David G. Beiser

Nitrite Therapy After Cardiac Arrest Reduces Reactive Oxygen Species Generation, Improves Cardiac and Neurological Function, and Enhances Survival via Reversible Inhibition of Mitochondrial Complex I

Background— Three-fourths of cardiac arrest survivors die before hospital discharge or suffer significant neurological injury. Except for therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO2−) increases cellular resilience to focal ischemia/reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia/reperfusion insult of cardiopulmonary arrest. Methods and Results— We developed a mouse model of cardiac arrest characterized by 12 minutes of normothermic asystole and a high cardiopulmonary resuscitation rate. In this model, global ischemia and cardiopulmonary resuscitation were associated with blood and organ nitrite depletion, reversible myocardial dysfunction, impaired alveolar gas exchange, neurological injury, and an ≈50% mortality. A single low dose of intravenous nitrite (50 nmol=1.85 &mgr;mol/kg=0.13 mg/kg) compared with blinded saline placebo given at cardiopulmonary resuscitation initiation with epinephrine improved cardiac function, survival, and neurological outcomes. From a mechanistic standpoint, nitrite treatment restored intracardiac nitrite and increased S-nitrosothiol levels, decreased pathological cardiac mitochondrial oxygen consumption resulting from reactive oxygen species formation, and prevented oxidative enzymatic injury via reversible specific inhibition of respiratory chain complex I. Conclusion— Nitrite therapy after resuscitation from 12 minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction, death, and neurological impairment in survivors.

Clinical and hemodynamic comparison of 15: 2 and 30:2 compression-to- ventilation ratios for cardiopulmonary resuscitation

Objective:To compare cardiopulmonary resuscitation (CPR) with a compression to ventilation (C:V) ratio of 15:2 vs. 30:2, with and without use of an impedance threshold device (ITD). Design:Prospective randomized animal and manikin study. Setting:Animal laboratory and emergency medical technician training facilities. Subjects:Twenty female pigs and 20 Basic Life Support (BLS)-certified rescuers. Interventions, Measurements, and Main Results: Animals:Acid-base status, cerebral, and cardiovascular hemodynamics were evaluated in 18 pigs in cardiac arrest randomized to a C:V ratio of 15:2 or 30:2. After 6 mins of cardiac arrest and 6 mins of CPR, an ITD was added. Compared to 15:2, 30:2 significantly increased diastolic blood pressure (20 ± 1 to 26 ± 1; p < .01); coronary perfusion pressure (18 ± 1 to 25 ± 2; p = .04); cerebral perfusion pressure (16 ± 3 to 18 ± 3; p = .07); common carotid blood flow (48 ± 5 to 82 ± 5 mL/min; p < .001); end-tidal CO2 (7.7 ± 0.9 to 15.7 ± 2.4; p < .0001); and mixed venous oxygen saturation (26 ± 5 to 36 ± 5, p < .05). Hemodynamics improved further with the ITD. Oxygenation and arterial pH were similar. Only one of nine pigs had return of spontaneous circulation with 15:2, vs. six of nine with 30:2 (p < 0.03). Humans: Fatigue and quality of CPR performance were evaluated in 20 BLS-certified rescuers randomized to perform CPR for 5 mins at 15:2 or 30:2 on a recording CPR manikin. There were no significant differences in the quality of CPR performance or measurement of fatigue. Significantly more compressions per minute were delivered with 30:2 in both the animal and human studies. Conclusions:These data strongly support the contention that a ratio of 30:2 is superior to 15:2 during manual CPR and that the ITD further enhances circulation with both C:V ratios.

Network models of the basal ganglia

Over the past year, a number of conceptual and mathematical models of the basal ganglia and their interactions with other areas of the brain have appeared in the literature. Even though the models each differ in significant ways, several computational principles, such as convergence, recurrence and competition, appear to have emerged as common themes of information processing in the basal ganglia. Simulation studies of these models have provoked new types of questions at the many levels of inquiry linking biophysics to behavior.

Induced hypothermia by central venous infusion: Saline ice slurry versus chilled saline

Objective:Surface cooling improves outcome in selected comatose survivors of cardiac arrest. Internal cooling with considerable volumes of intravenous cold saline may accelerate hypothermia induction. This study compares core temperatures in swine after central catheter infusions of saline ice slurry (saline with smoothed 100-&mgr;m-size ice particles) vs. an equal volume of chilled saline. We hypothesized that slurry would achieve core hypothermia (32–34°C) more consistently and at a faster rate. Design:A total of 11 swine were randomized to receive microparticulate ice slurry, chilled saline infusion, or anesthesia alone in a monitored laboratory setting. Interventions:Intravenous bolus (50 mL/kg) of slurry or chilled 1.5% NaCl saline. Slurry was composed of a 1:1 mixture of ice and distilled H2O plus NaCl. Measurements:Cerebral cortex, tympanic membrane, inferior vena cava, rectal temperatures, electrocardiogram, arterial blood pressure, and arterial oxygen saturation were recorded for 1 hr after bolus. Main Results:Compared with anesthetized controls, core brain temperatures of the saline and slurry groups dropped by 3.4 ± 0.4°C and 5.3 ± 0.7°C (p = .009), respectively. With an infusion rate of 120 mL/min, cooling rates for the saline and slurry groups were −11.6 ± 1.8°C/hr and −18.2 ± 2.9°C/hr, respectively, during the first 20 mins. Four of four animals in the slurry group vs. zero of four animals in the saline group achieved target cortical temperatures of <34°C. Conclusions:Cold intravenous fluids rapidly induce hypothermia in swine with intact circulation. A two-phase (liquid plus ice) saline slurry cools more rapidly than an equal volume of cold saline at 0°C. Ice-slurry could be a significant improvement over other cooling methods when rate of cooling and limited infusion volumes are important to the clinician.

