Norepinephrine increases blood pressure but not survival with anthrax lethal toxin in rats.
OBJECTIVE
The response of anthrax lethal toxin (LeTx) induced shock and lethality to conventional therapies has received little study. Previously, fluids worsened outcome in LeTx-challenged rats in contrast to its benefit with lipopolysaccharide (LPS) or Escherichia coli. The current study investigated norepinephrine treatment.


RESULTS
Sprague-Dawley rats (n = 232) weighing between 230 and 250 g were challenged with similar lethal (80%) 24-hour infusions of either LPS or LeTx, or with diluent only. Toxin-challenged animals were also randomized to receive 24-hour infusions with one of three doses of norepinephrine (0.03, 0.3, or 3.0 microg/kg/min) or placebo started 1 hour after initiation of challenge. All toxin animals received similar volumes of fluid over the 24 hours (equivalent to 4.0-4.3 mL/kg/hr). Although the intermediate norepinephrine dose (0.3 microg/kg/min for 24 hours) improved survival with LPS (p = 0.04) and increased blood pressure before the onset of lethality with LeTx (p < 0.0001), it did not improve survival with the latter (p = ns). Furthermore, neither increasing nor decreasing norepinephrine doses improved survival with LeTx.


CONCLUSIONS
Hypotension with LeTx may not be a primary cause of lethality in this model. Rather, LeTx may cause direct cellular injury insensitive to vasopressors. These findings suggest that during anthrax infection and shock, along with hemodynamic support, toxin-directed treatments may be necessary as well.
Li
Yan
Y
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Cui
Xizhong
X
Su
Junwu
J
Haley
Michael
M
Macarthur
Heather
H
Sherer
Kevin
K
Moayeri
Mahtab
M
Leppla
Stephen H
SH
Fitz
Yvonne
Y
Eichacker
Peter Q
PQ
D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000401:mortality*; D000942:Antigens, Bacterial / Q000008:administration & dosage; D001427:Bacterial Toxins / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects*; D009638:Norepinephrine / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy*; D015996:Survival Rate; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D014662:Vasoconstrictor Agents; C030325:anthrax toxin; D009638:Norepinephrine