Innate immune response after resuscitation with hemoglobin-based oxygen carrier and recombinant factor VIIA in uncontrolled hemorrhagic shock in a swine model.
BACKGROUND
Rapid resuscitation with oxygen-carrying fluids is critically important in hemorrhagic shock (HS) combat casualties in remote areas where blood is not available. Hemoglobin-based oxygen carrier-201 (HBOC-201) has been shown to increase survival and reduce immune activation following HS in animal models. Recombinant factor VIIa (rfVIIa), a systemic hemostatic agent, is Food and Drug Administration approved for use in acute hemorrhage in hemophilic patients. The combination of HBOC-201 and rfVIIa may form the basis of a prospective multifunctional blood substitute and provide benefits in the rapid restoration of hemostasis, decreased inflammation and improved survival of HS combat casualties. In the present study, we evaluated innate immune responses in a swine model of uncontrolled HS following resuscitation with HBOC-201 +/- rfVIIa.


METHODS
Thirty-two pigs underwent uncontrolled hemorrhage/liver crush injury, followed by resuscitation with five doses of HBOC-201 or HBOC + rfVIIa (90 microg/kg, or 180 microg/kg, or 360 microg/kg) and simulated 4 hours hospital arrival. Immune parameters were evaluated by flow cytometry and enzyme-linked immunosorbent assay.


RESULTS
Survival differences to 72 hours of animals resuscitated with HBOC, HBOC + rfVIIa (90), (180), and (360) were not statistically significant and resulted in survival of 25%, 63%, 63% and 50%, respectively. At the prehospital phase all groups exhibited minimal immunomodulation, characterized by stable CD4/CD8 ratio, marginal increase of apoptosis and insignificant fluctuations of adhesion markers; increase of plasma cytokines was comparable across all groups, except tumor necrosis factor-alpha, that was significantly elevated in the HBOC group.


CONCLUSIONS
HBOC-201 + rfVIIa triggered minimum immune activation in an uncontrolled HS swine and there was a nonsignificant survival benefit.
Naval Medical Research Center, Combat Casualty Care Directorate, Silver Spring, Maryland, USA. malkevichn.ctr.ru@nmrc.navy.mil
Nina V
NV
Malkevich
Feng
F
Dong
Christine A
CA
Vandermolen
Nora B
NB
Philbin
Jennifer P
JP
Rice
Anke
A
Scultetus
Jiang
J
Hong
Francoise
F
Arnaud
Carrie H
CH
Hall
Gerald
G
McGwin
L Bruce
LB
Pearce
M
M
Handrigan
Stephen
S
Ahlers
Richard M
RM
McCarron
Daniel
D
Freilich
D000818:Animals; D001802:Blood Substitutes / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015942:Factor VIIa / Q000008:administration & dosage*; D006454:Hemoglobins / Q000008:administration & dosage*; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D053208:Kaplan-Meier Estimate; D011336:Probability; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage; D012151:Resuscitation / Q000379:methods* / Q000401:mortality; D012680:Sensitivity and Specificity; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D015996:Survival Rate; D013552:Swine
D001802:Blood Substitutes; D006454:Hemoglobins; D011994:Recombinant Proteins; C096798:HBOC 201; C103587:recombinant FVIIa; D015942:Factor VIIa