High-dose selenium supplementation to reduce ischemia/reperfusion injury - Novel approach in intensive care: Selenium does make a difference!

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Selenium serves as an antioxidant in our body, interacting at various levels with important mediators. Its central role is to hamper oxidative stress, no matter whether it comes from ischemic/reperfusion injury after acute events such as strokes or heart attacks, or from elective surgery in which vessels are intentionally ligated, depriving the surrounding tissue of oxygen. Initially, the lack of oxygen during ischemia leads to tissue damage, but reperfusion triggers further harm, E. Müller, Herne, Germany, explained. He reminded the audience of the altered microcirculation after an acute stroke, and the inflammatory cascade which gets activated during sepsis, a condition associated with an increase in reactive oxygen species and a reduced endogenous anti-oxidative capacity. "Reperfusion injury is a problem under investigation," he said, a problem which occurs after myocardial infarction, ischemic stroke, organ transplantation, vascular and reconstructive surgery and sepsis.

In an attempt to minimize tissue damage after such severe events, hypothermia has become standard procedure in the operating theater. An additional effective, safe and cheap way to improve reperfusion, for example after myocardial infarction or vascular surgery, is selenium supplementation. A logical approach, since researchers lately found that plasma selenium levels in critically ill patients - with a systemic inflammatory response syndrome and severe sepsis/septic shock - were below standard values of healthy subjects and decreased even further during hospitalization in the ICU, in particular in patients with organ failure and especially when attributed to infection. These findings, published by Sakr et al. [1], showed that selenium concentrations correlated well with survival. Lower plasma selenium concentrations seem to be associated with greater tissue damage, infections, organ failure and an increased ICU mortality (fig. [1]).

Fig. 1 Sakr et al. 2007: Survivors have higher selenium levels (slide: Müller).

SIC study revealed convincing results

Müller presented the results of a randomized, placebo-controlled, multicenter trial [2] which revealed a survival benefit for sepsis patients who initially received high doses of 1,000 µg of selenium as sodium selenite as a 30-minute bolus injection followed by daily intravenous infusions (1,000 µg of selenium) for a period of 14 days (compared to subjects receiving placebo). This trial - the SIC study (Selenium in Intensive Care) - was performed in 11 ICUs throughout Germany and included 249 patients with severe systemic inflammatory response syndrome (SIRS), sepsis and septic shock and APACHE (Acute Physiology and Chronic Health Evaluation) III scores above 70. The 28-day mortality rate was 56.7 % in the placebo group, and was clearly reduced to 42.4 % in the selenium group (p = 0.049, odds ratio 0.56, confidence interval 0.32-1.00). Absolute reduction in mortality was 14.3 %, the number of patients needed to treat was seven (NNT = 7) (fig. [2]). Above all, in the subgroup of patients with septic shock, mortality was 26.2 % lower in patients receiving selenium (NNT = 4). Müller summed up the benefits of selenium adjustment: Thanks to high selenium levels, mortality declined. Moreover, the benefit of supplementing the essential trace element was reflected by a low number needed to treat (NNT). The speaker compared NNTs of various adjuvant treatment options demonstrating that the lowest NNT was found when sodium selenite was supplemented.

Fig. 2 Angstwurm et al. 2007: selenase significatly reduces mortality (slide: Müller).

The study results underline that high-dose adjuvant selenium supplementation is an important treatment approach to improve outcome in patients with sepsis and that in the most critically ill, adjuvant selenium supplementation was most effective. The authors argued that high physiological selenium levels are obviously necessary to cope with the challenges of severe sepsis. And they clearly favored selenium supplementation in the critically ill which is inexpensive, safe and in addition easy to perform.

Importance of antioxidants in the critically ill

"The symposium brings back the basics. The minimum has to be replaced", B. A. Cotton, Houston, Texas, USA, said, referring to low selenium levels. He compared selenium to a super soldier who is in charge of eliminating oxidative stress. Oxidative stress is linked to higher mortality, and endogenous anti-oxidant depletion contributes to oxidative stress, he explained. "You have soldiers and you have to send reinforcements." Selenium supplementation is similar to electrolyte administration in sports, he explained. "But many people tend to dismiss something that is so easy."

That anti-oxidative therapy does have an effect was not only demonstrated in Europe but also in the USA, and Cotton summed up his experience with antioxidants in the critically ill. Initially he presented the data [3] of a randomized, prospective trial of anti-oxidant supplementation in critically ill ICU patients who underwent surgery and either received placebo (n = 301) or high amounts of ascorbic acid and alpha-tocopherol every eight hours (n = 294). Supplementation led to more vent-free days and a reduced mortality rate. Other investigators found supplementing antioxidants facilitates ventilator weaning [4]. Based on the evidence, Cotton proposed that all patients requiring trauma unit admission receive high-dose supplemental anti-oxidant therapy for seven days, as he did with his patients, i.e. 200 µg selenium intravenously qd, ascorbic acid and alpha-tocopherol for seven days or until they are discharged.

Possible advantages in vascular surgery

Reactive oxygen species (ROS) and NO are also released in vascular surgery during ischemia and reperfusion, T. Zimmermann, Berlin, Germany, emphasized. Vascular surgery acts as an initial trigger for ROS/NO/peroxynitrite formation. When ROS reacts with NO, peroxynitrite is formed. On top of visible dangers such as reperfusion injury, edema after reperfusion, embolism, compartment syndrome, vascular injury or rhabdomyolysis, there are invisible dangers, i.e. perpetuation of lipidperoxidation and atherosclerosis, the vicious NO/ONOO-cycle. Zimmermann referred to NO as the "good", O₂- as "the bad" and ONOO- as the "ugly", explaining that NO acts as a ROS scavenger and leads to desired effects such as vasodilation. He added: "The vicious cycle can only be broken by ROS inactivation. This permanent oxidative stress can be eliminated by well-targeted antioxidants such as sodium selenite. Sodium selenite is able to reduce 'the bad' and so inhibit 'the ugly'."

Treatment optimization: The sooner, the better

The speaker presented data of 20 patients with infrarenal aortic aneurysms and 20 with peripheral arterial occlusive disease (pAOD), stages IIb-IV. Blood samples were collected preoperatively, before and after clamping, at the end of the surgical procedure and on the first, second, third and seventh day after surgery. NO and selenium were measured in plasma. Without selenium supplementation, O₂-levels increased considerably in pAOD-patients and NO levels markedly dropped in patients with aortic aneurysms. Selenium was able to clearly reverse these effects (fig. [3]).

Fig. 3 Positive effect of selenium adjustment (1,000 ìg or bolus pre-op, 1,000 ìg/24 h as continuous infusion) in patients with aortic aneurysms (a. without selenium and b. with) (slide: Zimmermann).

Zimmermann explained that pre-, intra- and postoperative administration of sodium selenite leads to an immediate inhibition of ROS and peroxynitrite. Thus to optimize therapy, he suggested determining ROS and NO in real time and immediately starting treatment with antioxidants in the early reperfusion phase (after declamping). Since the reperfusion phase has a biphasic course, anti-oxidative treatment is necessary beyond the immediate postoperative phase, he added.

Post-resuscitation care: Do we need antioxidants after return of spontaneous circulation?

"Cardiac arrest is not a disease of the elderly," H.-J. Busch, Freiburg, Germany, said. According to the Freiburg Cardiac Arrest Register, one out of two patients who are affected is not even 65 years old. Nine out of ten patients die after cardiac arrest, triggered in 70-80 % by coronary heart disease and in 10-15 % by cardiomyopathies or myocarditis. But although intensive care improved in the last decade, survival after cardiac arrest did not. In Europe, after successful resuscitation, 15 000-230 000 patients are in need of intensive care every year. The speaker stressed the fact that problems after return of spontaneous circulation are hypoxic brain injury, acute heart failure after resuscitation, systemic inflammatory response syndrome, and impairment of the tissue-dependent microcirculation. After cardiac arrest, patients at the ICU he is working at showed significant (p < 0.05) selenium deficiencies (patients after cardiopulmonary resuscitation: 76.5 ± 21 µg/l; controls with coronary heart disease: 88.2 ± 12 µg/l; healthy controls: 106 ± 4.4 µg/l) which worsened during their stay in ICU. Busch further observed differences in serum selenium concentrations after cardiac arrest in patients without (86.4 ± 12 µg/l) and with (73 ± 19 µg/l) hypoxic brain injury. As demonstrated in a study including patients with myocardial infarction, the selenium status correlates with the extent of damage [5]. And early selenium administration may improve neurological outcome after cardiac arrest - this was at least indicated by a recently published retrospective analysis of unconscious patients after cardiopulmonary resuscitation [6].

Therefore, Busch favors an extended treatment approach in post resuscitation care including anti-oxidative treatment. Besides early hemodynamic stabilization, therapeutic hypothermia, metabolic support, anti-inflammatory treatment and treatment of the impaired microcirculation, he insisted on anti-oxidative treatment, highlighting possible advantages of sodium selenite in postresuscitation care. Post-resuscitation care should focus on minimizing transient and persistent ischemia/reperfusion injury.

Dr. Yvette C. Zwick, München

This article has been kindly supported by biosyn Arzneimittel GmbH. The contents come from the symposium "New approaches in selenium therapy" during the 29th ISICEM in Brussels, Belgium, March 25, 2009. Sponsor: biosyn Arzneimittel GmbH. The author is a free-lance journalist.

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