Protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines.
BACKGROUND
Anthrax-associated shock is closely linked to lethal toxin (LT) release and is highly lethal despite conventional hemodynamic support. We investigated whether protective antigen-directed monoclonal antibody (PA-mAb) treatment further augments titrated hemodynamic support.


RESULTS
Forty sedated, mechanically ventilated, instrumented canines challenged with anthrax LT were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinephrine), PA-mAb alone (administered at start of LT infusion [0 hours] or 9 or 12 hours later), or both, and observed for 96 hours. Although all 8 controls died, 2 of 8 animals receiving hemodynamic support alone survived (median survival times 65 vs 85 hours, respectively; P = .03). PA-mAb alone at 0 hour improved survival (5 of 5 animals survived), but efficacy decreased progressively with delayed treatment (9 hours, 2 of 3 survived; 12 hours, 0 of 4 survived) (P = .004 comparing survival across treatment times). However, combined treatment increased survival irrespective of PA-mAb administration time (0 hours, 4 of 5 animals; 9 hours, 3 of 3 animals; and 12 hours, 4 of 5 animals survived) (P = .95 comparing treatment times). Compared to hemodynamic support alone, when combined over PA-mAb treatment times (0, 9, and 12 hours), combination therapy produced higher survival (P = .008), central venous pressures, and left ventricular ejection fractions, and lower heart rates, norepinephrine requirements and fluid retention (P ≤ .03).


CONCLUSIONS
PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock.
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. peichacker@mail.cc.nih.gov
Amisha V
AV
Barochia
Xizhong
X
Cui
Junfeng
J
Sun
Yan
Y
Li
Steven B
SB
Solomon
Thi-Sau
TS
Migone
G Mani
GM
Subramanian
Sally D
SD
Bolmer
Peter Q
PQ
Eichacker
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D000907:Antibodies, Bacterial / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D001794:Blood Pressure; D004285:Dogs; D005440:Fluid Therapy; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects*; D009638:Norepinephrine / Q000627:therapeutic use; D012769:Shock / Q000382:microbiology / Q000401:mortality / Q000628:therapy*; D013318:Stroke Volume; D013997:Time Factors
D000316:Adrenergic alpha-Agonists; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D009638:Norepinephrine