Browsing by Subject "cardiac arrest"
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Item Correlation of End-Tidal Carbon Dioxide to Neurological Outcome in Out-of-Hospital Cardiac Arrest(2014-12-01) Phillips, Sabrina D.; Kirchhoff, Claire; Gwirtz, Patricia A.; Mukerjee, AninditaBackground: Previous studies have established that end tidal carbon dioxide (ETCO2) can positively predict a return of spontaneous circulation (ROSC) and survivability in out-of-hospital cardiac arrest (OHCA). Objective: To assess if ETCO2 predicts neurological outcome as measured by cerebral performance category (CPC) score in an independent cohort of patients suffering OHCA. Methods: This was a retrospective chart review conducted at MedStar Mobile Healthcare of patients who suffered non-traumatic OHCA between January 2014 and July 2014. ETCO2 values were continuously recorded while standard advanced cardiac life support (ACLS) protocols were followed. Results: OHCA was confirmed in 689 patients. ACLS was initiated in 421 patients. Of those, 214 patients were transported to the hospital. There was a good neurologic outcome (CPC 1or 2) in 22 patients and a poor neurologic outcome (CPC of 3, 4, or 5) in 183 patients. Initial ETCO2 (p=0.027, OR 1.002, 95% CI 1.000-1.003) and ETCO2 after ROSC (p=0.007, OR 0.997, 95% CI 0.995-0.999) were correlated to neurological outcome when using binary logistic regression. Conclusion: Initial ETCO2 and ETCO2 after ROSC are predictors of neurological outcome in OHCA. After further research this data can be incorporated into criteria on whether to perform cardiopulmonary resuscitation on patients suffering OHCA.Item DELAYED NEURONAL DEATH IN SWINE FOLLOWING CARDIAC ARREST AND RESUSCITATION(2014-03) Nguyen, Anh Q.; Cherry, Brandon H.; Myoung-Gwi, Ryou; Williams, Arthur G.; Hollrah, Roger; Baker, Charla L.; Choudhury, Gourav; Olivencia-Yurvati, Albert H.; Mallet, Robert T.Purpose (a): Cardiac arrest, a leading cause of death in the U.S., kills >90% of its victims, and survivors often are disabled by permanent brain injury inflicted by ischemia-reperfusion. Purkinje cells of the cerebellum and CA1 neurons of the hippocampus are especially vulnerable to post-ischemic neuronal death. We tested the hypothesis that cardiac arrest in a swine model caused delayed neuronal death. Methods (b): Yorkshire swine (25-35 kg) were subjected to cardiac arrest-resuscitation (n = 9) or non-arrest sham (n = 5) protocols. Ventricular fibrillation was induced by electrical pacing. Precordial compressions (100/min) were given at 6-10 min arrest, and then sinus rhythm was restored with transthoracic countershocks. NaCl was infused iv at 0.1 mmol/kg/min during CPR and the first 60 min after return of spontaneous circulation (ROSC). At 7 d ROSC, brain regions were fixed in 4% paraformaldehyde and H&E stained. Results (c): More than 70% of the Purkinje cells were shrunken, lacked dendrites and displayed condensed cytoplasm at 7 d ROSC; in contrast, in shams the majority of Purkinje cells retained the characteristic thick dendrites and well-defined nuclei. Conclusions (d): Thus, cardiac arrest-resuscitation produced marked changes in cerebellar neurons evident 7d after acute insult.Item Intravenous Pyruvate to Prevent Renal Injury Following Cardiac Arrest and Resuscitation(2014-08-01) Hollrah, Roger A.; Robert T. Mallet; Myoung-Gwi Ryou; Rong MaIntroduction: Cardiac arrest followed by resuscitation and recovery of spontaneous circulation (ROSC) produces systemic ischemia reperfusion (I/R), affecting all internal organs, including the kidney. This type of stress generates both a robust increase in reactive oxygen and nitrogen species (RONS) and an intense inflammatory response, which can result in renal cell death. The glycoprotein erythropoietin (EPO) has been shown to combat renal I/R injury by offering cyto-protection against inflammation and oxidative damage, as well as inhibiting apoptosis. The endogenous intermediary metabolite pyruvate has been observed to stabilize specific genetic machinery responsible for the production of EPO. This study was conducted to test the efficacy of intravenous pyruvate in exploiting these endogenous mechanisms of EPO to protect the kidney from cardiac arrest-induced, I/R injury. Hypothesis: Pyruvate administration during cardiopulmonary resuscitation (CPR), defibrillation, and ROSC will protect the kidneys from I/R injury by suppressing oxidative stress and inflammation via increased EPO production at the renal corticomedullary border. Methods: Yorkshire swine underwent 10 minutes of cardiac arrest, CPR effected by precordial compressions, and defibrillation, and were recovered for either 4 hours (acute) or 3 days (chronic). The animals were randomly assigned to 1 of 4 groups. Two groups underwent the cardiac arrest protocol described above: one group received intravenous infusion of 2M sodium pyruvate at a rate of 0.1 mmol∙kg-1∙min-1 during CPR and the first 60 minutes of recovery; the other group received an equimolar infusion of NaCl. The other two groups were surgically prepared and infused with NaCl or sodium pyruvate, but were not subjected to cardiac arrest, CPR, or defibrillation. For the acute protocol (n=28), animals were sacrificed 4hr after cardiac arrest, while in the chronic protocol (n=18), animals recovered for 3d before sacrifice. To evaluate the impact of cardiac arrest and pyruvate treatment on renal metabolism and antioxidant defense, proteins were extracted from snap-frozen renal corticomedullary border tissue for spectrophotometric activity assays of a panel of 10 metabolic and antioxidant enzymes; myeloperoxidase (MPO), an enzyme marker of pro-inflammatory leukocytes, was analyzed to assess inflammation. Plasma was sampled before cardiac arrest and at the time of biopsy to measure creatinine concentration, an indirect measure of glomerular filtration rate (GFR). Enzyme-linked immunosorbent assay (ELISA) kits were used to measure EPO content and Kidney Injury Molecule-1 (KIM-1) content, a receptor expressed on renal tubular cells that plays an important role in apoptosis. Tissue sections were stained with hematoxylin and eosin (H&E) and examined under light microscopy to count neutrophils and monocytes and to compare structure integrity across the different treatment groups and protocols. Results: In this study global I/R stress imposed on the kidneys by reversible cardiac arrest did not appreciably alter the activity of the 10 panel enzymes. Despite having no histological evidence of neutrophil infiltration (H&E stained slides), an increase in renal MPO activity was evident at 4 h recovery in the NaCl group which was prevented by pyruvate treatment (P [less than] 0.05). There was no evidence of ultrastructural damage to renal cortical and outer medullary structures. There was a noticeable increase in renal EPO content at 4 h ROSC vs. the sham group. An apparent, albeit not statistically significant, increase in KIM-1 content was observed in the two CPR groups vs. the NaCl-infused sham group. Plasma creatinine concentrations did not change appreciably between pre-arrest baseline and 3 d recovery. Interpretation and Conclusion: The I/R stress produced by the present cardiac arrest-resuscitation failed to alter appreciably the activities of the 10 panel enzymes, suggesting the oxidative stress was not sufficient to overwhelm the kidney’s endogenous antioxidant defenses. Plasma creatinine concentrations were also stable, implying the GFR was maintained and the glomerular ultrastructures were unaffected by I/R. The increase in MPO activity at 4 h ROSC implied a transient infiltration of inflammatory leukocytes, although none were visible on histological examination. The increase in KIM-1 content, though not statistically significant, suggests modest renal apoptotic activity after cardiac arrest and reperfusion. The transient increase in renal EPO content in the NaCl-infused post-arrest vs. sham pigs supports the possibility that even a brief period of renal ischemia by cardiac arrest can evoke renal EPO production. Collectively, these results indicate the renal I/R imposed by cardiac arrest and resuscitation does not inflict appreciable damage on the kidneys or its enzyme systems, at least within the first 3 d of post-arrest recovery. Abbreviations: AKI: acute kidney injury; ARF: acute renal failure; CK: creatine kinase; CPR: cardiopulmonary resuscitation; CS: citrate synthase; EPO: erythropoietin; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; G6PDH: glucose 6-phosphate dehydrogenase; GFR: glomerular filtration rate; GP: glutathione peroxidase; GR: glutathione reductase; HIF-1: hypoxia-inducible factor 1; I/R: ischemia-reperfusion; KIM-1: kidney injury molecule 1; LDH: lactate dehydrogenase; MPO: myeloperoxidase; PFK: phosphofructokinase; PHD: prolyl hydroxylase; RONS: reactive oxygen and nitrogen species; ROSC: recovery of spontaneous circulation.Item Intravenous pyruvate to protect heart and brain during closed-chest resuscitation and recovery from cardiac arrest(2014-08-01) Cherry, Brandon H.; Mallet, Robert T.; Olivencia-Yurvati, Albert H.; Raven, Peter B.Cardiac arrest is a leading cause of death in the United States and Western Europe. Cardiopulmonary resuscitation (CPR) is the only means of sustaining the victim until application of defibrillatory countershocks. Although it has been over 50 years since its advent, CPR remains a work in progress. Many initially resuscitated victims later die from the damage sustained from ischemia-reperfusion, and treatments to combat the extensive ischemia-reperfusion injury sustained during cardiac arrest-resuscitation remain