Late immunoneutralization of procalcitonin arrests the progression of lethal porcine sepsis.
BACKGROUND
Procalcitonin (ProCT) is becoming increasingly recognized as a mediator as well as a marker of sepsis. Serum ProCT concentrations rise soon after induction of sepsis and remain elevated over a prolonged period of time. In contrast, many pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), rise and decline early in the course of sepsis. Researchers have improved survival in animal models of sepsis by prophylactically blocking IL-1beta and TNF-alpha with immunotherapy, but therapeutic treatment has been less successful in clinical trials. We hypothesized that the sustained elevation of ProCT in the serum would allow for effective therapeutic immunoneutralization of this peptide late in the course of sepsis.


METHODS
Lethal polymicrobial sepsis was induced in 10 castrated, male Yorkshire pigs by intraabdominal spillage of cecal contents (1 gm/kg) and intraabdominal instillation of 2 x 10(11) cfu of a toxigenic strain of E. coli (O18:K1:H7). The treated group (n = 5) received an intravenous infusion of purified rabbit antiserum to the aminoterminus of porcine ProCT. The control group (n = 5) received nonreactive, purified rabbit IgG. The purified antiserum was infused to all animals 3 h after the induction of sepsis, at which time very severe physiologic dysfunction was manifest, and many of the animals appeared to be preterminal. Physiologic and metabolic parameters were measured until death or for 15 h after induction of sepsis, at which time all surviving animals were euthanized.


RESULTS
Therapeutic immunoneutralization of serum ProCT improved most measured physiologic and metabolic parameters in septic pigs. Specifically, there was a significant increase in mean arterial pressure, urine output and cardiac index in all animals treated with ProCT antibody. Serum creatinine was significantly lower in treated animals. Although acidosis was not as severe in treated animals, as indicated by higher pH values and lower lactate concentrations, these results did not achieve statistical significance. Significantly, 11 h after the induction of sepsis there was 100% mortality in the control group while only one animal in the treated group expired.


CONCLUSIONS
The prolonged elevation of ProCT concentrations in sepsis allows neutralization of this peptide to be effective during the course of this disorder. These findings suggest that immunoneutralization of ProCT may be a useful treatment in clinical situations where sepsis is already fully established.
Martinez
J M
JM
Department of Surgery, George Washington University, Washington, DC, USA. jcwhite1@erols.com
Wagner
K E
KE
Snider
R H
RH
Nylen
E S
ES
Muller
B
B
Sarani
B
B
Becker
K L
KL
White
J C
JC
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002116:Calcitonin / Q000097:blood / Q000276:immunology*; D002432:Cecum; D004927:Escherichia coli Infections; D006023:Glycoproteins / Q000097:blood / Q000276:immunology*; D006439:Hemodynamics / Q000187:drug effects / Q000276:immunology; D007116:Immunization, Passive / Q000379:methods*; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D008297:Male; D023421:Models, Animal; D010538:Peritonitis; D011498:Protein Precursors / Q000097:blood / Q000276:immunology*; D011817:Rabbits; D013552:Swine; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology* / Q000628:therapy*; D013997:Time Factors
D015415:Biomarkers; D006023:Glycoproteins; D018836:Inflammation Mediators; D011498:Protein Precursors; D002116:Calcitonin