Differential Effects of Targeted Temperature Management on Sex-Dependent Outcomes After Experimental Asphyxial Cardiac Arrest.

Asphyxial cardiac arrest (ACA) survivors face lasting neurological disability from hypoxic ischemic brain injury. Sex differences in long-term outcomes after cardiac arrest (CA) are grossly understudied and underreported. We used rigorous targeted temperature management (TTM) to understand its influence on survival and lasting sex-specific neurological and neuropathological outcomes in a rodent ACA model.

FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia-ischemia.

Background: Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking.

Methods: We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic-ischemic (HI) brain injury (25 min 8% O/92% N) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor β-klotho.

PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury.

Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a variety of conditions. There is a paucity of data on the efficacy of the known experimental PHLPP inhibitors, and not all may be suited for targeting acute brain injury.

Targeting TNFα-mediated cytotoxicity using thalidomide after experimental cardiac arrest in rats: An exploratory study.

Cardiac arrest (CA) results in a central and systemic cytokine and inflammatory response. Thalidomide has been reported to be neuroprotective by selectively decreasing TNFα synthesis. We hypothesized that thalidomide would decrease the systemic and organ-specific TNFα/cytokine response and biomarkers of injury in rats subjected to 10 min CA.

Hypoxia-ischemia-mediated effects on neurodevelopmentally regulated cold-shock proteins in neonatal mice under strict temperature control.

Background: Neonates have high levels of cold-shock proteins (CSPs) in the normothermic brain for a limited period following birth. Hypoxic-ischemic (HI) insults in term infants produce neonatal encephalopathy (NE), and it remains unclear whether HI-induced pathology alters baseline CSP expression in the normothermic brain.

Methods: Here we established a version of the Rice-Vannucci model in PND 10 mice that incorporates rigorous temperature control.

Cardiac Arrest Induced by Asphyxia Versus Ventricular Fibrillation Elicits Comparable Early Changes in Cytokine Levels in the Rat Brain, Heart, and Serum.

Background Current postresuscitative care after cardiac arrest (CA) does not address the cause of CA. We previously reported that asphyxial CA (ACA) and ventricular fibrillation CA (VFCA) elicit unique injury signatures. We hypothesized that the early cytokine profiles of the serum, heart, and brain differ in response to ACA versus VFCA.

Minocycline fails to improve neurologic and histologic outcome after ventricular fibrillation cardiac arrest in rats.

Background: Prolonged cardiac arrest (CA) produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities. Among other potential mechanisms, microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults. Minocycline is neuroprotective in some brain ischemia models, either by blunting the microglial response or by a direct effect on neurons.

Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest.

Introduction: Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA.

Phenotyping Cardiac Arrest: Bench and Bedside Characterization of Brain and Heart Injury Based on Etiology.

Objectives: Cardiac arrest etiology may be an important source of between-patient heterogeneity, but the impact of etiology on organ injury is unknown. We tested the hypothesis that asphyxial cardiac arrest results in greater neurologic injury than cardiac etiology cardiac arrest (ventricular fibrillation cardiac arrest), whereas ventricular fibrillation cardiac arrest results in greater cardiovascular dysfunction after return of spontaneous circulation.

Design: Prospective observational human and randomized animal study.

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches.

Unique brain region-dependent cytokine signatures after prolonged hypothermic cardiac arrest in rats.

We previously showed that prolonged cardiac arrest (CA) produces neuronal death with microglial proliferation. Microglial proliferation, but not neuronal death, was attenuated by deeper hypothermia. Microglia are reportedly a major source of cytokines.

Global and regional differences in cerebral blood flow after asphyxial versus ventricular fibrillation cardiac arrest in rats using ASL-MRI.

Both ventricular fibrillation cardiac arrest (VFCA) and asphyxial cardiac arrest (ACA) are frequent causes of CA. However, only isolated reports compared cerebral blood flow (CBF) reperfusion patterns after different types of CA, and even fewer reports used methods that allow serial and regional assessment of CBF. We hypothesized that the reperfusion patterns of CBF will differ between individual types of experimental CA.

Regional TNFα mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats.

Cardiac arrest (CA) triggers neuroinflammation that could play a role in a delayed neuronal death. In our previously established rat model of ventricular fibrillation (VF) CA characterized by extensive neuronal death, we tested the hypothesis that individual brain regions have specific neuroinflammatory responses, as reflected by regional brain tissue levels of tumor necrosis factor (TNF)α and other cytokines. In a prospective study, rats were randomized to 6min (CA6), 8min (CA8) or 10min (CA10) of VF CA, or sham group.

Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats.

