Search

Introduction: Derangement of the cerebrovascular unit (CVU) following ischemia-reperfusion from cardiac arrest contributes to overall brain injury. MRI can detect perfusion changes, but imaging timing and severity of injury vary in the clinical population. Hypothesis: We hypothesized that a large-animal model with fixed periods of global ischemia followed by standardized reperfusion and time to image acquisition would demonstrate a reliable gradient of perfusion changes. Such a model would allow neuroprotective strategies to be tested using early imaging biomarkers to quantify effects on cerebral perfusion. Methods: 10 healthy swine were placed under isoflurane anesthesia and underwent control MRI with dynamic susceptibility contrast (DSC) perfusion. Following imaging, animals were randomized to sham, 10, 15, 20, and 30-minute arrest groups, after which extracorporeal membrane oxygenation (ECMO) catheters were placed in the distal aorta and right atrium. Ventricular fibrillation was then induced by a bipolar pacing catheter for the fixed period of ischemia, after which animals were reperfused at 2.8-3.5 L/min with unblended oxygenated blood. After 4 minutes they were defibrillated. Over the next 2 hours they were weaned from pump and decannulated with epinephrine and fluid boluses given for hemodynamic support. Animals were then re-imaged within 2 hours post-resuscitation using the same pre-arrest protocol. DSC post-processing was performed and regions of interest were drawn in the bilateral frontal lobes to quantify perfusion parameters. Results: Baseline hemodynamic parameters, including BP, Heart Rate, ETCO2, and SpO2 were similar between animals. When comparing pre- to post-arrest MRI, there was a linear correlation of increasing Cerebral Blood Volume (CBV) with ischemic duration (r=0.69, p=0.028), and downward trend of Cerebral Blood Flow (CBF) with duration (r=-0.48, p=0.164). Conclusion: MRI DSC perfusion abnormalities were observed early in the post arrest period following fixed periods of ischemia with CBV correlated with ischemia duration consistent with dysfunctional vasodilation and uncoupling of the CVU. CBF showed a downward trend with injury severity. The effect of vasopressors and fluids on these findings is unclear.

Introduction: Reperfusion/ischemic brain injury following arrest is a major cause of death/disability among patients surviving to admission. Aside from targeted temperature management, no proven neuroprotective strategies exist. Melatonin (anti-epileptic/antioxidant) and ketamine (glutamate inhibitor), along with controlled reintroduction of oxygenated blood have been proposed to reduce secondary injury. Hypothesis: We hypothesized that a combination of above therapies would reduce the ischemic burden measured on MRI following cardiac arrest if administered upon initial reperfusion. Methods: 6 swine underwent isoflurane anesthesia and control MRI (DTI b2000/20 directions, DSC). Swine were randomized to fixed periods of cardiac arrest (2 swine to 20 min and 1 to 30 min in both control and treated groups), and ECMO catheters placed in the distal aorta and right atrium, then ventricular fibrillation induced by a bipolar pacing catheter. Following ischemia, swine were reperfused at 2.8-3.5 L/min with either unblended oxygenated blood in the control group, or 21% oxygenated blood increased to 30% after 4 minutes and then titrated to maintain PaO2 of 80-100 mm Hg, melatonin 5 mg/kg bolus then 5 mg/kg/hr and ketamine 4 mg/kg/hr for 2 hours in the treated group. After 4 min swine were defibrillated until return of heartbeat. Animals were weaned from pump, decannulated, and epinephrine and fluid boluses administered for hemodynamic support, then re-imaged within 2 hours post-resuscitation using same protocol. Whole brain ADC measurements were performed on gray and white matter. Frontal lobe regions of interest drawn for DSC perfusion parameters. Results: Baseline hemodynamic parameters: BP, Heart Rate, End-Tidal CO2, and SpO2 were similar between animals. There was no difference in percent change ADC in gray or white matter between treated and untreated swine (p=0.9), or difference in CBV (p=0.67). CBF showed an upward trend in treated animals (p=0.17). Conclusions: A multimodal neuroprotective strategy of melatonin, ketamine, and controlled reoxygenation failed to demonstrate measurable impact on MRI markers of ischemia-reperfusion injury in this pilot study. The translation of promising neuroprotectants might be triaged using the employed model.

Introduction: Hypoxic ischemic brain injury (HIBI) results from loss of oxygen or perfusion during cardiac arrest and is the most common cause of death/disability in patients surviving to admission. Diagnostic tests are crucial to identify irreversible injury thresholds for neuroprognostication. MRI DTI can detect cellular injury in response to HIBI, but imaging timing and severity of hypoxia vary widely. Hypothesis: We hypothesized that a model with fixed periods of ischemia followed by both standardized reperfusion and time to image acquisition would demonstrate a reliable gradient of injury. Such a model would allow neuroprotective strategies to be tested using early imaging biomarkers to quantify effects on cytoarchitecture. Methods: Eleven healthy swine (49 + 5 kg) under isoflurane anesthesia underwent control MRI with DTI at b2000/20 directions. Two animals each were then randomized to sham, 10, 15, 20, and one to 30-minutes of arrest. For reperfusion, extracorporeal membrane oxygenation (ECMO) catheters were placed in the distal aorta and right atrium, after which ventricular fibrillation was induced by a bipolar pacing catheter. Following the fixed period of ischemia, animals were reperfused at 2.8-3.5 L/min with unblended oxygenated blood. After 4 minutes they were defibrillated. Over two hours they were weaned from pump and decannulated with epinephrine and fluid boluses for hemodynamic support. Animals were re-imaged within two hours post-resuscitation using the same pre-arrest protocol. Whole brain ADC measurements were performed in the gray and white matter. Results: Baseline hemodynamic parameters: BP, Heart Rate, End-Tidal CO2, and SpO2 were similar between animals. When comparing pre- to post-arrest MRI, there was a strong linear correlation between percent gray matter ADC change (r=-0.87, p Conclusion: MRI DTI changes observed following fixed periods of ischemia with ADC in gray and white matter correlated well with ischemia duration in the first few hours post arrest. These findings support the feasibility of MRI for measuring severity of insult in HIBI and an animal model that might serve as translational endpoint for neuroprotectant strategies.