Lance B. Becker

Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes.

Reactive oxygen species (ROS) have been proposed to participate in the induction of cardiac preconditioning. However, their source and mechanism of induction are unclear. We tested whether brief hypoxia induces preconditioning by augmenting mitochondrial generation of ROS in chick cardiomyocytes. Cells were preconditioned with 10 min of hypoxia, followed by 1 h of simulated ischemia and 3 h of reperfusion. Preconditioning decreased cell death from 47 ± 3% to 14 ± 2%. Return of contraction was observed in 3/3 preconditioned versus 0/6 non-preconditioned experiments. During induction, ROS oxidation of the probe dichlorofluorescin (sensitive to H2O2) increased ∼2.5-fold. As a substitute for hypoxia, the addition of H2O2 (15 μmol/liter) during normoxia also induced preconditioning-like protection. Conversely, the ROS signal during hypoxia was attenuated with the thiol reductant 2-mercaptopropionyl glycine, the cytosolic Cu,Zn-superoxide dismutase inhibitor diethyldithiocarbamic acid, and the anion channel inhibitor 4,4′-diisothiocyanato-stilbene-2,2′-disulfonate, all of which also abrogated protection. ROS generation during hypoxia was attenuated by myxothiazol, but not by diphenyleneiodonium or the nitric-oxide synthase inhibitor l-nitroarginine. We conclude that hypoxia increases mitochondrial superoxide generation which initiates preconditioning protection. Furthermore, mitochondrial anion channels and cytosolic dismutation to H2O2 may be important steps for oxidant induction of hypoxic preconditioning.

Outcome of CPR in a large metropolitan area — where are the survivors?

STUDY OBJECTIVES Survival from out-of-hospital cardiac arrest in cities with populations of more than 1 million has not been studied adequately. This study was undertaken to determine the overall survival rate for Chicago and the effect of previously reported variables on survival, and to compare the observed survival rates with those previously reported. DESIGN Consecutive prehospital arrest patients were studied prospectively during 1987. SETTING The study area was the city of Chicago, which has more than 3 million inhabitants in 228 square miles. The emergency medical services system, with 55 around-the-clock ambulances and 550 paramedics, is single-tiered and responds to more than 200,000 emergencies per year. TYPE OF PARTICIPANTS We studied 3,221 victims of out-of-hospital cardiac arrest on whom paramedics attempted resuscitation. MEASUREMENTS AND MAIN RESULTS Ninety-one percent of patients were pronounced dead in emergency departments, 7% died in hospitals, and 2% survived to hospital discharge. Survival was significantly greater with bystander-witnessed arrest, bystander-initiated CPR, paramedic-witnessed arrest, initial rhythm of ventricular fibrillation, and shorter treatment intervals. CONCLUSIONS The overall survival rates were significantly lower than those reported in most previous studies, all based on smaller communities; they were consistent with the rates reported in the one comparable study of a large city. The single factor that most likely contributed to the poor overall survival was the relatively long interval between collapse and defibrillation. Logistical, demographic, and other special characteristics of large cities may have affected the rates. To improve treatment of cardiac arrest in large cities and maximize the use of community resources, we recommend further study of comparable metropolitan areas using standardized terms and methodology. Detailed analysis of each component of the emergency medical services systems will aid in making improvements to maximize survival of out-of-hospital cardiac arrest.

Chest compression rates during cardiopulmonary resuscitation are suboptimal: a prospective study during in-hospital cardiac arrest.

Background—Recent data highlight a vital link between well-performed cardiopulmonary resuscitation (CPR) and survival after cardiac arrest; however, the quality of CPR as actually performed by trained healthcare providers is largely unknown. We sought to measure in-hospital chest compression rates and to determine compliance with published international guidelines. Methods and Results—We developed and validated a handheld recording device to measure chest compression rate as a surrogate for CPR quality. A prospective observational study of adult cardiac arrests was performed at 3 hospitals from April 2002 to October 2003. Resuscitations were witnessed by trained observers using a customized personal digital assistant programmed to store the exact time of each chest compression, allowing offline calculation of compression rates at serial time points. In 97 arrests, data from 813 minutes during which chest compressions were delivered were analyzed in 30-second time segments. In 36.9% of the total number of segments, compression rates were <80 compressions per minute (cpm), and 21.7% had rates <70 cpm. Higher chest compression rates were significantly correlated with initial return of spontaneous circulation (mean chest compression rates for initial survivors and nonsurvivors, 90±17 and 79±18 cpm, respectively; P=0.0033). Conclusions—In-hospital chest compression rates were below published resuscitation recommendations, and suboptimal compression rates in our study correlated with poor return of spontaneous circulation. CPR quality is likely a critical determinant of survival after cardiac arrest, suggesting the need for routine measurement, monitoring, and feedback systems during actual resuscitation.

Generation of superoxide in cardiomyocytes during ischemia before reperfusion

Although a burst of oxidants has been well described with reperfusion, less is known about the oxidants generated by the highly reduced redox state and low O2 of ischemia. This study aimed to further identify the species and source of these oxidants. Cardiomyocytes were exposed to 1 h of simulated ischemia while oxidant generation was assessed by intracellular dihydroethidine (DHE) oxidation. Ischemia increased DHE oxidation significantly (0.7 ± 0.1 to 2.3 ± 0.3) after 1 h. Myxothiazol (mitochondrial site III inhibitor) attenuated oxidation to 1.3 ± 0.1, as did the site I inhibitors rotenone (1.0 ± 0.1), amytal (1.1 ± 0.1), and the flavoprotein oxidase inhibitor diphenyleneiodonium (0.9 ± 0.1). By contrast, the site IV inhibitor cyanide, as well as inhibitors of xanthine oxidase (allopurinol), nitric oxide synthase (nitro-l-arginine methyl ester), and NADPH oxidase (apocynin), had no effect. Finally, DHE oxidation increased with Cu- and Zn-containing superoxide dismutase (SOD) inhibition using diethyldithiocarbamate (2.7 ± 0.1) and decreased with exogenous SOD (1.1 ± 0.1). We conclude that significant superoxide generation occurs during ischemia before reperfusion from the ubisemiquinone site of the mitochondrial electron transport chain.Although a burst of oxidants has been well described with reperfusion, less is known about the oxidants generated by the highly reduced redox state and low O(2) of ischemia. This study aimed to further identify the species and source of these oxidants. Cardiomyocytes were exposed to 1 h of simulated ischemia while oxidant generation was assessed by intracellular dihydroethidine (DHE) oxidation. Ischemia increased DHE oxidation significantly (0.7 +/- 0.1 to 2.3 +/- 0.3) after 1 h. Myxothiazol (mitochondrial site III inhibitor) attenuated oxidation to 1.3 +/- 0.1, as did the site I inhibitors rotenone (1.0 +/- 0.1), amytal (1.1 +/- 0.1), and the flavoprotein oxidase inhibitor diphenyleneiodonium (0.9 +/- 0.1). By contrast, the site IV inhibitor cyanide, as well as inhibitors of xanthine oxidase (allopurinol), nitric oxide synthase (nitro-L-arginine methyl ester), and NADPH oxidase (apocynin), had no effect. Finally, DHE oxidation increased with Cu- and Zn-containing superoxide dismutase (SOD) inhibition using diethyldithiocarbamate (2.7 +/- 0.1) and decreased with exogenous SOD (1.1 +/- 0.1). We conclude that significant superoxide generation occurs during ischemia before reperfusion from the ubisemiquinone site of the mitochondrial electron transport chain.

Recommended Guidelines for Reviewing, Reporting, and Conducting Research on In-Hospital Resuscitation: The In-Hospital ‘Utstein Style’ A Statement for Healthcare Professionals From the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Australian Resuscitation Council, and the Resuscitation Councils of Southern Africa