Neuro-cognitive disabilities are a well-recognized complication of hypothermic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and microglial proliferation and activation that are only partially mitigated by hypothermia. Microglia, and possibly other cells, are suggested to elaborate tumor necrosis factor alpha (TNF-α), which can trigger neuronal death cascades and exacerbate edema after CNS insults.

Extracorporeal versus conventional cardiopulmonary resuscitation after ventricular fibrillation cardiac arrest in rats: a feasibility trial.

Objectives: Extracorporeal cardiopulmonary resuscitation with cardiopulmonary bypass potentially provides cerebral reperfusion, cardiovascular support, and temperature control for resuscitation from cardiac arrest. We hypothesized that extracorporeal cardiopulmonary resuscitation is feasible after ventricular fibrillation cardiac arrest in rats and improves outcome versus conventional cardiopulmonary resuscitation.

Design: Prospective randomized study.

Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats.

Trauma patients who suffer cardiac arrest (CA) from exsanguination rarely survive. Emergency preservation and resuscitation using hypothermia was developed to buy time for resuscitative surgery and delayed resuscitation with cardiopulmonary bypass (CPB), but intact survival is limited by neuronal death associated with microglial proliferation and activation. Pharmacological modulation of microglia may improve outcome following CA.

Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs.

Several laboratory studies suggested that induced hypothermia during hemorrhagic shock improves survival. Inhaled hydrogen sulfide (H2S) induced hypothermia and decreased metabolism in mice and rats but not in piglets. We tested the hypothesis that i.

Deep hypothermia attenuates microglial proliferation independent of neuronal death after prolonged cardiac arrest in rats.

Introduction: Conventional resuscitation of exsanguination cardiac arrest (CA) victims is generally unsuccessful. Emergency preservation and resuscitation is a novel approach that uses an aortic flush to induce deep hypothermia during CA, followed by delayed resuscitation with cardiopulmonary bypass. Minocycline has been shown to be neuroprotective across a number of brain injury models via attenuating microglial activation.

Blood-brain barrier integrity in a rat model of emergency preservation and resuscitation.

Unlabelled: Emergency Preservation and Resuscitation (EPR) represents a novel approach to treat exsanguination cardiac arrest (CA) victims, using an aortic flush to induce hypothermia during circulatory arrest, followed by delayed resuscitation with cardiopulmonary bypass (CPB). The status of the blood-brain barrier (BBB) integrity after prolonged hypothermic CA is unclear. The objective of this study was to assess BBB permeability in two EPR models in rats, associated with poor outcome.

Protein nitration and poly-ADP-ribosylation in brain after rapid exsanguination cardiac arrest in a rat model of emergency preservation and resuscitation.

Background: Emergency preservation and resuscitation (EPR) of 60 min in rats is achievable with favorable outcome, while 75 min is associated with substantial mortality and impaired neurological outcome in survivors. We hypothesized that 75 min but not 60 min of EPR would be associated with activation of two potential secondary injury cascades in brain as reflected by protein nitration and poly (ADP-ribose) polymerase (PARP) activation.

Methods: Rats were rapidly exsanguinated over 5 min.

Assessment of the delta opioid agonist DADLE in a rat model of lethal hemorrhage treated by emergency preservation and resuscitation.

Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims. EPR uses a cold aortic flush to induce deep hypothermic preservation during no-flow to buy time for transport and damage control surgery, followed by resuscitation with cardiopulmonary bypass (CPB). We reported previously that 20-60 min EPR in rats was associated with intact outcome, while 75 min EPR resulted in high mortality and neurological impairment in survivors.

Prolonged deep hypothermic circulatory arrest in rats can be achieved without cognitive deficits.

Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) enable surgical repair of cardiovascular defects. However, neurological complications can result after both CPB and DHCA. We sought to investigate if 75 min of CPB or DHCA caused motor, cognitive or histological deficits in rats.

Emergency preservation and resuscitation with profound hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest from rapid exsanguination in dogs.

We have used a rapid induction of profound hypothermia (<10 degrees C) with delayed resuscitation using cardiopulmonary bypass (CPB) as a novel approach for resuscitation from exsanguination cardiac arrest (ExCA). We have defined this approach as emergency preservation and resuscitation (EPR). We observed that 2 h but not 3 h of preservation could be achieved with favorable outcome using ice-cold normal saline flush to induce profound hypothermia.

Exsanguination cardiac arrest in rats treated by 60 min, but not 75 min, emergency preservation and delayed resuscitation is associated with intact outcome.

Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims to buy time for surgical hemostasis. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass (CPB). We previously reported that 20 min of EPR was feasible with intact outcome.

Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: a feasibility trial.

Objective: Emergency preservation and resuscitation (EPR) comprise a novel approach for resuscitation of exsanguination cardiac arrest victims. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass. Development of a rat EPR model would enable study of the molecular mechanisms of neuronal injury and the screening of novel agents for emergency preservation.