The potential role of micronutrients in sepsis has created much recent interest and may offer novel therapies. Oxidant stress and inflammation are important components of sepsis pathobiology. Several micronutrients, notably zinc and selenium, are known to have antioxidant and anti-inflammatory properties and are, therefore, plausible candidates for adjunctive therapies in sepsis.
Selenium plays a major role in the intra-cellular antioxidant system as a structural component of the selenoprotein enzymes, including glutathione peroxidase. These enzymes catalyze the reduction of hydroperoxidases to less toxic products, thereby protecting cells against oxidative stress. Selenium can also modulate the inflammatory cascade by inhibiting pro-inflammatory gene expression.
Selenium plasma concentrations are significantly lower in critically ill patients compared with age-matched healthy control subjects. Current evidence suggests that selenium concentrations are lowest in patients with sepsis and that low plasma selenium concentrations correlate with poor outcomes and organ failure (Alhazzani et al. Crit Care Med. 2013;41:1555). Whether these associations represent pathological responses or epiphenomena is not entirely known. Nonetheless, because selenium is critical for the selenoprotein enzymes that function in antioxidant defense, it is biologically plausible that selenium supplementation may improve the outcomes of patients with sepsis.
A recent clinical trial (Heyland et al. N Engl J Med. 2013;368:1489) showed that early administration of glutamine and/or a combination of antioxidants (selenium, zinc, beta-carotene, vitamin C, and vitamin E) did not improve mortality in critically ill adults with multiorgan failure. Glutamine administration was actually associated with increased mortality in this study.
This trial offers strong evidence that selenium administration, in combination with other antioxidants, does not improve clinical outcomes in critically ill patients, although it is difficult to assign effect to any one micronutrient, as selenium was administered in combination with other agents. Furthermore, this study enrolled patients with heterogeneous forms of critical illness, thereby making it difficult to isolate any beneficial effect in more specific conditions, such as sepsis.
A recent meta-analysis by (Alhazzani and colleagues et al. (Crit Care Med. 2013;41:1555) examined the effect of isolated selenium supplementation on mortality in critically ill patients with sepsis. They reported a trend toward reduced mortality (odds ratio for mortality = 0.73, P =.03) in patients receiving selenium at higher than the daily recommended dose. Selenium supplementation had no effect on secondary outcomes, including a reduction of nosocomial pneumonia or length of stay. The quality of this evidence was graded as "low" based on the high risk of bias and imprecision, but the authors encouraged further well-designed trials addressing the efficacy of selenium supplementation in sepsis.
A trial of IV selenium supplementation in sepsis was recently completed by the German Sepsis Network with an estimated total enrollment of 1,180 subjects (clinicaltrials.gov: NCT00832039). The primary outcome of this study was all-cause mortality at 28 days. This study, when published, may provide more conclusive evidence to support or oppose selenium supplementation in sepsis.
Zinc supplementation may also have a therapeutic role in sepsis. Zinc is involved in both innate and adaptive immune function. Notably, zinc-deficient states produce lymphopenia, impaired natural killer and phagocytic cell function, and impaired cytokine production. Zinc directly regulates signal transduction mechanisms involved in immunity and inflammation. Zinc also serves important roles in oxidative stress responses, neurocognitive function, growth, and development.
Metallothioneins are metal-binding proteins involved in zinc homeostasis. They serve roles in the scavenging of free radicals, detoxification of heavy metals, and participate in the inflammatory response to stress. It has been estimated that approximately 10% of the human proteome potentially interacts with zinc (Andreini et al. J Proteome Res. 2006;5:196).
Transcriptomic studies demonstrated that within 1 day of admission for septic shock, children’s genomes demonstrate decreased expression of a large number of genes involved in zinc homeostasis (Wong et al. Physiol Genomics. 2007;30:146). When comparing pediatric survivors with nonsurvivors of septic shock, nonsurvivors had significantly lower serum zinc concentrations. Furthermore, metallothionein expression was increased in the nonsurvivors, suggesting a functional consequence of altered zinc homeostasis.
The role of metallothionein expression and zinc homeostasis was further investigated in a study involving a heterogeneous cohort of critically ill children (Cvijanovich et al. Pediatr Crit Care Med. 2009:10:29). All patients in this study had low serum zinc concentrations on days 1 and 3 of illness. Furthermore, on day 1 of illness, there was a positive correlation between zinc levels and metallothionein protein expression.