Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock

Objective: To test the effect of a continuous infusion of the nitric oxide (NO) synthase (S) inhibitor aminoethyl-isothiourea (AE-ITU) on survival tim e, hemodynamics, and oxygen transport in a porcine model of live group A st reptococcal (GAS) sepsis. Furthermore, to examine the role of endothelin-l, histamine, and reactive oxygen species (ROS) in streptococcal shock. Design: Prospective, randomized trial. Setting: Laboratory at a university hospital. Subjects Twenty-eight pigs with an average weight of 25 kg. Interventions: Sixteen animals received a continuous infusion of live Strep tococcus pyogenes 1.3 x 10(10) colony forming units/hr: eight received flui ds only, and the other eight received an intravenous infusion of AE-ITU 10 mg/kg/hr starting 30 mins before the GAS challenge. Six control pigs receiv ed AE-ITU 10 mg/kg/hr iv for 5 hrs. Another six animals received half the d ose of GAS over 5 hrs. Measurements and Main Results:GAS infusion caused a rapid increase in pulmo nary, hepatic, and systemic vascular resistance, followed by hypotension wi th a 90% lethality at 4 hrs. Treatment with AE-ITU increased 4-hr survival in septic animals from 1/8 to 8/8 and 5-hr survival from 0/8 to 5/8, preven ted hypotension, and increased urine output. AE-ITU attenuated the decrease in cardiac output, liver blood flow, and oxygen delivery, and hepatic arte rial blood flow as a fraction of cardiac output increased (all p < .05). Pl asma nitrate/nitrite levels decreased in all animals. Inducible NOS and end othelial constitutive NOS activities in liver, gut, and lung were not incre ased during sepsis, nor were they decreased after AE-ITU. Plasma levels of endothelin-l and methylhistamine increased in all septic animals and were n ot modified by AE-ITU. AE-ITU prevented the increase in monocyte ROS produc tion caused by GAS. In control animals, AE-ITU caused an increase in mean a rterial pressure, liver blood flow, and oxygen delivery. Conclusions:ln this model of porcine GAS-induced septic shock, which was no t associated with enhanced NO production, infusion of the NOS inhibitor AE- ITU prolonged survival, prevented hypotension, and improved cardiac contrac tility, organ perfusion, and tissue oxygenation. These beneficial effects o f AE-ITO might be a result of the combined effect of ROS scavenging and mod ulation of local NO production, thus improving the balance of vasodilator a nd vasoconstrictor forces and reducing oxidative stress. (Crit Care Med 200 0; 28:2697-2706).