Early immunoneutralization of calcitonin precursors attenuates the adverse physiologic response to sepsis in pigs.
OBJECTIVE
The 116 amino acid prohormone procalcitonin and some of its component peptides (collectively termed calcitonin precursors) are important markers and mediators of sepsis. In this study, we sought to evaluate the effect of immunoneutralization of calcitonin precursors on metabolic and physiologic variables of sepsis in a porcine model.


METHODS
A prospective, controlled animal study.


METHODS
A university research laboratory.


METHODS
30-kg Yorkshire pigs.


METHODS
Sepsis was induced in 15 pigs by intraperitoneal instillation of a suspension of cecal content (1 g/kg animal body weight) and a toxinogenic Escherichia coli solution (2 x 10(11) colony-forming units). During induction of sepsis, seven pigs received an intravenous infusion of purified rabbit antiserum, reactive to the aminoterminal portion of porcine prohormone procalcitonin. Another eight control pigs received an intravenous infusion of purified nonreactive rabbit antiserum. For all 15 animals, physiologic data (urine output, core temperature, arterial pressure, heart rate, cardiac index, and stroke volume index) and metabolic data (serum blood urea nitrogen and creatinine, arterial lactate, and pH) were collected or recorded hourly until death at 15 hrs.


RESULTS
In this large-animal model of rapidly lethal peritonitis, serum calcitonin precursors were significantly elevated. Amino-prohormone procalcitonin-reactive antiserum administration resulted in a significant improvement or a beneficial trend in a majority of the measured physiologic and metabolic derangements induced by sepsis. Specifically, arterial pressure, cardiac index, stroke volume index, pH, and creatinine were all significantly improved, while urine output and serum lactate had beneficial trends. Treated animals also experienced a statistically significant increase of short-term survival.


CONCLUSIONS
These data from a large-animal model with polymicrobial sepsis demonstrate the salutary effect of early immunoneutralization of calcitonin precursors on physiologic and metabolic variables. Immunologic blockade of calcitonin precursors may offer a novel therapeutic approach to human sepsis.
Wagner
Kristin E
KE
Department of Surgery, George Washington University and Veterans Affairs Medical Center, Washington, DC, USA.
Martinez
Jose M
JM
Vath
Steven D
SD
Snider
Richard H
RH
Nylén
Eric S
ES
Becker
Kenneth L
KL
Müller
Beat
B
White
Jon C
JC
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D002116:Calcitonin / Q000097:blood / Q000276:immunology* / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide; D002302:Cardiac Output; D004927:Escherichia coli Infections / Q000097:blood / Q000276:immunology / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D007106:Immune Sera / Q000008:administration & dosage*; D007668:Kidney / Q000503:physiopathology; D019344:Lactic Acid / Q000097:blood; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood / Q000276:immunology* / Q000502:physiology; D011817:Rabbits; D018805:Sepsis / Q000097:blood / Q000276:immunology / Q000401:mortality / Q000503:physiopathology*; D013552:Swine
D000906:Antibodies; C000606589:CALCA protein, human; D007106:Immune Sera; D011498:Protein Precursors; D019344:Lactic Acid; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide