Is Selenium Monotherapy the Cornerstone of this Strategy?
This article explores the evolving paradigm of pharmaconutrition using antioxidant micronutrients, looking at the available evidence for antioxidant supplementation in the critically ill. In particular it discusses the protective mechanisms of action of selenite in critically ill SIRS patients and how selenium supplementation as a pharmaconutrient can be best applied.
Why are Antioxidants Required in the Critically Ill?
Critical illness is characterised by a significant redix
imbalance, which leads to mitochondrial dysfunction, systemic inflammatory
response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS).
Although in the last few years there have been important developments in
supportive techniques for use in intensive care units (ICUs) around the world,
sepsis-related organ dysfunction remains the most common cause of death in the
ICU (Galley, 2012). Over the last two decades, many observational studies have
evaluated oxidative stress in the critically ill. Oxidative stress is defined
as a state in which the levels of toxic reactive oxygen species (ROS) and
reactive nitrogen oxide species (RNOS) overcome the endogenous antioxidant
defenses of the host. In fact, during critical illness antioxidant capacity is
drastically decreased due to an excessive production of ROS and RNOS. ROS
activate the nuclear transcription factor kappa B (NF-κB), which is one of the steps
involved in amplifying SIRS (Manzanares and Hardy et al. 2012).
SIRS is associated with
redistribution of micronutrients (vitamins and trace elements) from the
circulating compartment to the interstitial compartment and different tissues,
especially those involved in protein synthesis and immune cell proliferation.
Trace elements escape to the interstitial compartment by capillary leakage,
which is a distinctive characteristic of SIRS (Manzanares et al. 2009).
Furthermore, low levels of trace elements may be explained by several other
causes, such as losses through biological fluids and haemodilution, previous
insufficient intake, low levels in enteral formulas and parenteral mixtures,
and continuous renal replacement therapies (CRRTs) (Hardy et al. 2012). In this
scenario, it is most likely that micronutrient status is always compromised
during critical illness, despite standard micronutrient dietary intake.
What Does the Most Up-to-Date Evidence Show About Antioxidant Supplementation in the Critically Ill?
In 2005, for the first time, a meta-analysis demonstrated that
antioxidants were associated with a significant reduction in ICU mortality
(risk ratio [RR], 0.65; 95% confidence interval [CI], 0.44–0.97; P=0.03)
(Heyland et al. 2005). The authors further demonstrated that daily doses of
selenium (higher than 500 μg) showed a tendency towards a
decrease in mortality (RR, 0.52; 95% CI, 0.24–1.14; P=0.10). Four years later,
the same Canadian group updated these results, showing that antioxidant
supplementation was still associated with a significant reduction
in mortality (RR, 0.76; 95% CI, 0.64, 0.91; P=0.002). Moreover, the specific
effects of parenteral selenium on mortality were similar (RR, 0.84; 95 % CI,
0.67, 1.05; P=0.13).
recently, an updated systematic review and metaanalysis, which aggregated 20
trials that had reported mortality as an outcome, concluded that combined
antioxidant supplementation was associated with a significant reduction in
mortality (RR, 0.82; 95% CI, 0.72–0.93; P=0.002) (Manzanares et al. 2012).
Supplementation with antioxidant micronutrients showed a significant reduction
in duration of mechanical ventilation (weighed mean difference, -0.67 days; 95%
CI, -1.22, - 0.13; P=0.02) and a trend towards a reduction in infections (RR,
0.88; 95% CI, 0.76, 1.02; P= 0.08). However, it was not possible to demonstrate
any significant overall effect on ICU or hospital length of stay (LOS). Of
practical interest is the fact that antioxidant micronutrients were associated
with a significant reduction in overall mortality among patients with higher
risk of death (>10% mortality in control group) (RR, 0.79; 95 % CI, 0.68, 0.92;
P=0.003). This finding supports the notion that patients with more severe
insults and higher mitochondrial dysfunction resulting from bioenergetic
failure experience the largest depletion of antioxidants (Manzanares et al. 2012). These patients may therefore exhibit a greater
clinical improvement with antioxidant supplementation than less sick patients.
When aggregated, selenium supplementation was
specifically associated with a trend towards a reduction in mortality (RR,
0.89; 95% CI, 0.77–1.03; P=0.12). The seven selenium trials demonstrated a
trend towards a reduction in infections (RR. 0.87; 95% CI, 0.74–1.02; P=0.08),
whereas three of the trials that didn’t use selenium demonstrated no effect on
infections (RR, 1.10; 95% CI, 0.60–2.04; P=0.75). Thus, parenteral selenium monotherapy,
administered as a loading dose followed by a continuous infusion, may be
strongly recommended to reduce mortality and infections in critically ill SIRS
patients (Hardy et al. 2012).
What do We Know About the Protective Mechanisms of Action of Selenite in Critically Ill SIRS Patients?