elusive. The major mechanism of injury underlying ischemia-reperfusion is the intense overproduction of reactive oxygen and nitrogen species (RONS) that accumulate during reperfusion and compromise normal cell function. RONS formed during resuscitation trigger lipid peroxidation, disable enzymes vital for cell metabolism and survival and, ultimately, induce cell death within affected organs. In order to prevent extensive damage to the central nervous system culminating in permanent neurocognitive disability and death, prospective treatments must possess robust antioxidant properties, traverse the blood-brain barrier between the cerebral circulation and brain parenchyma, and be non-toxic at effective doses. Pyruvate is a natural intermediary metabolite, energy-yielding substrate and antioxidant. Pyruvate neutralizes RONS, thereby dampening oxidative stress and preventing covalent oxidative modification of enzymes and lipid membranes, and generates ATP to support brain function. Pyruvate readily traverses the blood-brain barrier and is non-toxic over a wide range of doses, including those previously demonstrated to protect the heart during cardiopulmonary bypass and the brain during stroke, thereby supporting oxygen and fuel delivery to the recovering brain. Moreover, pyruvate has been shown to promote cardiac electromechanical and metabolic recovery following cardiac arrest and open-chest CPR. This study tested whether infusion of pyruvate during, CPR and early recovery can decrease the biomarkers of oxidative stress after cardiac arrest. Isoflurane-anesthetized pigs were subjected to 6 min electrically-induced, untreated ventricular fibrillation, followed by 4 min closed-chest CPR, defibrillation and either 1 or 4 h recovery. Beginning at 5.5 min arrest, either sodium pyruvate or NaCl control were infused iv for the duration of CPR and for the first 60 min after recovery of spontaneous circulation (ROSC). Arterial blood was sampled pre-arrest and at 5, 15, 30, 60, 120, 180, and 240 min ROSC for analyses of blood gases and plasma constituents. At either 1 h (i.e. end of treatment infusion) or 4 h ROSC, a craniotomy was performed, the pig was euthanized, the brain was removed, and biopsies from hippocampus and cerebellum were snap-frozen in liquid nitrogen for biochemical analysis. The first phase of this project tested the hypothesis that intravenous administration of sodium pyruvate during precordial compressions and the first 60 min ROSC restores hemodynamic, metabolic, and electrolyte homeostasis in a closed chest porcine model of cardiac arrest. Resuscitation with pyruvate sharply decreased the incidence of lethal pulseless electrical activity (PEA) following defibrillatory countershocks, and lowered the dosage of vasoconstrictor phenylephrine required to maintain systemic arterial pressure. Pyruvate also enhanced glucose clearance, elevated arterial bicarbonate, and raised arterial pH. The second phase of this project tested the hypothesis that pyruvate prevents the decrease in activity of the brain’s antioxidant enzymes following cardiac arrest and hyperoxic (100% O2). Activities of glutathione peroxidase and glutathione reductase were decreased at 60 min ROSC vs. sham in both the hippocampus and cerebellum. Pyruvate partially preserved glutathione peroxidase activity at 1 h ROSC, but by 4 h, after 3 h of pyruvate clearance from the circulation, the enzyme’s activity fell to the same extent as in NaCl-infused pigs. Interestingly, the glutathione peroxidase/reductase activity fell sharply in non-arrested sham pigs between the time points corresponding to 1 and 4 h ROSC, suggesting that hyperoxia resulting from ventilation with 100% produced sufficient oxidative stress to inactivate the enzymes. Similarly, lactate dehydrogenase activity fell between 1 and 4 h ROSC in hippocampus and especially cerebellum. In sham pigs, lactate dehydrogenase activity decreased from the time points corresponding to 1 and 4 h ROSC, and pyruvate had no effect on lactate dehydrogenase in either region of the brain. Thus, cardiac arrest and hyperoxic ventilation disabled a critical antioxidant system in two ischemia-sensitive brain regions. Pyruvate afforded partial protection of these enzymes which waned after pyruvate cleared from the circulation. We conclude that 1) Pyruvate infusion during cardiac arrest, CPR and early recovery promotes conversion from ventricular fibrillation to a productive sinus rhythm instead of lethal PEA; 2) Pyruvate hastened glucose clearance, a prognostic measure used clinically; 3) Pyruvate elevated the arterial bicarbonate concentration and raised arterial pH, which combats the acidemia normally observed following ROSC; 4) Cardiac arrest-resuscitation and hyperoxic ventilation disabled the glutathione peroxidase-reductase system, a critical component of