Background Cardiac arrest (CA) patients who survived by cardiopulmonary resuscitation (CPR) can present different levels of neurological deficits ranging from minor cognitive impairments to persistent vegetative state and brain death. The pathophysiology of the resulting brain injury is poorly understood and whether changes in post-CA brain metabolism contribute to the injury are unknown. Here we utilized [ 18 F]FDG-PET to study in vivo cerebral glucose metabolism 72 hours following CA in a murine cardiac arrest model. Methods Anesthetized and ventilated adult C57BL/6 mice underwent 12-minute KCl-induced CA followed by CPR. Seventy-two hours following cardiac arrest, surviving mice were intraperitoneally injected with [ 18 F]FDG (~186 µCi/200 µL) and imaged on Molecubes preclinical micro PET/CT imaging systems after a 30-minute awake uptake period. Brain [ 18 F]FDG uptake was determined by the VivoQuant software on fused PET/CT images with the 3D brain atlas. Upon completion of PET imaging, remaining [ 18 F]FDG radioactivity in the brain, heart, and liver was determined using a gamma counter.Results Global increases in brain [ 18 F]FDG uptake in post-CA mice were observed compared to shams and controls. The median standardized uptake value (SUV) of [ 18 F]FDG for CA animals was 1.79 vs. sham 1.25 (p<0.05) and control animals 0.78 (p<0.01). This increased uptake was consistent throughout the 60-minute imaging period and across all brain regions reaching statistical significance in the midbrain, pons, and medulla. Biodistribution analyses of various key organs yielded similar observations that the median [ 18 F]FDG uptake for brain were 7.04%ID/g tissue for CA mice vs 5.537%ID/g tissue for sham animals, p<0.05).Conclusions This study has successfully applied [ 18 F]FDG-PET/CT to measure changes in brain metabolism in a murine model of asystolic CA. Our results demonstrate increased [ 18 F]FDG uptake in the brain 72 hours following CA, suggesting increased metabolic demand in the case of severe neurological injury. Further study is warranted to determine the etiology of these changes.

Background Neurological injury following successful resuscitation from sudden cardiac arrest (CA) is common. The pathophysiological basis of this injury remains poorly understood, and treatment options are limited. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized. Here, we hypothesize that microglial activation that occurs following brief asystolic CA is associated with neurological injury and represents a potential therapeutic target. Methods Adult C57BL/6 male and female mice were randomly assigned to 12-min, KCl-induced asystolic CA, under anesthesia and ventilation, followed by successful cardiopulmonary resuscitation (n = 19) or sham intervention (n = 11). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. Mice were killed at 72 h for histological studies; neuronal degeneration was assessed using Fluoro-Jade C staining. Microglial characteristics were assessed by immunohistochemistry using the marker of ionized calcium binding adaptor molecule 1, followed by ImageJ analyses for cell integrity density and skeletal analyses. Results Neurological injury in post-cardiopulmonary-resuscitation mice vs. sham mice was evident by poorer neurological scores (difference of 3.626 ± 0.4921, 95% confidence interval 2.618–4.634), sensory and motor functions (worsened by sixfold and sevenfold, respectively, compared with baseline), and locomotion (75% slower with a 76% decrease in total distance traveled). Post-CA brains demonstrated evidence of neurodegeneration and neuroinflammatory microglial activation. Conclusions Extensive microglial activation and neurodegeneration in the CA1 region and the dentate gyrus of the hippocampus are evident following brief asystolic CA and are associated with severe neurological injury.

AbstractBackgroundCardiac arrest (CA) patients who survived by cardiopulmonary resuscitation (CPR) can present different levels of neurological deficits ranging from minor cognitive impairments to persistent vegetative state and brain death. The pathophysiology of the resulting brain injury is poorly understood and whether changes in post-CA brain metabolism contribute to the injury are unknown. Here we utilized [18F]FDG-PET to study in vivo cerebral glucose metabolism 72 hours following CA in a murine cardiac arrest model.MethodsAnesthetized and ventilated adult C57BL/6 mice underwent 12-minute KCl-induced CA followed by CPR. Seventy-two hours following cardiac arrest, surviving mice were intraperitoneally injected with [18F]FDG (~186 μCi/200 μL) and imaged on Molecubes preclinical micro PET/CT imaging systems after a 30-minute awake uptake period. Brain [18F]FDG uptake was determined by the VivoQuant software on fused PET/CT images with the 3D brain atlas. Upon completion of PET imaging, remaining [18F]FDG radioactivity in the brain, heart, and liver was determined using a gamma counter.ResultsGlobal increases in brain [18F]FDG uptake in post-CA mice were observed compared to shams and controls. The median standardized uptake value (SUV) of [18F]FDG for CA animals was 1.79 vs. sham 1.25 (p<0.05) and control animals 0.78 (p<0.01). This increased uptake was consistent throughout the 60-minute imaging period and across all brain regions reaching statistical significance in the midbrain, pons, and medulla. Biodistribution analyses of various key organs yielded similar observations that the median [18F]FDG uptake for brain were 7.04%ID/g tissue for CA mice vs 5.537%ID/g tissue for sham animals, p<0.05).ConclusionsThis study has successfully applied [18F]FDG-PET/CT to measure changes in brain metabolism in a murine model of asystolic CA. Our results demonstrate increased [18F]FDG uptake in the brain 72 hours following CA, suggesting increased metabolic demand in the case of severe neurological injury. Further study is warranted to determine the etiology of these changes.

Background Neurological injury is often evident following resuscitation from cardiac arrest and yet, the pathophysiology of this injury is not well understood. Moreover, treatment options are limited to targeted temperature management (TTM) and conservative care. We hypothesize that neuroinflammation and blood brain barrier (BBB) injury are associated with neurological injury following cardiac arrest and represent potential targets for therapeutic intervention. Methods We randomized adult C57BL/6 male/female mice to either a 12‐minute KCl‐induced asystolic CA ‐ under anesthesia and ventilation ‐ followed by CPR (N=12) or sham intervention (N=9). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. BBB permeability was assessed by injection of fluorescein isothiocyanate (FITC) dextran beads. Changes to immune cell number in the brain was assessed by immunohistochemistry using the microglia marker (Iba1+). Results Neurological injury following cardiac arrest was evident by neurological scores (difference of 3.419 ± 0.5576, 95% CI 2.25–4.586), sensory scores (difference of −61.39 ± 16.65 seconds, 95% CI −97.10 to −25.67), motor scores (difference of −107.3 ± 6.503 seconds, 95% CI −121.2 to −93.35) and video analysis of distance (difference of 8.914 meters ± 1.411, 95% CI 4.425 −13.40) and speed (difference of 0.07428 m/s ±0.01175, 95% CI 0.03687 to 0.1117). Post‐CA brains demonstrated increased bead fluorescence compared to controls indicative of increased blood brain barrier injury. Moreover, Iba1+ cell number was approximately 2.47 times greater and integrity density was approximately 4.66 times greater post‐CA suggesting neuroinflammation following CA. Conclusions Global neurological injury is evident following asystolic cardiac arrest in mice but is particularly prominent in regard to motor movements. This injury is associated with BBB injury and nueroinflammation. Ongoing studies are determining the mechanisms and possible therapeutic targets of this injury. Support or Funding Information The project described was supported by Grant Number T32HL007381 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Background Cardiopulmonary resuscitation (CPR) following sudden cardiac death is associated with neurological injury but the pathophysiology of this injury remains poorly understood. In this study we investigated the effects of post‐cardiac arrest CPR on neurological outcomes and hypothesized that injury would be associated with neuroinflammation and central nervous system mitochondrial injury. Method C57BL/6 adult mice underwent either asystolic cardiac arrest (CA) (N=19) followed by CPR or sham operation (SHAM) (N=12). Neurobehavioral assessment and survival analysis were made in animals following CPR. Brain tissue was harvested from both SHAM and CA mice for brain slice electrophysiological studies, microglial morphometric analysis, and mitochondrial respiration measurements. Results Post‐CA neurological injury was evident as evaluated by neurological scores (difference of 3.626 ± 0.4921, 95%CI 2.618‐4.634), sensory scores (difference of ‐65.79 ± 14.7 seconds, 95%CI ‐96.21 to ‐35.37), motor scores (difference of ‐107.2 ± 6.558 seconds, 95%CI ‐120.7 to ‐93.61) and video analysis of distance (mean difference of 8.361 meters ± 0.5061, 95%CI 10.52 to 6.203) and speed (difference of 0.0689 m/s ± 0.004242, 95%CI 0.08715 to 0.05065). 24 hours post‐CA, synaptic long‐term potentiation (LTP) and maximal mitochondrial oxygen consumption (OCR) (mean difference ‐107.4 ± 37.79 pmol/min, p=0.0467, N=3/group) were depressed. These outcomes were also associated with morphometric changes in microglia. Microglia demonstrated shorter process lengths per soma (mean difference of 139.5 ± 29.62, p=0.0013, N=4/group) as well as less process endpoints per soma (mean difference of 42.21 ± 9.123, p=0.0018, N=4/group) compared to control microglia, suggesting post‐CA microglial activation. Conclusion These results indicate that neurological injury following post‐CA CPR is associated with impaired synaptic plasticity, depressed mitochondrial respiration, and neuroinflammation. Future studies evaluating the basis and interactions of these post‐CA phenomena are warranted.