Selenium supplementation in critically ill patients: A systematic review and meta-analysis

doi:10.1016/j.jcrc.2013.08.017

Journal of Critical Care

Volume 29, Issue 1, February 2014, Pages 150-156

https://doi.org/10.1016/j.jcrc.2013.08.017 Get rights and content

Abstract

Purpose

The oxidative stress is recognized as a constant feature in critical illness. Nevertheless, the use of antioxidant therapy remains controversial. We tried to demonstrate that intravenous selenium supplementation could promote antioxidant status and help protect against infection and organ failure, improving outcome in critically ill patients.

Materials and Methods

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the exogenous supplementation of selenium versus standard therapy without any adjuvant in critically ill adults.

Results

Nine RCTs met inclusion criteria. Selenium supplementation was associated with a reduction in 28-day mortality of borderline statistical significance (risk ratio = 0.84, 95% confidence interval 0.71–0.99, P = .04). The analysis of pre-defined subgroups detected no significant effects regarding the supplementation with doses of selenium ≤ 500 μg/d, administration of a load dose with a bolus and duration of treatment. Only 2 studies analyzed 6-month mortality and could not show a difference. No effects could be demonstrated on hospital length of stay, pulmonary infections, or renal failure.

Conclusions

The use of high-dose selenium might be associated with a beneficial effect on 28-day mortality in critically ill patients. Nevertheless, the use of selenium as adjuvant therapy needs further evaluations.

Introduction

It is known that critical illness is typically characterized by oxidative stress, an alteration of the normal intracellular balance between the constant formation of oxidants, including reactive oxygen species (ROS) and reactive nitrogen species, and biological system's ability to detoxify the reactive intermediates or to repair the resulting damage [1], [2]. The increase of free radicals production, the inadequate response of the defense systems involved in the detoxification of the cell by ROS, or both of these conditions, can damage biologically relevant molecules, such as DNA, RNA, proteins, and unsaturated fatty acids of the cell membranes, which may ultimately lead to cell death [3], [4]. In critically ill patients, oxidative stress plays an important role in pathophysiological events leading to mitochondrial dysfunction and to systemic inflammatory response syndrome (SIRS), which may be complicated and result in acute respiratory distress syndrome and multiple organ dysfunction syndrome [5]. The antioxidant endogenous defense systems are extremely effective at counteracting ROS and the other reactive species. These antioxidants systems include both enzymatic proteins (such as superoxide dismutase, glutathione peroxidase, and catalase) and secondary antioxidants (or non-enzymatic) [6], [7].

Selenium is a trace mineral and it is essential to the function of glutathione peroxidase, since it is a structural component of the active site of this selenoenzyme [6]. Evidence suggests that in critically ill patients plasma selenium is significantly below the normal range; furthermore, it has been demonstrated that depletion of this micronutrient is associated with a worse clinical outcome: low selenium levels were associated with a greater number of infectious complications and a higher incidence of mortality [8].

Since it seems evident the theoretical rationale of the use of antioxidants, such as selenium, in the critically ill patient, in the last decades, several clinical trials attempted to demonstrate if selenium supplementation can determine some effective clinical benefit. Recently, Manzanares et al has published a comprehensive meta-analysis of the use of antioxidants in critically ill patients [9]. Selenium is universally recognized as one of the most promising antioxidants [10].

The aim of this study is to systematically review the efficacy of intravenous selenium supplementation as monotherapy in critically ill patients. Furthermore, we wished to assess the robustness of the conclusions by predicting the potential impact of a new study on the statistical significance and heterogeneity of our meta-analysis, which explores the need and potential impact of further research in this field.

Section snippets

Objectives

The primary aim of this review was to investigate the effect of intravenous selenium supplementation on 28-day mortality in critically ill patients.

The secondary objective was to evaluate the effects of selenium supplementation on other outcomes, such as mortality at 6 months, length of intensive care unit stay, number of nosocomial respiratory infections, incidence of renal failure and/or need for a renal replacement therapy (RRT).

Types of studies

We included all randomized (RCTs) and quasi-randomized

Description of studies

Our search results are detailed in Fig. 1.

Nineteen randomized controlled trials investigating intravenous selenium supplementation in critically ill patients were assessed for eligibility. Of these, we included 9 trials in our meta-analysis [12], [14], [15], [16], [17], [18], [19], [20], [21] and we described them herein (Table E1, available online).

We excluded the remaining 10 RCTs. The reasons for exclusion were a different kind of intervention, with administration of a cocktail containing

Discussion

Critically ill patients experience a severe state of oxidative stress, resulting in the dysfunction of the systems responsible for energy production in cells [1], [7]. This imbalance can cause damage to biologically relevant molecules and lead to mitochondrial dysfunction and SIRS with worsening of patient-related outcomes [4], [5].

In this context, supplemental selenium (in combination with standard therapy) could represent an important therapeutic option. Therefore, we performed a

Acknowledgments

We would like to thank Tessa Piazzini MLS, for her assistance and electronic searches advice during the identification of trials for this work.

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Cited by (61)

Efficacy and safety of selenium or vitamin E administration alone or in combination in ICU patients: A systematic review and meta-analysis
2023, Clinical Nutrition ESPEN
Micronutrient administration that contributes to antioxidant defense has been extensively studied in critically ill patients, but consensus remains elusive. Selenium and vitamin E are two important micronutrients that have synergistic antioxidant effects. This meta-analysis aimed to assess the effect of selenium or vitamin E administration alone and the combination of both on clinical outcomes in patients hospitalized in the ICU.
After electronic searches on PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), SinoMed, VIP database and Wanfang data, initially 1767 papers were found, and 30 interventional studies were included in this analysis. We assessed the risk-difference between treatment and control (standard treatment) groups by pooling available data on length of stay (ICU length of stay and hospital length of stay), mortality (ICU mortality, hospital mortality, 28-day mortality, 6-month mortality and all-cause mortality), duration of mechanical ventilation, adverse events and new infections.
By analyzing the included studies, we found no significant effect of selenium administration alone on mortality, mechanical ventilation duration, or adverse events in ICU patients. However, after excluding studies with high heterogeneity, the meta-analysis showed that selenium alone reduced the length of hospital stay (MD: −1.38; 95% CI: −2.52, −0.23; I-square: 0%). Vitamin E administration alone had no significant effect on mortality, duration of mechanical ventilation, or adverse events in ICU patients. However, after excluding studies with high heterogeneity, the meta-analysis showed that vitamin E alone could reduce the length of ICU stay (MD: −1.27; 95% CI: −1.86, −0.67; I-square: 16%). Combined administration of selenium and vitamin E had no significant effect on primary outcomes in ICU patients.
Selenium administration alone may shorten the length of hospital stay, while vitamin E alone may reduce the length of ICU stay. The putative synergistic beneficial effect of combined administration of selenium and vitamin E in ICU patients has not been observed, but more clinical studies are pending to confirm it further.
Rebalancing the unbalanced aged immune system – A special focus on zinc
2022, Ageing Research Reviews
Nowadays, aging is understood as a dynamic and multifaceted dysregulation process that spares almost no human organ or cell. The immune system being among the most affected, it has been shown predominantly that its integrity determines the tightrope walk between the difference of escaping or suffering from age-related diseases.
Next to drug-based anti-aging strategies, micronutrient intervention may represent an emerging but less radical way to slow immune aging. While a sufficient supply of a variety of micronutrients is undeniably important, adequate intake of the trace element zinc appears to tower over others in terms of reaching old age. Inconveniently, zinc deficiency prevalence among the elderly is high, which in turn contributes to increased susceptibility to infection, decreased anti-tumor immunity as well as attenuated response to vaccination.
Driven by this research, this review aims to provide a comprehensive and up-to-date overview of the various rebalancing capabilities of zinc in the unbalanced immune system of the elderly. This includes an in-depth and cell type-centered discussion on the role of zinc in immunosenescence and inflammaging. We further address upcoming translational aspects e.g. how zinc deficiency promotes the flourishing of certain pathogenic taxa of the gut microbiome and how zinc supply counteracts such alterations in a manner that may contribute to longevity. In the light of the ongoing COVID-19 pandemic, we also briefly review current knowledge on the interdependency between age, zinc status, and respiratory infections. Based on two concrete examples and considering the latest findings in the field we conclude our remarks by outlining tremendous parallels between suboptimal zinc status and accelerated aging on the one hand and an optimized zinc status and successful aging on the other hand.
The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review
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Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival.
The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19.
We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020.
Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials.
Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.
Daily parenteral selenium therapy in critically ill patients: An updated systematic review and meta-analysis of randomized controlled trials
2021, Clinical Nutrition ESPEN
Citation Excerpt :
It may be because of various doses and types of Se, route of administration (enteral or parenteral), and duration of therapy. On the other hand, there is no systematic review and meta-analysis to compare the effects of Se in doses lower or higher than 1000 μg per day and the duration lower or higher than 10 days, as mentioned at the ASPEN guidelines [7,8]. In addition, the previous meta-analysis resulted that Se supplementation has no effect on renal failure [9].
Patients hospitalized at the intensive care unit (ICU) are more prone to oxidative stress. Antioxidants such as selenium (Se) may have beneficial effects on outcomes in these patients. Studies and systematic reviews in this field have inconclusive results.
An updated systematic search was done to find clinical trials published in PubMed, Cochrane's library, ISI web of Science, Scopus, and Ovid databases from January 1980 up to April 2020, to assess the effects of daily Se supplementation on patient's survival, hospital and ICU stay, duration of mechanical ventilation, infection, acute renal failure (ARF) occurrence and serum creatinine levels.
From 1394 papers found in the first step of the search, after deleting duplicate findings, 24 studies were included in this meta-analysis. Results of the pooled random-effect size analysis of 24 trials showed no remarkable effect of daily parenteral Se administration on patient's hospital and ICU stay, duration of mechanical ventilation, infectious complications, ARF, survival and serum creatinine levels (p > 0.05). The subgroup analysis showed that daily parenteral Se administration (in doses higher than 1000 μg/d) increased the length of ICU stay by 4.48-folds (95%CI: −0.5, 9.46, p = 0.07). Parenteral Se supplementation at the first and following dose of ≤1000 μg reduced the number of ARF at the hospitalized patients by 76% and 45%, respectively (p = 0.02, and p = 0.05).
High doses of Se increases days of ICU stay, but low doses decreases the number of ARF occurrence in ICU patients. More trials are needed to assess its effect on ARF occurrence.
Effect of high-dose sodium selenite in cardiac surgery patients: A randomized controlled bi-center trial
2018, Clinical Nutrition
Citation Excerpt :
Improved survival due to selenium supplementation (without or in combination with other antioxidants) was also demonstrated in critically ill patients by hitherto five meta-analyses [see 20, 21]. However, other studies on selenium supplementation in these patients did not find such beneficial effects [19–25]. In contrast to sepsis, elective cardiac surgery can be considered as quite ideal model to investigate the effect of selenium supplementation on inflammatory responses in man insofar the study population typically consists of a large number of suitable patients often suffering from a single (i.e. cardiac) disease without preexisting inflammation that underwent a defined hit (i.e. cardiac surgery) being followed by inflammatory responses over a relative short period of time.
Cardiac surgery is accompanied by oxidative stress and systemic inflammatory response, which may be associated with organ dysfunction and increased mortality. Selenium and selenoenzymes are important constituents of anti-oxidative defense. We hypothesized that high-dose sodium selenite supplementation can attenuate the postoperative inflammation and might, therefore, improve clinical outcome.
Randomized, placebo-controlled, double-blinded, bi-center study on 411 adult patients undergoing elective cardiac surgery. Patients received an intravenous bolus of 4000 μg selenium (in the form of sodium selenite) or placebo after induction of anesthesia and 1000 μg/d selenium or placebo during their intensive care unit (ICU) stay. Primary outcome measure was the Sequential Organ Failure Assessment (SOFA) score on the second postoperative day. Secondary endpoints included the change in perioperative selenium levels, change of inflammatory and cardiac markers, use of vasoactive medication, incidence of acute kidney injury, ICU and hospital length of stay, and mortality.
The perioperative administration of high-dose sodium selenite prevented the postoperative drop of blood and serum selenium levels, reduced the number of patients depending on postoperative vasoactive support but failed to reduce the postoperative SOFA score and its related organ-specific scores compared to placebo. Except for an increase of postoperative procalcitonin and bilirubin levels in the sodium selenite group, other inflammatory markers, organ function variables and clinical endpoints remained unchanged.
The perioperative administration of high-dose sodium selenite in cardiac surgery patients prevented the postoperative fall of blood selenium levels and reduced the need for postoperative vasoactive support by a yet unknown mechanism.
Registered under ClinicalTrials.gov Identifier no. NCT01141556.
Antioxidant reserve of the lungs and ventilator-associated pneumonia: A clinical trial of high dose selenium in critically ill patients
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To evaluate the effect of supplemental selenium administration on the incidence of ventilator-associated pneumonia (VAP) in critically ill patients.
Ninety-nine mechanically ventilated patients were randomized to receive either selenium or isotonic saline infusion for 10 days. The primary endpoint was serum glutathione peroxidase-3 (GPX-3) activity and secondary endpoints were development of VAP or death, ICU stay and vasopressor requirement. Serum concentrations of selenium and GPX-3 were measured on Day-1, Day-4 and Day-10. Chi Square and log-rank analyses were used for statistical analyses and odds ratios were calculated.
Serum selenium and GPX-3 activity levels increased steadily in the treatment group within 10 days (P < 0.025), while they remained unchanged in the placebo group. The incidence of VAP was 19.4/1000 days of mechanical ventilation in the placebo group while it was 15.8/1000 ventilated days in the treatment group (P = 0.250). The risk of VAP or death was similar between the treatments and placebo groups.
Despite increasing the antioxidant activity, selenium supplementation did not affect the incidence of VAP in critically ill patients. The risk of developing VAP or death within 30 days of ICU admission remained the same in the treatment and the controls.

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Clinical PotpourriSelenium supplementation in critically ill patients: A systematic review and meta-analysis

Abstract

Purpose

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Objectives

Types of studies

Description of studies

Discussion

Acknowledgments

Neuroscience

Br J Anaesth

Clin Nutr

Clin Nutr

Am J Clin Nutr

J Clin Epidemiol

Redox imbalance in the critically ill

Br Med Bull

Oxidative stress: from basic research to clinical application

Am J Med

Oxidative stress in critically ill patient

Am J Crit Care

Hypoxia accelerates nitric oxide-dependent inhibition of mitochondrial complex I in activated macrophages

Am J Physiol Regul Integr Comp Physiol

Studies on free radicals, antioxidants, and co-factors

Clin Interv Aging

Seleno-enzymes and seleno-compounds: the two faces of selenium

Crit Care

Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis

Crit Care

Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient

Intensive Care Med

The effect of selenium therapy on mortality in patients with sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials

Crit Care Med

Efecto antiinflamatorio del selenio en pacientes septicos

Rev Asoc Mex Med Crit y Ter Int

Clinical Potpourri
Selenium supplementation in critically ill patients: A systematic review and meta-analysis