N(G)-monomethyl-L-arginine improves survival in a pig model of abdominal sepsis.
OBJECTIVE
To test the effect of a continuous infusion of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on survival rate and hemodynamics in a pig model of endogenous peritoneal live bacterial sepsis.


METHODS
Prospective, randomized trial.


METHODS
Laboratory at a university medical center.


METHODS
Thirty-five pigs with an average weight of 26 kg (range 21 to 33).


METHODS
After surgical preparation, animals (control, n=6) given anesthesia and fluids were observed for 9 hrs. Fifteen experimental animals received 0.5 g of cecal content/kg of body weight intraperitoneally after surgery. Nine of these animals received standard anesthesia and fluids and were observed for 9 hrs or until death. Six animals received a continuous infusion of L-NMMA (10 mg/kg/hr) 3 hrs after sepsis induction. Starting 3 hrs after surgery, five nonrandomized animals were given anesthesia and fluids and received a 6-hr continuous infusion of L-NMMA (10 mg/kg/hr). An additional nine animals were anesthetized and blood samples were taken to determine plasma nitrate concentrations in nonoperated pigs.


RESULTS
L-NMMA treatment increased 9-hr survival in septic animals from 11% to 83% (p < .001), prevented a further decrease in mean arterial pressure and restored mean arterial pressure to control levels (p < .00002 vs. nontreated septic animals). Mean pulmonary arterial pressure increased slightly during L-NMMA infusion (p < .0003). Coronary blood flow was preserved during L-NMMA treatment. Cardiac index and urine production reached and maintained control levels during L-NMMA treatment of septic animals. Mean central venous pH did not deteriorate during L-NMMA treatment. Animals treated with L-NMMA had plasma nitrate concentrations similar to nonseptic control animals. The results from the nonseptic control group receiving L-NMMA suggest that a substantial part of the effect of L-NMMA in this model of septic shock may be due to inhibition of the constitutive nitric oxide production.


CONCLUSIONS
In this porcine model of peritoneal sepsis, infusion of L-NMMA increased survival rate and maintained mean arterial pressure without worsening tissue oxygenation. Coronary blood flow, cardiac index, systemic vascular resistance, and urine production were well maintained during L-NMMA treatment.
Strand
O A
OA
Department of Infectious Diseases, Institute for Experimental Medical Research, Ullevål University Hospital, Oslo, Norway.
Leone
A M
AM
Giercksky
K E
KE
Skovlund
E
E
Kirkebøen
K A
KA
D000818:Animals; D016470:Bacteremia / Q000188:drug therapy* / Q000503:physiopathology; D003422:Critical Care; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006439:Hemodynamics / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010538:Peritonitis / Q000188:drug therapy* / Q000503:physiopathology; D011446:Prospective Studies; D011897:Random Allocation; D013552:Swine; D019323:omega-N-Methylarginine / Q000008:administration & dosage*
D004791:Enzyme Inhibitors; D009566:Nitrates; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase