RESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
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.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Humanos , Preescolar , Presión Arterial , Estudios Retrospectivos , Paro Cardíaco/terapia , Hemodinámica/fisiología , Presión Sanguínea/fisiologíaRESUMEN
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.
RESUMEN
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.
RESUMEN
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.