Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock.
OBJECTIVE
To investigate the physiologic effects of nitric oxide synthase inhibition with N-nitro-L-arginine methyl ester in an acute resuscitated model of porcine septic shock.


METHODS
Randomized control trial.


METHODS
Animal research facility.


METHODS
Domestic Yorkshire swine.


METHODS
Twenty-four animals were randomly divided into one of four treatment groups as follows: normal saline resuscitation (NSR) (control group); NSR plus 200 micrograms/kg of lipopolysaccharide (LPS) at 1 hour after baseline (LPS group); NSR, LPS, and a continuous infusion of 50 micrograms/kg per minute of N-nitro-L-arginine methyl ester (NAME) at 1 hour after baseline (LPS/NAME group); and NSR and NAME (NAME group). All animals received NSR at 1 mL/kg per minute starting at baseline.


METHODS
Mean arterial pressure (MAP), systemic vascular resistance index (SVRI), mean pulmonary arterial pressure (MPAP), and pulmonary vascular resistance index (PVRI) were measured at baseline and hourly for 4 hours. Values at baseline and 3 hours are given below as mean (+/- SE).


RESULTS
All variables remained unchanged in the control group. The administration of LPS produced a systemic hyperdynamic response characterized by a decrease in MAP and SVRI from 66.0 +/- 3.9 to 55.0 +/- 2.8 mm Hg (P < .05) and from 422.0 +/- 22.0 to 272.0 +/- 29.0 mm Hg.min.kg/L (P < .05), respectively. The administration of LPS produced an increase in MPAP and PVRI from 16.3 +/- 0.8 to 30.0 +/- 1.3 mm Hg (P < .05) and from 37.0 +/- 5.3 to 119.0 +/- 13.0 mm Hg.min.kg/L (P < .05), respectively. In the LPS/NAME group, NAME infusion normalized MAP and increased SVRI from 506.0 +/- 40.0 to 642.0 +/- 72.0 mm Hg.min.kg/L (P < .05). Infusion of NAME potentiated LPS-induced pulmonary hypertension, increasing MPAP and PVRI from 16.8 +/- 0.6 to 36.0 +/- 2.8 mm Hg (P < .05) and from 59.0 +/- 3.5 to 319.0 +/- 64.0 mm Hg.min.kg/L (P < .05), respectively. Infusion of NAME alone increased MAP from 74.0 +/- 1.3 to 100.0 +/- 4.1 mm Hg (P < .05) and had no significant effect on MPAP and PVRI.


CONCLUSIONS
The potentiation of LPS-induced pulmonary hypertension following NAME infusion suggests that inhibition of nitric oxide synthase may have a limited role in the treatment of septic shock.
Robertson
F M
FM
Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, Tex.
Offner
P J
PJ
Ciceri
D P
DP
Becker
W K
WK
Pruitt
B A
BA
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002496:Central Venous Pressure / Q000187:drug effects; D004926:Escherichia coli; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase; D010101:Oxygen Consumption / Q000187:drug effects; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D012151:Resuscitation; D012772:Shock, Septic / Q000503:physiopathology*; D012965:Sodium Chloride; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D012965:Sodium Chloride; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester