Reply

Reply: We thank Drs Loukili and Liaudet for their interest in our article "A large-bolus injection, but not a continuous infusion of sodium selenite improves outcome in peritonitis" (1) and for providing some further insight into the underlying molecular mechanisms that may account for the beneficial anti-inflammatory effects of the selenocompound, selenite, that were demonstrated in our study. Clinical studies using selenocompounds in critically ill patients have generally not taken into consideration the possibility of a pro-oxidative action of the selenocompound, especially when administered as a bolus. The effects of a large dose of selenite, especially as a bolus administration, should be separated from the effects of a moderate (below the low adverse effect level) dose of selenite, which may have a nutritionally beneficial effect based on the induction of anti-oxidant selenoenzymes by selenium (2). Failure to do this may explain, in part, why the results of different studies have been inconsistent, notably the discrepant results of two recent large, multicenter randomized clinical trials (3, 4). We therefore wanted to test the hypothesis that a controlled use of the pro-oxidant effects of sodium selenite could be beneficial in this setting. One of the many observations that may support a seemingly paradoxical therapeutic use of a pro-oxidative dose of selenite in septic shock is the in vitro observation that selenite, at a concentration greater than 5 μmol/L (comparable with those achieved in our study), inhibits the DNA-binding activity of transcription factors, like nuclear factor κB and activator protein 1, by direct modification of essential thiol groups (5, 6). Moreover, in a preliminary study using a rat LPS model, Dr Forceville et al. (7) observed that an intraperitoneal injection of a large dose of selenite improved survival. Indeed, we found that a bolus administration of sodium selenite was associated with amelioration of microcirculatory perfusion and cardiac function, lower plasma IL-6 levels, and improved survival in our ovine experimental model of sepsis. Importantly, these beneficial effects were not the result of the anti-oxidant effects of selenium-containing selenoproteins because they were not observed in animals that received a continuous infusion of a similar dose of sodium selenite. Our study was not designed to explore the mechanisms involved in the observed effects of selenite. It would, for example, have been interesting to have determined the difference between modulation of redox potential involving paired electrons with high energy and modulation of free radicals involving one electron with high energy (5). However, this may have made the message more complex. The modification of redox potential conduct to interact with many pathophysiological cascades, including nuclear factor κB, especially in circulating cells should certainly be studied further. In addition to the possible mechanism on IKK mentioned by Drs Loukili and Liaudet, another potential mechanism is the ADMA/DDAH system, an important intracellular regulator of NOS activity (8). Inhibition of DDAH enzyme activity may be of therapeutic significance in the treatment of septic shock because excessive iNOS activity and NO overproduction play a central role in sepsis-induced vasodilatation and microcirculatory dysfunction. Intriguingly, oxidant compounds have been observed to abrogate DDAH activity because a crucial cysteine residue held in its active center is susceptible to oxidation (8). A study is under way to investigate whether DDAH inhibition plays a part in the observed beneficial effects elicited by the pro-oxidant doses and blood concentrations of sodium selenite in our recent study. Unraveling the complex effects of oxidative stress in sepsis and inflammation and assessing the potential effects of pro-oxidant and anti-oxidant agents will clearly be an exciting field of research for some years to come. Zhen WangM Réanimation Polyvalente CH Meaux Hôpital Saint Faron France Jean-Louis Vincent Erasme Hospital Université Libre de Bruxelles Belgium