Although the optimal time to start antioxidant therapy has not yet been established, both experimental and clinical data support the concept that antioxidant micronutrients are more effective when initiated prior to injury or as early as possible after the insult. Selenium is an essential trace element with antioxidant, immunological, and anti-inflammatory properties. Selenium is essential for the activity of selenoenzymes such as selenoprotein P1, which may be protective against endothelial oxidant injury, and glutathione peroxidase, which belongs to the body's first line of antioxidant defense. Selenite is able to inhibit the activation of NF-kB by controlling selenoprotein gene expression and thus down-regulating the synthesis of proinflammatory cytokines.
An intravenous loading dose of
selenite given as bolus has a biphasic action, initially as a pro-oxidant and
then as an antioxidant (Vincent JL et al. 2009; Manzanares et al. 2009).
Furthermore, in a sheep model of severe sepsis, the bolus of sodium selenite
was able to improve haemodynamics, delaying arterial hypotension, and improving
cardiac index, with delayed hyperlactataemia, and fewer sepsis-induced
microvascular alterations (Wang et al. 2010). Various clinical trials have
successfully implemented the bolus plus continuous infusion protocol (Angstwurm
et al. 2007; Manzanares et al. 2011), showing improvement in relevant clinical
outcomes, especially mortality and infectious complications. Conversely,
continuous high-dose selenite infusion, without the initial bolus, has been
clinically ineffective (Forceville X et al. 2007).
What is the Current Concept of Pharmaconutrition?
The concept of pharmaconutritional supplementation in
supraphysiological doses is quite different from the classical nutritional concept
of nutrient replacement, which is designed to replenish losses and target
restoration of normal function (Berger M 2012). Pharmaconutrition considers pharmaconutrients
as drugs or nutraceuticals.
Selenium Supplementation as a Pharmaconutrient for the Critically Ill: When,How and How Much?
There is enough evidence in current literature to consider antioxidant cocktails and/or parenteral selenite supplementation as monotherapy in critically ill SIRS patients. The best antioxidant cocktail approach has not yet been determined. However, we know that initiating high-dose intravenous sodium selenite (1000–2000μg as a bolus over 30 minutes to two hours) immediately on admission to the ICU (within the first 24 hours), and thereafter as a continuous infusion at a daily dose between 500-1600 μg for up to 10 to 14 days, is a novel and successful strategy in the critically ill. This concept of pharmaconutrition, using selenium as monotherapy, is quite distinct from the routine incorporation of selenium (and other micronutrients) in standard parenteral or enteral nutrition. High-dose sodium selenite should be supplemented in the most seriously ill ICU patients, including those with severe sepsis and septic shock. High-risk cardiac surgery patients may also benefit in the near future, but more evidence from on-going clinical trials is awaited before recommendations can be made for this patient population.
What is the Future for Antioxidant Micronutrient Supplementation for Intensive Care?
The largest randomised controlled trial on antioxidants in
combination with high-dose glutamine supplementation has been the Reducing
Deaths due to OXidative Stress (REDOXS) Study, which is unpublished; but it
seems to have failed to demonstrate any improvement on clinical outcomes in
MODS patients. In this multicentre trial, more than 1,200 patients were
enrolled to receive intravenous glutamine in combination with enteral or
parenteral antioxidant cocktails, including vitamins C (1500 mg), E (500 mg), b-carotene (10 mg), zinc (20 mg), and selenium (300 μg). Although this strategy was safe, it was
unfortunately unable to demonstrate efficacy by improving relevant clinical outcomes,
including ICU and 90 day survival, in critically ill SIRS patients.
can we explain the unexpected REDOXS results regarding antioxidants
supplementation? Perhaps the absence of an intravenous bolus of selenite as a
loading dose inhibited stimulation of the protective effects of selenium as an anti-inflammatory
strategy for ICU patients with organ failure. This could be considered as a methodological
weakness. Furthermore, some patients received an insufficient daily dose of
intravenous selenium. In fact, according to the recent metaanalysis on
antioxidant micronutrients (Manzanares et al. 2012), a daily parenteral dose
greater than 500 μg is
necessary for better clinical outcomes. Although some patients in the REDOXS
protocol received 800 μg of
selenium, this was administered by either the enteral or the parenteral route,
and we do not know enough about the pharmacokinetic profile of enterally
administered selenium in SIRS patients. We suspect that enteral absorption in
septic shock patients is unpredictable and these doses may have been
Among the antioxidant micronutrient strategies, parenteral selenite should be the cornerstone of a pharmaconutrition approach for the critically ill. We believe, there is sufficient evidence to consider initiating high dose intravenous selenium therapy routinely in SIRS patients, immediately on admission to the ICU. Nonetheless, more research is needed to define the true role of pharmaconutrients in the prevention or treatment of cellular and tissue dysfunctions. A research strategy that combines basic investigations into the pharmacokinetic and pharmacodynamic profiles of pharmaconutrients, with well-powered prospective clinical trials for safety and efficacy, will clarify the future of pharmaconutrition in critical care medicine and clinical nutrition. This type of study would be able to further elucidate the best antioxidant micronutrient approach, including safety, tolerability, and feasibility of highdose antioxidants in ICU patients.