title: Small-volume d-β-hydroxybutyrate solution infusion increases survivability of lethal hemorrhagic shock in rats.
abstract: A small-volume therapeutic approach based on the biochemistry of hibernating mammals was evaluated to test the hypothesis that passive hypothermia and systemic administration of d-β-hydroxybutyrate (d-BHB) plus melatonin will increase survival of animals subjected to hemorrhagic shock ([HS] 60% blood loss). Anesthetized Sprague-Dawley male rats (320 ± 23 g) underwent controlled loss of 60% blood volume. Rats were instrumented to measure mean arterial pressure, body temperature (Tb), and heart rate. A passive decrease in rat Tb in response to HS significantly increased survival over animals maintained at 37°C (n = 5-6). Infusion of 4 M d-BHB, at a volume of only 5.5% of the total blood removed, significantly prolonged survival to a mean of 3 h compared with 90 min using equal osmolar 4 M NaCl (n = 6). In experiments where the shed blood was returned after 1 h of 60% blood loss, 4% fluid replacement with 4 M d-BHB plus 43 mM melatonin significantly prolonged survival up to 10 days after blood return compared with 4 M NaCl plus 43 mM melatonin and other control solutions (n = 10). We conclude that a slow decrease in animal Tb resulting from 60% blood loss, combined with infusion of 4 M d-BHB plus 43 mM melatonin, was beneficial for long-term survival after return of shed blood. This HS therapy is designed as a portable low-volume solution for further evaluation in a large-animal model and is ultimately intended for use in HS patients by first responders.
authors.affiliation: Department of Biology, University of Minnesota Duluth, Duluth, Minnesota 55812, USA.
authors.forename: Amanda H
authors.initials: AH
authors.lastname: Klein
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wendroth
authors.forename: Lester R
authors.initials: LR
authors.lastname: Drewes
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Andrews
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000008:administration & dosage* / Q000097:blood; D000818:Animals; D005440:Fluid Therapy / Q000379:methods; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy*
chemical_list: D008550:Melatonin; D020155:3-Hydroxybutyric Acid