Brian J. O'Neil

Brain ischemia and reperfusion: molecular mechanisms of neuronal injury.

Brain ischemia and reperfusion engage multiple independently-fatal terminal pathways involving loss of membrane integrity in partitioning ions, progressive proteolysis, and inability to check these processes because of loss of general translation competence and reduced survival signal-transduction. Ischemia results in rapid loss of high-energy phosphate compounds and generalized depolarization, which induces release of glutamate and, in selectively vulnerable neurons (SVNs), opening of both voltage-dependent and glutamate-regulated calcium channels. This allows a large increase in cytosolic Ca(2+) associated with activation of mu-calpain, calcineurin, and phospholipases with consequent proteolysis of calpain substrates (including spectrin and eIF4G), activation of NOS and potentially of Bad, and accumulation of free arachidonic acid, which can induce depletion of Ca(2+) from the ER lumen. A kinase that shuts off translation initiation by phosphorylating the alpha-subunit of eukaryotic initiation factor-2 (eIF2alpha) is activated either by adenosine degradation products or depletion of ER lumenal Ca(2+). Early during reperfusion, oxidative metabolism of arachidonate causes a burst of excess oxygen radicals, iron is released from storage proteins by superoxide-mediated reduction, and NO is generated. These events result in peroxynitrite generation, inappropriate protein nitrosylation, and lipid peroxidation, which ultrastructurally appears to principally damage the plasmalemma of SVNs. The initial recovery of ATP supports very rapid eIF2alpha phosphorylation that in SVNs is prolonged and associated with a major reduction in protein synthesis. High catecholamine levels induced by the ischemic episode itself and/or drug administration down-regulate insulin secretion and induce inhibition of growth-factor receptor tyrosine kinase activity, effects associated with down-regulation of survival signal-transduction through the Ras pathway. Caspase activation occurs during the early hours of reperfusion following mitochondrial release of caspase 9 and cytochrome c. The SVNs find themselves with substantial membrane damage, calpain-mediated proteolytic degradation of eIF4G and cytoskeletal proteins, altered translation initiation mechanisms that substantially reduce total protein synthesis and impose major alterations in message selection, down-regulated survival signal-transduction, and caspase activation. This picture argues powerfully that, for therapy of brain ischemia and reperfusion, the concept of single drug intervention (which has characterized the approaches of basic research, the pharmaceutical industry, and clinical trials) cannot be effective. Although rigorous study of multi-drug protocols is very demanding, effective therapy is likely to require (1) peptide growth factors for early activation of survival-signaling pathways and recovery of translation competence, (2) inhibition of lipid peroxidation, (3) inhibition of calpain, and (4) caspase inhibition. Examination of such protocols will require not only characterization of functional and histopathologic outcome, but also study of biochemical markers of the injury processes to establish the role of each drug.

The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) Trial

OBJECTIVES The purpose of this study was to compare the efficiency, cost, and safety of a diagnostic strategy employing early coronary computed tomographic angiography (CCTA) to a strategy employing rest-stress myocardial perfusion imaging (MPI) in the evaluation of acute low-risk chest pain. BACKGROUND In the United States, >8 million patients require emergency department evaluation for acute chest pain annually at an estimated diagnostic cost of >

Part 7: Adult Advanced Cardiovascular Life Support 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care

10 billion. METHODS This multicenter, randomized clinical trial in 16 emergency departments ran between June 2007 and November 2008. Patients were randomly allocated to CCTA (n = 361) or MPI (n = 338) as the index noninvasive test. The primary outcome was time to diagnosis; the secondary outcomes were emergency department costs of care and safety, defined as freedom from major adverse cardiac events in patients with normal index tests, including 6-month follow-up. RESULTS The CCTA resulted in a 54% reduction in time to diagnosis compared with MPI (median 2.9 h [25th to 75th percentile: 2.1 to 4.0 h] vs. 6.3 h [25th to 75th percentile: 4.2 to 19.0 h], p < 0.0001). Costs of care were 38% lower compared with standard (median

Prospective multicenter evaluation of the pulmonary embolism rule-out criteria

2,137 [25th to 75th percentile:

Part 10: Acute Coronary Syndromes 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care

1,660 to

Clinical Characteristics, Management, and Outcomes of Patients Diagnosed With Acute Pulmonary Embolism in the Emergency Department: Initial Report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry)

3,077] vs.

A randomized controlled trial comparing the Arctic Sun to standard cooling for induction of hypothermia after cardiac arrest

3,458 [25th to 75th percentile:

SCCT guidelines on the use of coronary computed tomographic angiography for patients presenting with acute chest pain to the emergency department: A Report of the Society of Cardiovascular Computed Tomography Guidelines Committee

2,900 to

A Multicenter Randomized Controlled Trial Comparing Central Laboratory and Point-of-Care Cardiac Marker Testing Strategies: The Disposition Impacted by Serial Point of Care Markers in Acute Coronary Syndromes (DISPO-ACS) Trial

4,297], p < 0.0001). The diagnostic strategies had no difference in major adverse cardiac events after normal index testing (0.8% in the CCTA arm vs. 0.4% in the MPI arm, p = 0.29). CONCLUSIONS In emergency department acute, low-risk chest pain patients, the use of CCTA results in more rapid and cost-efficient safe diagnosis than rest-stress MPI. Further studies comparing CCTA to other diagnostic strategies are needed to optimize evaluation of specific patient subsets. (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment [CT-STAT]; NCT00468325).

Fluorescent histochemical localization of lipid peroxidation during brain reperfusion following cardiac arrest.

Basic life support (BLS), advanced cardiovascular life support (ACLS), and post–cardiac arrest care are labels of convenience that each describe a set of skills and knowledge that are applied sequentially during the treatment of patients who have a cardiac arrest. There is overlap as each stage of care progresses to the next, but generally ACLS comprises the level of care between BLS and post–cardiac arrest care. ACLS training is recommended for advanced providers of both prehospital and in-hospital medical care. In the past, much of the data regarding resuscitation was gathered from out-of-hospital arrests, but in recent years, data have also been collected from in-hospital arrests, allowing for a comparison of cardiac arrest and resuscitation in these 2 settings. While there are many similarities, there are also some differences between in- and out-of-hospital cardiac arrest etiology, which may lead to changes in recommended resuscitation treatment or in sequencing of care. The consideration of steroid administration for in-hospital cardiac arrest (IHCA) versus out-of-hospital cardiac arrest (OHCA) is one such example discussed in this Part. The recommendations in this 2015 American Heart Association (AHA) Guidelines Update for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) are based on an extensive evidence review process that was begun by the International Liaison Committee on Resuscitation (ILCOR) after the publication of the ILCOR 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations 1 and was completed in February 2015.2 In this in-depth evidence review process, the ILCOR task forces examined topics and then generated prioritized lists of questions for systematic review. Questions were first formulated in PICO (population, intervention, comparator, outcome) format,3 and then a search strategy and inclusion and exclusion criteria were defined and a search for relevant articles was performed. The evidence was evaluated by using …