Inhibition of intraluminal pancreatic enzymes with nafamostat mesilate improves clinical outcomes after hemorrhagic shock in swine.
BACKGROUND
Recent studies suggest that intraluminal pancreatic enzymes play a major role in the initiation of the inflammatory cascade by the gut after hemorrhagic shock. Previous animal models have shown that the inhibition of enteral pancreatic enzymes with a serine protease inhibitor, nafamostat mesilate (NM), decreases leukocyte activation and transfusion requirements after hemorrhagic shock. The objective of this study was to determine whether enteroclysis with NM would improve the clinical outcomes in swine after hemorrhagic shock and intestinal hypoperfusion.


METHODS
Thirty-three male Yucatan minipigs weighing 25 kg to 30 kg underwent a controlled hemorrhage of 25 mL/kg with mesenteric clamp for further gut ischemia. Animals were allocated to three groups: (1) shock only (n = 15), (2) shock + enteroclysis with 100 mL/kg GoLYTELY (GL) as a carrier (n = 11), and (3) shock + enteroclysis with GL + 0.37 mmol/L NM (GL+NM, n = 7). Animals were resuscitated, recovered from anesthesia, observed for 3 days, and graded on a daily 4-point clinical scoring system. A score of 0 indicated a moribund state or early death, and a score of 4 indicated normal behavior.


RESULTS
Pigs treated with GL + NM had significantly higher mean postoperative recovery scores (3.8 +/- 0.4, essentially normal behavior with no early deaths) compared with animals within the shock only and shock + GL groups (2.1 +/- 1 with one early death and 2.2 +/- 1.2 with two early deaths, respectively, analysis of variance p < 0.003).


CONCLUSIONS
The inhibition of intraluminal pancreatic enzymes using enteroclysis with the serine protease inhibitor, NM, after hemorrhagic shock significantly improves the clinical outcome.
Kim
Hubert D
HD
Department of Surgery, University of California, Irvine Medical Center, Orange, California 92868, USA.
Malinoski
Darren J
DJ
Borazjani
Boris
B
Patel
Madhukar S
MS
Chen
Joseph
J
Slone
Johnathan
J
Nguyen
Xuan-Mai T
XM
Steward
Earl
E
Schmid-Schonbein
Geert W
GW
Hoyt
David B
DB
D000704:Analysis of Variance; D000818:Animals; D001550:Benzamidines; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004385:Duodenostomy; D004573:Electrolytes / Q000627:therapeutic use; D004750:Enteral Nutrition; D006146:Guanidines / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012151:Resuscitation / Q000379:methods; D015842:Serine Proteinase Inhibitors / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D012771:Shock, Hemorrhagic / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000401:mortality; D013552:Swine; D013556:Swine, Miniature; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000517:prevention & control; D016896:Treatment Outcome
D001550:Benzamidines; D004573:Electrolytes; C033608:Golytely; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D011092:Polyethylene Glycols; C032855:nafamostat