Roger Harris on Oxidative Stress

• What is Oxidative stress• Why is Oxidative Stress important• How does Selenium fit into Oxidative stress• Selenium (Se) in critical illness• What’s the current evidence for Se in ICU

• Oxidant production is normally balanced by antioxidant systems (Reduction by enzyme scavengers and dietary antioxidants)

• Redox imbalance is caused by excessive production of ROS / NOS or decrease in antioxidants + destruction of enzyme scavengers.

• When ROS > Reductive capacity there is OXIDATIVE STRESS

• Selenium is a trace mineral found in minute quantities in the body

• RDA 60ug /day• Serum Se level for optimal Selenoprotein

function is around 100ug/L• In Serum 40% GSH-Px / 10% Albumin / 50%

Selenoprotein-P• Found in Bread, cereals, fish, meat

• Plasma Se levels fall in critical illness• 1998 Forceville et al showed low plasma

selenium at ICU admission correlated with mortality

• Se level inversely correlated with APACHE 2• Se level inversely correlated with Sepsis

Severity

Critcal Care Medicine 1998;26:1536-44

© Williams & Wilkins 1998. All Rights Reserved. Published by Lippincott Williams & Wilkins, Inc. 3

Figure 1

Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients.Forceville, Xavier; Vitoux, Dominique; Gauzit, Remy; Combes, Alain; Lahilaire, Pierre; Chappuis, Philippe

Critical Care Medicine. 26(9):1536-1544, September 1998.

Figure 1 . Admission plasma selenium concentration related to Acute Physiology and Chronic Health Evaluation (APACHE) II severity score. Dashed line, mean +/- SD normal plasma selenium value (1.00 +/- 0.15 [micro sign]mol/L). r2 = .11; p < .0001.

© Williams & Wilkins 1998. All Rights Reserved. Published by Lippincott Williams & Wilkins, Inc. 5

Figure 2

Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients.Forceville, Xavier; Vitoux, Dominique; Gauzit, Remy; Combes, Alain; Lahilaire, Pierre; Chappuis, Philippe

Critical Care Medicine. 26(9):1536-1544, September 1998.

Figure 2 . Admission plasma selenium concentration related to severity of sepsis. p <or=to .05 for sepsis vs. severe sepsis; p <or=to .05 for sepsis vs. septic shock (analysis of variance). Dashed line, mean +/- SD normal plasma selenium concentration (1.00 +/- 0.15 [micro sign]mol/L); n, number of patients, including, in parentheses, number of nonsurviving patients, for each sepsis severity grade. Values are expressed as median (middle line in the box) with the top and bottom of the box encompassing the 25th to the 75th percentiles; capped lines indicate the tenth to 90th percentiles of the data; circles, values above the 90th and below the tenth percentiles.

• Why exactly is the Se level low in SIRS– Change in Albumin concentration– Changes in distribution of Selenoprotein-P– Consumed in REDOX– Haemo-diluton– Reduced Nutritional intake

• 1999 Angstwurm etal demonstrated increased plasma Se levels and GSH-Px after replacing Se

• Activity of the Se-dependent enzyme GSH-Px parallels serum Se with increasing activity after replacement.

• Similar results in small studies with Trauma

Critical care medicine 1999;27:1807-13

© 1999 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Figure 1Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome.Angstwurm, Matthias; Schottdorf, Juergen; Schopohl, Jochen; Gaertner, Roland

Critical Care Medicine. 27(9):1807-1813, September 1999.

Figure 1 . Serum selenium concentrations ([mu]g/L) in patients in the Se- (control) group and the Se+ (selenium-treated) group at days 0, 3, 7, and 14. Se+ vs. Se-: day 0, p > .05; day 3, p p p = .003. Bold lines represent the median, boxes represent 75th and 25th percentiles, the small lines at the top and bottom of each box indicate the 95th and 5th percentiles of the distribution. Dotted lines represent the normal range (70-120 [mu]g/L, 0.88-1.52 [mu]mol/L).

© 1999 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 3

Figure 2Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome.Angstwurm, Matthias; Schottdorf, Juergen; Schopohl, Jochen; Gaertner, Roland

Critical Care Medicine. 27(9):1807-1813, September 1999.

Figure 2 . Serum glutathione peroxidase activities (U/L) in patients in the Se- (control) group and the Se+ (selenium-treated) group at days 0, 3, 7, and 14. Se+ vs. Se-: day 0, p > .05; day 3, p p p = .013. Bold lines represent the median, boxes represent the 75th and 25th percentiles, the small lines at the top and bottom of each box indicate the 95th and 5th percentiles of the distribution. Dotted lines represent the normal range (>96 U/L).

• Se is essential trace element for maintaining balance in Oxidation- Reduction

• Reactive Oxygen and Nitrogen species can damage cells

• No clear evidence that large doses of Se avoid the reduce mortality