Circulatory arrest as a model for studies of global ischemic injury and neuroprotection.
Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8-12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8-iso-PGF(2alpha)), an indicator of oxidative damage, and prostaglandin F(2alpha) metabolite (15-keto-dihydro-PGF(2alpha)), an indicator of cyclooxygenase-2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S-100beta. Neurological outcome is assessed at >24 h after the incident. Our results show that plasma concentrations of 8-iso-PGF(2alpha) are greater after more extended periods of ischemia. PBN (alpha-phenyl-N-tert-butyl nitrone), a so-called spin-trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8-iso-PGF(2alpha) concentration is decreased during reperfusion. Use of water-soluble sulfonated PBN (S-PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.
Wiklund
Lars
L
Department of Surgical Sciences/Anesthesiology and Intensive Care Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. lars.wiklund@surgsci.uu.se
Sharma
Hari Shanker
HS
Basu
Samar
S
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology*; D016887:Cardiopulmonary Resuscitation; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D006323:Heart Arrest / Q000139:chemically induced / Q000473:pathology*; D006439:Hemodynamics / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D013552:Swine
D018696:Neuroprotective Agents