Cardiovascular toxicity of human cross-linked hemoglobin in a rabbit endotoxemia model.
OBJECTIVE
To determine the possible adverse effects of human cross-linked hemoglobin in endotoxemia.


METHODS
Prospective, controlled, laboratory trial.


METHODS
Animal research laboratory.


METHODS
New Zealand white rabbits.


METHODS
Conscious rabbits received intravenous infusions of either lipopolysaccharide (LPS) alone (10 micrograms/kg, Escherichia coli 0111:B4), human hemoglobin cross-linked between the alpha chains (alpha alpha Hb, 0.7 g/kg), or both LPS and alpha alpha Hb. The cardiovascular effects of alpha alpha Hb and LPS as single agents or administered together were then studied in anesthetized rabbits.


RESULTS
Mortality in conscious animals that received alpha alpha Hb followed by LPS 4 hrs later (n = 5), or LPS and alpha alpha Hb at the same time (n = 6) was 60% and 67%, respectively. In anesthetized animals, infusion of both LPS and alpha alpha Hb (n = 6) resulted in hypoxia, lactic acidosis, ventricular arrhythmias, and decreased myocardial contractility and left ventricular pressure. In contrast, anesthetized rabbits that received alpha alpha Hb (n = 5) or LPS (n = 5) alone did not develop hypoxia, acidosis, alteration in myocardial contractility, or arrhythmias. Furthermore, death did not occur in any of the conscious animals that received either LPS (n = 7) or alpha alpha Hb (n = 4) as single agents.


CONCLUSIONS
In an animal model of nonlethal endotoxemia, infusion of alpha alpha Hb significantly increases mortality. Our data suggest that mortality may be due to the acute increased cardiopulmonary toxicity of alpha alpha Hb in animals with underlying endotoxemia.
Krishnamurti
C
C
Department of Hematology and Vascular Biology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Carter
A J
AJ
Maglasang
P
P
Hess
J R
JR
Cutting
M A
MA
Alving
B M
BM
D000140:Acidosis, Lactic / Q000209:etiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000097:blood; D019446:Endotoxemia / Q000209:etiology* / Q000401:mortality; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects; D006441:Hemoglobin A / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D000860:Hypoxia / Q000209:etiology; D007970:Leukopenia / Q000209:etiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011817:Rabbits
D003432:Cross-Linking Reagents; D019332:Endothelin-1; D008070:Lipopolysaccharides; C028672:hemoglobin AA; D006441:Hemoglobin A