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CRITICAL CARE AND TRAUMA

Nitric Oxide Synthase Inhibition in Sepsis? Lessons Learned from Large-Animal Studies

Balázs Hauser, MD^*, Hendrik Bracht, MD^*, Martin Matejovic, MD, PhD, Peter Radermacher, MD^*, and Balasubramanian Venkatesh, MBBS, MD, FRCA, FFARCSI, FJFICM, MD

*Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum Ulm, Germany; Aneszteziológiai és Intenzív Terápiás Klinika, Semmelweis Egyetem, Budapest, Hungary; IPS, I. Interní Kliniky, Karlova Universita, Plzen, Czech Republic; and Princess Alexandra & Wesley Hospitals, University of Queensland, Brisbane, Australia

Address correspondence and reprint requests to Peter Radermacher, MD, Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Parkstrasse 11, D-89073 Ulm, Germany. Address e-mail to peter.radermacher{at}medizin.uni-ulm.de.

Nitric Oxide (NO) plays a controversial role in the pathophysiology of sepsis and septic shock. Its vasodilatory effects are well known, but it also has pro- and antiinflammatory properties, assumes crucial importance in antimicrobial host defense, may act as an oxidant as well as an antioxidant, and is said to be a "vital poison" for the immune and inflammatory network. Large amounts of NO and peroxynitrite are responsible for hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis, and ultimately multiorgan failure. Therefore, NO synthase (NOS) inhibitors were developed to reverse the deleterious effects of NO. Studies using these compounds have not met with uniform success however, and a trial using the nonselective NOS inhibitor N^G-methyl-l-arginine hydrochloride was terminated prematurely because of increased mortality in the treatment arm despite improved shock resolution. Thus, the issue of NOS inhibition in sepsis remains a matter of debate. Several publications have emphasized the differences concerning clinical applicability of data obtained from unresuscitated, hypodynamic rodent models using a pretreatment approach versus resuscitated, hyperdynamic models in high-order species using posttreatment approaches. Therefore, the present review focuses on clinically relevant large-animal studies of endotoxin or living bacteria-induced, hyperdynamic models of sepsis that integrate standard day-to-day care resuscitative measures.

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