood pressure (sBP). Secondary outcomes included intra-arrest physiologic goals, CPR quality targets, and patient outcomes. In an exploratory analysis, adjusted splines and receiver operating characteristic (ROC) curves were used to determine an optimal ABP-ADC associated with improved hemodynamics and outcomes using a multivariable model. RESULTS: Of 1129 CPR events, 273 had evaluable arterial waveform data. Mean age is 2.9 years + 4.9 months. Mean ABP-ADC was 32.5% + 5.0%. In univariable analysis, higher ABP-ADC was associated with lower sBP (p < 0.01) and failing to achieve sBP targets (p < 0.01). Other intra-arrest physiologic parameters, quality metrics, and patient outcomes were similar across ABP-ADC groups. Using spline/ROC analysis and clinical judgement, the optimal ABP-ADC cut point was set at 33%. On multivariable analysis, sBP was significantly higher (point estimate 13.18 mmHg, CI95 5.30-21.07, p < 0.01) among patients with ABP-ADC < 33%. Other intra-arrest physiologic and patient outcomes were similar. CONCLUSIONS: In this multicenter cohort, a lower ABP-ADC was associated with higher sBPs during CPR. Although ABP-ADC was not associated with outcomes, further studies are needed to define the interactions between CPR mechanics and intra arrest patient physiology.

Exploring the Therapeutic Potential of Phosphorylated Cis-Tau Antibody in a Pig Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) results in the generation of tau. As hyperphosphorylated tau (p-tau) is one of the major consequences of TBI, targeting p-tau in TBI may lead to the development of new therapy. Twenty-five pigs underwent a controlled cortical impact. One hour after TBI, pigs were administered either vehicle (n = 13) or PNT001 (n = 12), a monoclonal antibody for the cis conformer of tau phosphorylated at threonine 231. Plasma biomarkers of neural injury were assessed for 14 days. Diffusion tensor imaging was performed at day 1 and 14 after injury, and these were compared to historical control animals (n = 4). The fractional anisotropy data showed significant white matter injury for groups at 1 day after injury in the corona radiata. At 14 days, the vehicle-treated pigs, but not the PNT001-treated animals, exhibited significant white matter injury compared to sham pigs in the ipsilateral corona radiata. The PNT001-treated pigs had significantly lower levels of plasma glial fibrillary acidic protein (GFAP) at day 2 and day 4. These findings demonstrate a subtle reduction in the areas of white matter injury and biomarkers of neurological injury after treatment with PNT001 following TBI. These findings support additional studies for PNT001 as well as the potential use of this agent in clinical trials in the near future.

A Template for Translational Bioinformatics: Facilitating Multimodal Data Analyses in Preclinical Models of Neurological Injury.

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.

Non-invasive diffuse optical monitoring of cerebral physiology in an adult swine-model of impact traumatic brain injury.

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.

Imaging of White Matter Injury Correlates with Plasma and Tissue Biomarkers in Pediatric Porcine Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) causes significant white matter injury, which has been characterized by various rodent and human clinical studies. The exact time course of imaging changes in a pediatric brain after TBI and its relation to biomarkers of injury and cellular function, however, is unknown. To study the changes in major white matter structures using a valid model of TBI that is comparable to a human pediatric brain in terms of size and anatomical features, we utilized a four-week-old pediatric porcine model of injury with controlled cortical impact (CCI). Using diffusion tensor imaging differential tractography, we show progressive anisotropy changes at major white matter tracts such as the corona radiata and inferior fronto-occipital fasciculus between day 1 and day 30 after injury. Moreover, correlational tractography shows a large part of bilateral corona radiata having positive correlation with the markers of cellular respiration. In contrast, bilateral corona radiata has a negative correlation with the plasma biomarkers of injury such as neurofilament light or glial fibrillary acidic protein. These are expected correlational findings given that higher integrity of white matter would be expected to correlate with lower injury biomarkers. We then studied the magnetic resonance spectroscopy findings and report decrease in a N-acetylaspartate/creatinine (NAA/Cr) ratio at the pericontusional cortex, subcortical white matter, corona radiata, thalamus, genu, and splenium of corpus callosum at 30 days indicating injury. There was also an increase in choline/creatinine ratio in these regions indicating rapid membrane turnover. Given the need for a pediatric TBI model that is comparable to human pediatric TBI, these data support the use of a pediatric pig model with CCI in future investigations of therapeutic agents. This model will allow future TBI researchers to rapidly translate our pre-clinical study findings into clinical trials for pediatric TBI.