Bovine polymerized hemoglobin (hemoglobin-based oxygen carrier-201) resuscitation in three swine models of hemorrhagic shock with militarily relevant delayed evacuation--effects on histopathology and organ function.
OBJECTIVE
To test our hypothesis that hemoglobin-based oxygen carrier (HBOC)-201 resuscitation in hemorrhagic shock (HS) will not lead to increased organ injury and dysfunction.


METHODS
Three swine HS models simulating military-relevant delayed evacuation: a) moderate controlled HS, b) severe controlled HS, and c) severe uncontrolled HS.


METHODS
Military research laboratory.


METHODS
Swine.


METHODS
Swine were anesthetized/intubated and instrumented. To induce HS, in two controlled hemorrhage experiments, 40% (moderate controlled HS) or 55% (severe controlled HS) of blood volume was withdrawn; in an uncontrolled HS experiment, the liver was crushed/lacerated. During a 4-hr "prehospital phase," pigs were resuscitated with HBOC-201 (HBOC) or Hextend (HEX) or were nonresuscitated (NON). Upon "hospital arrival," liver injury was repaired (severe uncontrolled HS), blood or saline was infused, hemodynamics were monitored, and blood was collected. Upon animal death and/or 72 hrs, necropsy was followed by histopathologic evaluation of organ injury (hematoxylin and eosin, electron microscopy) and immunohistochemistry of oxidative potential (3-nitrotyrosine). Significance (p < .05) was assessed by Kruskal-Wallis, analysis of variance/Bonferroni, and mixed procedure tests.


RESULTS
Survival was significantly higher with HBOC than HEX only with severe uncontrolled HS (p = .002). Myocardial necrosis/fibroplasia, fluid requirements, cardiac output, and cardiac enzymes were generally similar or lower in HBOC than HEX pigs, but creatine kinase-MB (but not creatine kinase-MB/creatine kinase ratio) was higher with HBOC in moderate controlled HS. Alveolar/interstitial pulmonary edema was similar with HBOC and HEX, but Po2 was higher with HBOC in severe uncontrolled HS. Jejunal villar epithelial and hepatocellular necrosis were similarly minimal to moderate in all groups. Minimal biliary changes occurred exclusively with HBOC. Aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase were generally higher with HBOC than HEX. Mild renal papillary injury occurred more frequently with HBOC, but consistent patterns for urine output, blood urea nitrogen, and creatinine, were not seen. The 3-nitrotyrosine staining intensity was not different.


CONCLUSIONS
In comparison with hetastarch, HBOC-201 resuscitation of swine with HS increased survival (with severe HS), did not increase evidence of oxidative potential, and had histopathologic and/or functional effects on organs that were clinically equivocal (myocardium, lungs, hepatic parenchyma, jejunum, and renal cortex/medulla) and potentially adverse (hepatobiliary and renal papilla). The effects of HBOC-201-resuscitation in HS should be corroborated in controlled clinical trials.
Johnson
Todd
T
Naval Medical Research Center, Research Services and Combat Casualty Directorates, Silver Spring, MD, USA.
Arnaud
Francoise
F
Dong
Feng
F
Philbin
Nora
N
Rice
Jennifer
J
Asher
Ludmila
L
Arrisueno
Martin
M
Warndorf
Matthew
M
Gurney
Jennifer
J
McGwin
Gerald
G
Kaplan
Lewis
L
Flournoy
W Shannon
WS
Apple
Fred S
FS
Pearce
L B
LB
Ahlers
Stephen
S
McCarron
Richard
R
Freilich
Daniel
D
D000704:Analysis of Variance; D000818:Animals; D001802:Blood Substitutes / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004632:Emergency Medical Services; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000494:pharmacology* / Q000627:therapeutic use; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008887:Military Medicine; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013552:Swine; D013997:Time Factors; D014781:Viscera / Q000378:metabolism / Q000473:pathology
D001802:Blood Substitutes; D006454:Hemoglobins; D006895:Hydroxyethyl Starch Derivatives; C096798:HBOC 201