Derangements in blood glucose following initial resuscitation from in-hospital cardiac arrest: A report from the national registry of cardiopulmonary resuscitation

STUDY AIMS Hyperglycemia is associated with poor outcomes in critically ill patients. We examined blood glucose values following in-hospital cardiac arrest (IHCA) to (1) characterize post-arrest glucose ranges, (2) develop outcomes-based thresholds of hyperglycemia and hypoglycemia, and (3) identify risk factors associated with post-arrest glucose derangements. METHODS We retrospectively studied 17,800 adult IHCA events reported to the National Registry of Cardiopulmonary Resuscitation (NRCPR) from January 1, 2005 through February 1, 2007. RESULTS Data were available from 3218 index events. Maximum blood glucose values were elevated in diabetics (median 226 mg/dL [IQR, 165-307 mg/dL], 12.5 mmol/L [IQR 9.2-17.0 mmol/L]) and non-diabetics (median 176 mg/dL [IQR, 135-239 mg/dL], 9.78 mmol/L [IQR 7.5-13.3 mmol/L]). Unadjusted survival to hospital discharge was higher in non-diabetics than diabetics (45.5% [95% CI, 43.3-47.6%] vs. 41.7% [95% CI, 38.9-44.5%], p=0.037). Non-diabetics displayed decreased adjusted survival odds for minimum glucose values outside the range of 71-170 mg/dL (3.9-9.4 mmol/L) and maximum values outside the range of 111-240 mg/dL (6.2-13.3 mmol/L). Diabetic survival odds decreased for minimum glucose greater than 240 mg/dL (13.3 mmol/L). In non-diabetics, arrest duration was identified as a significant factor associated with the development of hypo- and hyperglycemia. CONCLUSIONS Hyperglycemia is common in diabetics and non-diabetics following IHCA. Survival odds in diabetics are relatively insensitive to blood glucose with decreased survival only associated with severe (>240 mg/dL, >13.3 mmol/dL) hyperglycemia. In non-diabetics, survival odds were sensitive to hypoglycemia (<70 mg/dL, <3.9 mmol/L).

Cardiac catheterization is underutilized after in-hospital cardiac arrest

BACKGROUND Indications for immediate cardiac catheterization in cardiac arrest survivors without ST elevation myocardial infarction (STEMI) are uncertain as electrocardiographic and clinical criteria may be challenging to interpret in this population. We sought to evaluate rates of early catheterization after in-hospital ventricular fibrillation (VF) arrest and the association with survival. METHODS Using a billing database we retrospectively identified cases with an ICD-9 code of cardiac arrest (427.5) or VF (427.41). Discharge summaries were reviewed to identify in-hospital VF arrests. Rates of catheterization on the day of arrest were determined by identifying billing charges. Unadjusted analyses were performed using Chi-square, and adjusted analyses were performed using logistic regression. RESULTS One hundred and ten in-hospital VF arrest survivors were included in the analysis. Cardiac catheterization was performed immediately or within 1 day of arrest in 27% (30/110) of patients and of these patients, 57% (17/30) successfully received percutaneous coronary intervention. Of those who received cardiac catheterization the indication for the procedure was STEMI or new left bundle branch block (LBBB) in 43% (13/30). Therefore, in the absence of standard ECG data suggesting acute myocardial infarction, 57% (17/30) received angiography. Patients receiving cardiac catheterization were more likely to survive than those who did not receive catheterization (80% vs. 54%, p<.05). CONCLUSION In patients receiving cardiac catheterization, more than half received this procedure for indications other than STEMI or new LBBB. Cardiac catheterization was associated with improved survival. Future recommendations need to be established to guide clinicians on which arrest survivors might benefit from immediate catheterization.

Inhibition of the Mitochondrial Fission Protein Dynamin-Related Protein 1 Improves Survival in a Murine Cardiac Arrest Model:

Objectives:Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation and the use of therapeutic hypothermia. Dynamin-related protein 1, a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that dynamin-related protein 1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest. Design:Laboratory investigation. Setting:University laboratory. Interventions:Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-minute KCl-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of Mdivi-1 (0.24 mg/kg), a small molecule dynamin-related protein 1 inhibitor or vehicle (dimethyl sulfoxide). Measurements and Main Results:Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by dynamin-related protein 1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during cardiopulmonary resuscitation inhibited dynamin-related protein 1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (116 ± 4 vs 143 ± 7 s; p < 0.001) during cardiopulmonary resuscitation and enhanced myocardial performance post–return of spontaneous circulation. These improvements were associated with significant increases in survival (65% vs 33%) and improved neurological scores up to 72 hours post cardiac arrest. Conclusions:Post–cardiac arrest inhibition of dynamin-related protein 1 improves time to return of spontaneous circulation and myocardial hemodynamics, resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.

A pilot study of ice‐slurry application for inducing laparoscopic renal hypothermia

To assess, in a pilot study, the feasibility of delivering a microparticulate ice slurry (MPS) to provide regional hypothermia, as renal cooling during laparoscopic procedures is cumbersome and inefficient.

Akt1 genetic deficiency limits hypothermia cardioprotection following murine cardiac arrest.

Therapeutic hypothermia (TH) cardioprotection has recently been associated with increased Akt signaling in a rat model of cardiac arrest. However, it is not known whether Akt is required for this beneficial effect of TH. We used a mouse model of cardiac arrest demonstrating TH cardioprotection to study the response of mice deficient in an Akt1 allele. We hypothesized that Akt1 mediates TH cardioprotection and that decreases in Akt1 content would diminish such protection. Adult C57BL/6 wild-type (WT) mice underwent an 8-min cardiac arrest. After 6 min, the mice were randomized to normothermia (WT(NT), 37 degrees C) or TH (WT(TH), 30 degrees C). Following cardiopulmonary resuscitation and the return of spontaneous circulation (ROSC), the animals were hemodynamically monitored for 240 min (R240). At R240, cardiac tissue Akt content and phosphorylation were assayed. Studies were repeated in Akt1 heterozygous (Akt1(+/-)) mice. As a result, baseline characteristics and ROSC rates were equivalent across groups. At R240, WT(TH) mice exhibited lower heart rate, larger stroke volume, and higher cardiac output than WT(NT) animals (P < 0.05). Cardioprotection in WT(TH) at R240 was associated with increased cardiac Akt phosphorylation at Ser473 and Thr308 compared with that in WT(NT) (P < 0.05). TH-associated alterations in Akt phosphorylation, stroke volume, heart rate, and cardiac output were abrogated in Akt1(+/-) animals. In conclusion, TH improves post-ROSC cardiac function and increases Akt phosphorylation in WT, but not Akt1(+/-), mice. The Akt1 isoform appears necessary for TH-mediated cardioprotection.

Altering CO2 during reperfusion of ischemic cardiomyocytes modifies mitochondrial oxidant injury.

Objective:Acute changes in tissue CO2 and pH during reperfusion of the ischemic heart may affect ischemia/reperfusion injury. We tested whether gradual vs. acute decreases in CO2 after cardiomyocyte ischemia affect reperfusion oxidants and injury. Design:Comparative laboratory investigation. Setting:Institutional laboratory. Subjects:Embryonic chick cardiomyocytes. Interventions:Microscope fields of approximately 500 chick cardiomyocytes were monitored throughout 1 hr of simulated ischemia (Po2 of 3–5 torr, Pco2 of 144 torr, pH 6.8), followed by 3 hrs of reperfusion (Po2 of 149 torr, Pco2 of 36 torr, pH 7.4), and compared with cells reperfused with relative hypercarbia (Pco2 of 71 torr, pH 6.8) or hypocarbia (Pco2 of 7 torr, pH 7.9). Measurements and Main Results:The measured outcomes included cell viability (via propidium iodide) and oxidant generation (reactive oxygen species via 2′,7′-dichlorofluorescin oxidation and nitric oxide [NO] via 4,5-diaminofluorescein diacetate oxidation). Compared with normocarbic reperfusion, hypercarbia significantly reduced cell death from 54.8% ± 4.0% to 26.3% ± 2.8% (p < .001), significantly decreased reperfusion reactive oxygen species (p < .05), and increased NO at a later phase of reperfusion (p < .01). The NO synthase inhibitor N-nitro-l-arginine methyl ester (200 &mgr;M) reversed this oxidant attenuation (p < .05), NO increase (p < .05), and the cardioprotection conferred by hypercarbic reperfusion (increasing death to 54.3% ± 6.0% [p < .05]). Conversely, hypocarbic reperfusion increased cell death to 80.4% ± 4.5% (p < .01). It also increased reactive oxygen species by almost two-fold (p = .052), without affecting the NO level thereafter. Increased reactive oxygen species was attenuated by the mitochondrial complex III inhibitor stigmatellin (20 nM) when given at reperfusion (p < .05). Cell death also decreased from 85.9% ± 4.5% to 52.2% ± 6.5% (p < .01). The nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin (300 &mgr;M) had no effect on reperfusion reactive oxygen species. Conclusions:Altering CO2 content during reperfusion can significantly affect myocardial postresuscitation injury, in part by modifying mitochondrial oxidants and NO synthase-induced NO production.