This scientific statement is the product of the Utstein ’95 Symposium held June 23-24, 1995, at Utstein Abbey, Island of Mosteroy, Rogaland County, Norway. Draft versions were circulated for comment to participants of the Utstein ’95 Symposium; the European Resuscitation Council Executive Committee; the Emergency Cardiac Care Committee of the American Heart Association; the Executive Committees of the Heart and Stroke Foundation of Canada, the Australian Resuscitation Council, and the Resuscitation Councils of Southern Africa; and several outside reviewers. The development of this statement was authorized by the Science Advisory and Coordinating Committee of the AHA and the Executive Committee of the European Resuscitation Council. We do not know the true effectiveness of in-hospital resuscitation. Observed results of the many published studies vary greatly. Studies originate from different settings and have different patient populations. Reports suffer from nonuniform nomenclature and variable inclusion definitions. Patients differ in the extent of comorbid conditions and interventions in place at the time of cardiac arrest. These differences prevent valid interhospital and intrahospital comparisons and make determining the effectiveness of current resuscitation techniques impossible. To develop these guidelines the task force used a consensus development process that originated with the “Utstein style” for reporting outcome data from out-of-hospital resuscitation events. Task force members performed an integrated review of published studies. An initial draft was prepared, discussed, and revised at a 2-day conference. Further drafts were revised and circulated among task force members and discussed face-to-face at three subsequent meetings. The task force defined a set of data elements that are essential or desirable for documenting in-hospital cardiac arrest. Data categories are hospital variables, patient variables, arrest variables, and outcome variables. The “In-Hospital Utstein-Style Template” was developed to summarize these data and recommendations for reporting a specific set of survival rates and outcomes. The task force …

Improving In-Hospital Cardiac Arrest Process and Outcomes With Performance Debriefing

BACKGROUND Recent investigations have documented poor cardiopulmonary resuscitation (CPR) performance in clinical practice. We hypothesized that a debriefing intervention using CPR quality data from actual in-hospital cardiac arrests (resuscitation with actual performance integrated debriefing [RAPID]) would improve CPR performance and initial patient survival. METHODS Internal medicine residents at a university hospital attended weekly debriefing sessions of the prior weeks resuscitations, between March 2006 and February 2007, reviewing CPR performance transcripts obtained from a CPR-sensing and feedback-enabled defibrillator. Objective metrics of CPR performance and initial return of spontaneous circulation were compared with a historical cohort in which a similar feedback-delivering defibrillator was used but without RAPID. RESULTS Cardiopulmonary resuscitation quality and outcome data from 123 patients resuscitated during the intervention period were compared with 101 patients in the baseline cohort. Compared with the control period, the mean (SD) ventilation rate decreased (13 [7]/min vs 18 [8]/min; P < .001) and compression depth increased (50 [10] vs 44 [10] mm; P = .001), among other CPR improvements. These changes correlated with an increase in the rate of return of spontaneous circulation in the RAPID group (59.4% vs 44.6%; P = .03) but no change in survival to discharge (7.4% vs 8.9%; P = .69). CONCLUSIONS The combination of RAPID and real-time audiovisual feedback improved CPR quality compared with the use of feedback alone and was associated with an increased rate of return of spontaneous circulation. Cardiopulmonary resuscitation sensing and recording devices allow for methods of debriefing that were previously available only for simulation-based education; such methods have the potential to fundamentally alter resuscitation training and improve patient outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00228293.

Intra-Arrest Cooling Improves Outcomes in a Murine Cardiac Arrest Model

Background—Recent clinical studies have demonstrated that hypothermia to 32° to 34°C provides significant clinical benefit when induced after resuscitation from cardiac arrest. However, cooling during the postresuscitation period was slow, requiring 4 to 8 hours to achieve target temperatures after return of spontaneous circulation (ROSC). Whether more rapid cooling would further improve survival remains unclear. We sought to determine whether cooling during cardiac arrest before ROSC (ie, “intra-arrest” hypothermia) has survival benefit over more delayed post-ROSC cooling, using a murine cardiac arrest model. Methods and Results—A model of potassium-induced cardiac arrest was established in C57BL/6 mice. After 8 minutes of untreated cardiac arrest, resuscitation was attempted with chest compression, ventilation, and intravenous fluid. Mice were randomized to 3 treatment groups (n=10 each): an intra-arrest hypothermia group, in which mice were cooled to 30°C just before attempted resuscitation, and then rewarmed after 1 hour; a post-ROSC hypothermia group, in which mice were kept at 37°C for 20 minutes after successful ROSC and then were cooled to 30°C for 1 hour; and a normothermic control group, in which mice were kept at 37°C. The intra-arrest hypothermia group demonstrated better 72-hour survival than delayed hypothermia and normothermia groups (6/10 versus 1/10 and 1/10 survivors, respectively, P <0.05), with similar differences seen at 6-hour survival and on neurological scoring. Conclusions—Timing of hypothermia is a crucial determinant of survival in the murine arrest model. Early intra-arrest cooling appears to be significantly better than delayed post-ROSC cooling or normothermic resuscitation.

