in the present issue of critical care , hein and colleagues report that administration of n - acetylcysteine ( nac ) , a precursor in glutathione synthesis , increased liver perfusion , decreased hepatic lactate production and thus improved liver function in patients with septic shock . the authors suggest that nac therapy may be beneficial in selected septic patients secondary to peritonitis but not following pneumonia . this study also introduces the use of proton magnetic resonance imaging and spectroscopy , which may provide clinicians with a noninvasive and reliable assessment of liver perfusion and liver function . these findings may have important implications for the management of patients with septic shock septic shock is characterized by a hyperdynamic state with high cardiac output and low peripheral vascular resistance associated with impaired uptake of oxygen . dysoxia has been demonstrated in septic shock , as reflected by an increase in regional and systemic lactate production and a high concentration of gastric carbon dioxide . during septic shock oxygenated blood can be directly bypassed from arterial vasculatures to venous ends through a ' shunt ' that results from a loss of vascular tone and thus capillary collapse . this underlying mechanism results in impaired tissue oxygen extraction capabilities that lead to cellular dysoxia [ 3 - 6 ] . the hepatosplanchnic region is particularly susceptible to this microcirculatory failure , and the gut has been considered the ' motor ' of septic shock . septic shock is also associated with excessive inflammatory responses including enhanced inflammatory cytokine production   and the release of oxygen free radicals . the relevance of the inflammatory responses to clinical outcome is evident from several studies demonstrating that concentrations of inflammatory mediators such as tumor necrosis factor alpha ( tnf- ) , il-6 and lipid peroxidation   in plasma were higher on admission to hospital and remained elevated in septic patients who subsequently died compared with survivors . fluid resuscitation and the use of vasoconstricting agents can improve hemodynamics and therefore oxygen delivery , but may not necessarily enhance , or in certain circumstances may even further reduce , regional blood flow and oxygen extraction . a variety of immunological inflammatory mechanisms , triggered in septic patients , can contribute to microcirculatory dysfunction , including alterations in coagulation , mitochondrial dysfunction , generation of oxygen free radicals and synthesis of interleukins . a number of studies have investigated the effects of vasodilators that combine with anti - inflammatory properties in septic conditions to test the hypothesis that such therapies would be able to improve microcirculation and thus oxygen extraction , while at the same time attenuating inflammatory responses . prostacyclin , a prostaglandin synthesized in endothelial cells , is a potent vasodilator and an inhibitor of platelet and leukocyte activation . in septic pigs , pretreatment with iloprost , an analog of prostacyclin , increased the cardiac output , increased splanchnic blood flow and increased gastric ph . in patients with sepsis , prostacyclin increased both oxygen delivery and oxygen consumption , probably via recruitment of shunted microcirculatory units that lead to improve tissue metabolism and function . however , induced hypotension and reduced renal perfusion during prostacyclin infusion may limit prostacyclin 's clinical application . pentoxifylline , a derivate of methylxanthine , inhibits the phosphodiesterase activity , thereby enhancing the intracellular content of camp that exerts both vasodilation and anti - inflammatory effects . pentoxifylline has been reported to inhibit platelet and leukocyte activation and lactate production , and to improve hemodynamics in a variety of animal and human sepsis . through inhibition of phosphodiesterase activity , pentoxifylline decreased production of tnf- and il-6 and reduced the mortality rate in premature infants with sepsis . several studies have demonstrated that nac improves the left ventricular stroke work index through three mechanisms : a decrease in afterload by nitric oxide synthesis ; an increase in cardiomyocyte contractility ; and an attenuation of cardiac depressing factors such as tnf-. moreover , nac inhibits platelet aggregation and decreases the synthesis of il-8 , an important chemokine for leukocyte infiltration . these anti - inflammatory effects of nac are probably related to its oxygen free radical scavenging properties . nac is one of the most extensively studied antioxidant agents in sepsis research . in a dog model of fluid - resuscitated endotoxic shock , zhang and colleagues demonstrated that the administration of nac improved whole body oxygen extraction capabilities associated with an enhanced regional blood flow in mesenteric , renal and femoral vasculatures . in a similar septic shock model , nac attenuates tnf- production and , spies and colleagues previously demonstrated that nac treatment improved hepatosplanchnic blood flow associated with an enhanced cardiac index . in the present study , the same group of investigators reports that nac therapy increases liver blood flow and hepatic function assessed by a technique of gadolinium - enhanced magnetic resonance imaging . using the proton magnetic resonance spectroscopy system , these investigators showed that nac infusion was able to decrease the liver lactate signal intensity by as much as 89% . it is intriguing that these beneficial effects of nac were seen in patients with septic shock that resulted from peritonitis but not from pneumonia . the protective effect of nac in septic shock demonstrated by hein and colleagues   is in agreement with those reported by others . spapen and colleagues showed that a short - term infusion of nac decreased il-8 production and shortened the intensive care unit stay in septic patients who survived . paterson and colleagues have recently , demonstrated that the administration of nac decreased nuclear factor-b activation associated with decreases in il-8 in septic patients . in a previous multicenter clinical trial in patients with acute respiratory distress syndrome , bernard and the number of days of acute lung injury was decreased , however , and there was also a significant increase in the cardiac index in the nac - treated group . this is an exciting time for intensivists involved in the care of patients with sepsis , particularly after the positive trial showing that activated protein c can improve survival in patients with septic shock . although the sample size was small in the extended case report , hein and colleagues have made a significant contribution to our understanding of the important role of antioxidant agents such as nac in developing novel therapies for septic shock . a large trial is needed to confirm the present report , where the selection of the target patient population is crucial for a successful management of septic patients . il = interleukin ; nac = n - acetylcysteine ; tnf- = tumor necrosis factor alpha .
excessive inflammatory responses and impaired oxygen utilization because of microcirculatory failure are implicated in septic shock . 
 recent studies have pointed out some beneficial effects in the treatment of septic shock of several vasodilators that exert anti - inflammatory properties . in particular , the antioxidant n - acetylcysteine has been demonstrated to enhance cardiac performance , and to improve hepatosplanchnic perfusion and liver function in patients with established septic shock . 
 these clinical observations may lead us to examine further the role of antioxidant agents in developing novel therapies for septic shock .