the brain’s antioxidant defenses, in hippocampus and cerebellum; and 5) Pyruvate delayed oxidative inactivation of glutathione peroxidase in the cerebellum, but this effect subsided as pyruvate elevated. These investigations demonstrate the therapeutic effects and limitations of pyruvate as a resuscitative treatment to hasten electrocardiographic and metabolic recovery post cardiac arrest.Item Pyruvate Intervention for Brain Injury Inflicted by Cardiac Arrest-Resuscitation(2016-05) Nguyen, Anh Q.; Mallet, Robert T.; Olivencia-Yurvati, Albert H.; Raven, Peter B.; Yang, Shaohua; Rickards, Caroline A.Fewer than 10% of the 360,000 people who suffer out-of-hospital cardiac arrest annually in the U.S. survive to hospital discharge. Many suffer brain injuries that greatly affect their daily activities and quality of life. Despite improvements in clinical outcomes from cardiac arrest as a result of therapeutic hypothermia, survival rates are still dismal. Additional interventions to be used alone or in combination with therapeutic hypothermia could potentially save many lives. The intermediate metabolite pyruvate has been proven to be neuroprotective when given acutely. The goal of this investigation is to examine the neuroprotective capabilities and mechanisms of pyruvate in a large animal model of cardiac arrest, closed-chest cardiopulmonary resuscitation (CPR) and countershock induced defibrillation. The central hypothesis is that pyruvate therapy suppresses matrix metalloproteinase (MMP) activity and thereby preserves blood-brain barrier (BBB) integrity, increases expression and content of the cytoprotective cytokine erythropoietin (EPO), and dampens inflammation following cardiac arrest, and, thus, improves neurobehavioral recovery from cardiac arrest. Experiments were conducted in Yorkshire swine, subjected to cardiac arrest, closed-chest cardiocerebral resuscitation (CCR), defibrillation by trans-thoracic countershock, and recovery. The project was divided into two studies with different durations of cardiac arrest, producing different intensities of brain damage. In the first study, swine were subjected to 6 min of untreated cardiac arrest and 4 min of CCR, following by defibrillation and recovery of spontaneous circulation (ROSC). In the second study, untreated cardiac arrest was extended to 10 min before 4 min CCR. Animals were euthanized at 1, 4, and 72 h ROSC, and the brain was biopsied for histological and biochemical analyses. For animals in 72 h ROSC groups, neurological assessment and testing were performed at 24, 48, and 72 h ROSC. At 3 d ROSC, the number of viable cerebellar Purkinje cells fell by 30% vs. Sham control, but pyruvate infusion during CCR and the first 60 min ROSC preserved these neurons. EPO mRNA abundance was sharply increased at 4 h ROSC and in the non-arrest Sham, indicating the surgical protocol, hyperoxic ventilation and anesthesia induced neuroprotective EPO, which may have limited brain injury. There were no differences in neurological scores among Sham, CPR, and CPR+Pyruvate, prompting study of more prolonged cardiac arrest to intensify brain injury. At 4 h ROSC in 10 min untreated cardiac arrest group, cardiac arrest unexpectedly decreased hippocampal and cerebellar MMP-2 activities and cerebellar EPO content, regardless of treatment. 72 h survival rate fell from 100% in study one (6 min pretreatment arrest) to only 2 of 6 pigs in study two (10 min pretreatment arrest), which wide disparity in neurological function among the 2 survivors. Collectively, these results indicate the prolonging pre-intervention arrest from 6 to 10 min sharply intensified brain injury, depleted cytoprotective EPO, and inactivated oxyradical-sensitive enzymes. Pyruvate treatment did not exert favorable effects on these variables, indicating that pyruvate may have had limited ability to traverse the blood brain barrier and protect the brain parenchyma in this large animal model of cardiac arrest and CCR.Item Pyruvate Protection of Myocardium and Brain Following Cardiopulmonary Arrest and Resuscitation(2006-12-01) Sharma, Arti B.; Robert T. Mallet; Neeraj Agarwal; James L. CaffreySharma, Arti Bashu, Pyruvate Protection of Myocardium and Brain Following Cardiopulmonary Arrest and Resuscitation. Doctor of Philosophy (Molecular Physiology), December 2006; 167 pp; 29 figures; bibliography, 206 titles. Approximately 350,000 people experience cardiac arrest in the United States each year, and merely 4-33% of the victims survive to hospital discharge. Cardiac and neurological injuries following resuscitation are the main factors responsible for mortality. Neurodeficit and cognitive dysfunction following recovery from cardiac arrest may persist for us to two years and greatly compromise quality of life in survivors. Loss of effective circulating blood volume during cardiac arrest results in ischemia, energy depletion, ionic imbalance, calcium overload, acidosis and oxidant mediated cytotoxicity. The burst of reactive oxygen species upon reperfusion imposes an oxidant burden resulting in modification of cellular components such as membrane phospholipids and proteins, and the initiation of inflammatory and cell death cascades. This injury is most pronounced in organs with high metabolic demands such as the heart and brain. Therapies aimed at reducing metabolic impairments such as energy depletion and oxidative stress may mitigate post-resuscitation complications, improve survival and enhance quality of life. Pyruvate, a natural metabolite of the glycolytic pathway, has been shown to enhance post-ischemic energy and antioxidant reserves, and effects improvements in calcium homeostasis and metabolic acidosis. The main purpose of this investigation was to evaluate pyruvate as a corrective metabolic intervention during cardiopulmonary resuscitation and examine its cardio- and neuroprotective effects following recovery from cardiopulmonary arrest. To address these objectives as a canine model of 5 min cardiopulmonary arrest, open chest cardiac compressions (OCCC) and resuscitation was developed. In the first study intravenous sodium pyruvate or control NaCl was administered during the first 30 min of resuscitation and its effects on cardiac function and metabolites examined through the first 3 h following return of spontaneous circulation. Cardiac arrest resulted in a severe collapse of myocardial phosphocreatine phosphorylation potential and antioxidant redox state. Pyruvate treatment substantially enhanced recovery of energy and antioxidant reserves during early reperfusion. Pyruvate also enhanced contractile performance and carotid blood flow at 15-25 min return of spontaneous circulation (ROSC), and better maintained cardiac function at 3 h ROSC. Thus a latent effect of temporary metabolic correction by intravenous pyruvate therapy during early resuscitation was manifest as improved cardiac function, 3 h after the acute insult. Oxidative stress during resuscitation can modify membrane lipids and proteins. Inactivation of myocardial enzymes may exacerbate ischemic derangements of myocardial metabolism. To study the impact of cardiac arrest on left ventricular enzymes, beagles were subjected to cardiac arrest and myocardial enzyme activities were measured in snap-frozen left ventricle. Severe depletion of glutathione (GSH) antioxidant redox state occurred during cardiac arrest, which recovered partially following cardiac massage and then completely during early ROSC. Concomitant with oxidant stress, activities of phosphofructokinase, citrate synthase, aconitase, malate dehydrogenase, creatine kinase, glucose 6-phosphate dehydrogenase and glutathione reductase fell sharply during arrest, and recovered gradually after resuscitation and ROSC, in parallel with GSH redox state. We then tested whether oxidative stress is responsible for the loss of enzyme activity during cardiac arrest. Metabolic (pyruvate) or pharmacological (N-acetylcysteine) antioxidants were infused iv for 30 min immediately before cardiac arrest. Antioxidant pretreatments augmented phosphofructokinase, aconitase and malate dehydrogenase activities before arrest, and enhanced these activities, as well as citrate synthase and glucose 6-phosphate dehydrogenase, during arrest. Cardiac arrest thus reversibly inactivates several important myocardial metabolic enzymes, while protection of these enzymes by antioxidants implicates oxidative stress as a principal mechanism of enzyme inactivation. The third part of this investigation was directed towards addressing the question whether metabolic correction with pyruvate therapy during ROSC, would extend protection and enhance neurological recovery over an extended period of 3 days following cardiac arrest-resuscitation. Neurological evaluation in the days following recovery from cardiac arrest revealed considerable impairment of function. Activation of matrix metalloproteinases and increased myeloperoxidase activity were also detected in frozen brain tissue. Loss of viable neuronal structure and cell death as indicted by histological evidence and TUNEL were detected 3 days following arrest. Treatment with pyruvate for the first hour of reperfusion prevented neurological deficit on days 1 and 2 of recovery, partially mitigated the inflammatory response and prevented neuronal loss. By preventing early metabolic disturbances during resuscitation and immediate reperfusion, intravenous pyruvate therapy protected the heart and brain from dysfunction and injury. The following figure summarizes these major findings. [see dissertation] Figure: Pyruvate mediated metabolic protection following cardiopulmonary arrest-resuscitation.