Preconditioning in Cardiomyocytes Protects by Attenuating Oxidant Stress at Reperfusion

Cardiomyocyte death after ischemia/reperfusion correlates with oxidant stress, and antioxidants confer protection in that model. Preconditioning (PC) with hypoxia or adenosine also confers protection, leading us to hypothesize that PC protects by attenuating oxidant generation during subsequent ischemia/reperfusion. Chick cardiomyocytes were preconditioned with 10 minutes of hypoxia or adenosine (100 micromol/L), followed by 1 hour of simulated ischemia and 3 hours of reperfusion. Adenosine PC decreased cell death from 50+/-3% to 18+/-4% and enhanced the return of contractions during reperfusion, as observed previously with hypoxic PC. A transient burst of dichlorofluorescein (sensitive to H2O2 oxidation that was significantly attenuated by PC initiated by hypoxia or adenosine was seen at reperfusion. The protein kinase C (PKC) inhibitor Go-6976 and the mitochondrial ATP-sensitive K(+) (K(ATP)) channel inhibitor 5-hydroxydecanoate each abolished protection and abrogated the PC-induced attenuation of reperfusion oxidant stress. By contrast, when given only at reperfusion, the K(+) channel opener pinacidil or the antioxidants 2-mercaptopropionylglycine and 1,10-phenanthroline decreased oxidant stress at reperfusion and improved survival and return of contractions. Thus, PC protection is associated with an attenuation of the oxidant burst at reperfusion, regardless of the method by which PC is triggered. Loss of PC protection associated with PKC inhibition or K(ATP) channel inhibitors is associated with a restoration of that oxidant stress. These results suggest a mechanism for PC protection and reveal a functional link between PKC activation and K(ATP) channel activation in that pathway.

Automatic External Defibrillators for Public Access Defibrillation: Recommendations for Specifying and Reporting Arrhythmia Analysis Algorithm Performance, Incorporating New Waveforms, and Enhancing Safety A Statement for Health Professionals From the American Heart Association Task Force on Automatic External Defibrillation, Subcommittee on AED Safety and Efficacy

These recommendations are presented to enhance the safety and efficacy of AEDs intended for public access. The task force recommends that manufacturers present developmental and validation data on their own devices, emphasizing high sensitivity for shockable rhythms and high specificity for nonshockable rhythms. Alternative defibrillation waveforms may reduce energy requirements, reducing the size and weight of the device. The highest levels of safety for public access defibrillation are needed. Safe and effective use of AEDs that are widely available and easily handled by nonmedical personnel has the potential to dramatically increase survival from cardiac arrest.

Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest

BACKGROUND Comatose survivors of out-of-hospital cardiac arrest (OHCA) have high in-hospital mortality due to a complex pathophysiology that includes cardiovascular dysfunction, inflammation, coagulopathy, brain injury and persistence of the precipitating pathology. Therapeutic hypothermia (TH) is the only intervention that has been shown to improve outcomes in this patient population. Due to the similarities between the post-cardiac arrest state and severe sepsis, it has been postulated that early goal-directed hemodyamic optimization (EGDHO) combined with TH would improve outcome of comatose cardiac arrest survivors. OBJECTIVE We examined the feasibility of establishing an integrated post-cardiac arrest resuscitation (PCAR) algorithm combining TH and EGDHO within 6h of emergency department (ED) presentation. METHODS In May, 2005 we began prospectively identifying comatose (Glasgow Motor Score<6) survivors of OHCA treated with our PCAR protocol. The PCAR patients were compared to matched historic controls from a cardiac arrest database maintained at our institution. RESULTS Between May, 2005 and January, 2008, 18/20 (90%) eligible patients were enrolled in the PCAR protocol. They were compared to historic controls from 2001 to 2005, during which time 18 patients met inclusion criteria for the PCAR protocol. Mean time from initiation of TH to target temperature (33 degrees C) was 2.8h (range 0.8-23.2; SD=h); 78% (14/18) had interventions based upon EGDHO parameters; 72% (13/18) of patients achieved their EGDHO goals within 6h of return of spontaneous circulation (ROSC). Mortality for historic controls who qualified for the PCAR protocol was 78% (14/18); mortality for those treated with the PCAR protocol was 50% (9/18) (p=0.15). CONCLUSIONS In patients with ROSC after OHCA, EGDHO and TH can be implemented simultaneously.