The novel hemoglobin-based oxygen carrier HRC 101 improves survival in murine sickle cell disease.
BACKGROUND
Erythrocyte transfusion decreases morbidity in sickle cell disease, but is not without risk. Use of a hemoglobin-based oxygen carrier could offer the benefits of erythrocyte transfusion while reducing related complications. The authors tested the hypothesis that the novel hemoglobin-based oxygen carrier, HRC 101, would improve survival during exposure to acute hypoxia in a murine model of sickle cell disease, the transgenic mouse expressing hemoglobin SAD (alpha2beta2).


METHODS
Wild-type (n = 30) and transgenic SAD (n = 36) mice received 0.02 ml/g HRC 101 (hemoglobin concentration, 10 g/dl) or an equal volume of 5% albumin. Thirty percent or 6% oxygen was administered to spontaneously breathing mice during halothane anesthesia (inspired concentration, 0.5%). The time to cessation of cardiac electrical activity was recorded. Survival was compared using Kaplan-Meier analysis.


RESULTS
Control mice survived the 60-min study period, whether breathing 30% or 6% oxygen. In contrast, all SAD mice given albumin and 6% oxygen died, with a median survival time of 9.0 min (interquartile range, 6.9-11.6 min; P < 0.0001). HRC 101 significantly increased survival in SAD mice breathing 6% oxygen. Of 12 SAD mice given HRC 101 and 6% oxygen, 4 survived the entire study period and 8 died, with a median survival time of 48 min (19-60 min; P < 0.0001 vs. albumin).


CONCLUSIONS
HRC 101 significantly decreased sickle-related mortality during exposure to acute hypoxic stress in transgenic mice expressing hemoglobin SAD. HRC 101 warrants further evaluation as a therapeutic modality in sickle cell disease.
Department of Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Canada. mark.crawford@sickkids.ca
Mark W
MW
Crawford
Tal
T
Shichor
Thomas
T
Engelhardt
Gord
G
Adamson
David
D
Bell
F J Lou
FJ
Carmichael
Peter C W
PC
Kim
D000418:Albumins / Q000008:administration & dosage; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D001802:Blood Substitutes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006221:Halothane / Q000008:administration & dosage; D006339:Heart Rate / Q000187:drug effects; D006454:Hemoglobins / Q000627:therapeutic use*; D006895:Hydroxyethyl Starch Derivatives / Q000627:therapeutic use*; D000860:Hypoxia / Q000188:drug therapy* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000008:administration & dosage* / Q000097:blood; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D000418:Albumins; D018685:Anesthetics, Inhalation; D001802:Blood Substitutes; C522784:HRC 101; D006454:Hemoglobins; D006895:Hydroxyethyl Starch Derivatives; D019344:Lactic Acid; D010100:Oxygen; D006221:Halothane