title: Development of a Nonhuman Primate (Rhesus Macaque) Model of Uncontrolled Traumatic Liver Hemorrhage.
abstract: Hemorrhage is the leading cause of potentially survivable trauma mortality, necessitating the development of improved therapeutic interventions. The objective of this study was to develop and characterize a reproducible clinically translatable nonhuman primate model of uncontrolled severe hemorrhage. Such a model is required to facilitate the development and meaningful evaluation of human-derived therapeutics. In Rhesus macaques, a laparoscopic left-lobe hepatectomy of 25% (n = 2), 50% (n = 4), or 60% (n = 6) was performed at T = 0 min, with no attempt at hemorrhage control until T = 120 min. A constant-rate infusion of normal saline was administered between T = 15 and 120 min to a total volume of 20 mL/kg. At T = 120 min, a laparotomy was performed to gain surgical hemostasis and quantify blood loss. Physiological parameters were recorded, and blood samples were collected at defined intervals until termination of the study at T = 480 min. Statistical analyses used Student t tests, with P < 0.05 considered statistically significant. Results are reported as mean ± SEM. The calculated percent blood loss for the 25% hepatectomy group was negligible (2.3% ± 0.2%), whereas the 50% and 60% hepatectomy groups exhibited 26.6% ± 7.1% and 24.9% ± 3.8% blood loss, respectively. At T = 5 min, blood pressure for the 25%, 50%, and 60% hepatectomy groups was reduced by 13.8%, 60.8%, and 63.2% from the respective baseline values (P < 0.05). In the 60% hepatectomy group, alterations in thromboelastometry parameters and systemic inflammatory markers were observed. The development of a translatable nonhuman primate model of uncontrolled hemorrhage is an ongoing process. This study demonstrates that 60% hepatectomy offers a significant reproducible injury applicable for the evaluation of human-derived therapeutics.
authors.affiliation: *Naval Medical Research Unit San Antonio, Department of Expeditionary and Trauma Medicine, JBSA Fort Sam Houston, Texas; and †Naval Medical Research Center, Department of Regenerative Medicine, Silver Spring, Maryland.
authors.forename: Forest R
authors.initials: FR
authors.lastname: Sheppard
authors.forename: Antoni
authors.initials: A
authors.lastname: Macko
authors.forename: Darren M
authors.initials: DM
authors.lastname: Fryer
authors.forename: Kassandra M
authors.initials: KM
authors.lastname: Ozuna
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Brown
authors.forename: Randy F
authors.initials: RF
authors.lastname: Crossland
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Tadaki
mesh_terms: D000818:Animals; D001794:Blood Pressure; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006439:Hemodynamics; D006470:Hemorrhage / Q000628:therapy*; D006498:Hepatectomy; D010535:Laparoscopy; D008099:Liver / Q000098:blood supply* / Q000503:physiopathology*; D008253:Macaca mulatta; D008297:Male; D016343:Monitoring, Intraoperative; D012771:Shock, Hemorrhagic / Q000628:therapy; D013916:Thrombelastography; D016896:Treatment Outcome
chemical_list: D018925:Chemokines; D016207:Cytokines