PENSA 2017 November 21, 2017 Antioxidant Dosing and Micronutrient Management in the Intensive Care Unit Lingtak-Neander Chan, PharmD, BCNSP, CNSC, FACN Professor of Pharmacy, Interdisciplinary Faculty in Nutritional Sciences University of Washington, Seattle, USA
OBJECTIVE To identify the issues and challenges of micronutrient management in the critically ill patient. > Antioxidants supplementation > Other Micronutrients
Physiological Functions of Micronutrients > Antioxidants > Cell division and proliferation > Neurological development and functions > Catalytic functions > Structural functions > Cell signaling pathways > Immune functions > Metabolic and endocrine regulations > Pigment formation
What is the merit of Antioxidant Therapy in ICU Patients > 213 adult ICU patients admitted to 6 hospitals in Spain > Primary diagnosis = Severe Sepsis (ISDC criteria) > Blood samples collected within 2 hours of diagnosis Variable Hazard Ratio on 30-day Survival Serum Lactic acid 1.08 [95% Confidence interval; 1.01-1.15] APACHE II Score 1.04 [95% Confidence interval; 1.01-1.08] Total Antioxidant Capacity (TAC) 1.50 [95% Confidence interval; 1.16-1.94] Lorente L. et al. J Crit Care 2015;30: 217.e7 217.e12
Kaplan-Meier Survival Prediction at 30 days Based on Serum Total Antioxidant Capacity (TAC) Cutoff = 2.80 mmol/l Lorente L. et al. J Crit Care 2015;30: 217.e7 217.e12
Alonso de Vega JM et al. Crit Care Med 2000;28:1812-14
Other Evidence Suggesting a Deficiency of Antioxidants in Critically Ill Patients > Serum selenium, zinc, ascorbic acid are lower in ICU patients, compared with healthy control > RBC selenium concentration predicts ICU and hospital mortality in patients with septic shock > Odd ratios (OR) on mortality with normal RBC selenium concentration : ICU mortality 0.95 [95% CI 0.916 0.986] Hospital mortality 0.96 [95% CI 0.920 0.992] (Costa NA, et al, Critical Care 2014, 18:R92) > Argument against : Acute phase reaction, redistribution
Acute illness and hypozincemia Besecker BY, et al. Am J Clin Nutr 2011; 93:1356-64
Linear Regression Analysis Between Plasma Concentrations of Zinc and C-Reactive Protein in Hypozincemic Patients 70 R 2 = 0.18; p < 0.0001 Plasma Zinc Concentration (mcg/dl) 60 50 40 30 20 10 0 0 50 100 150 200 250 300 350 Chan L-N et al, JPEN 2008;32(3):319-20. Plasma C-Reactive Protein Concentration (mg/l)
Odds Ratio for All Cause Mortality at 28 Days in ICU Patients received Antioxidants Heyland D, et al, N Engl J Med 2013;368:1489-97. Antioxidant Regimen: IV selenium 500 μg ; plus the following PO/EN vitamins and minerals Selenium 300 μg Zinc 20 mg beta carotene10 mg Vitamin E 500 mg Vitamin C1500 mg
SELENIUM Supplementation in the ICU compared Outcomes Relative Effect Mortality Overall RR = 0.82 [95% CI = 0.72 to 0.93] 28-day Mortality = 0.84 [95% CI = 0.69 to 1.02] ICU Length-of-stay Days on ventilator Hospital Length-of-stay Mean difference = - 0.54 day [95% CI -2.27 to 3.34] Mean difference = - 0.86 day [95%CI -4.39 to 2.67] Mean difference = -3.33 days [95% CI -5.22 to -1.44] Allingstrup M et al, Cochrane Database Syst Rev. 2015 Jul 27;(7):CD003703 Manzanares et al. Critical Care (2016) 20:356
High-Dose Vitamin C + Thiamin for Sepsis? Retrospective before-after clinical study 47 patients in both groups Micronutrient regimen: Thiamin 200 mg IV q12h x4 d, (50 ml NS/D5 over 30 min) Vitamin C 1.5 g Q6h, x4 d, (100 ml NS/D5 over 30-60 min) Plus hydrocortisone 50 mg IV q6hr Odd Ratio of mortality in the patients treated with the vitamin C protocol was 0.13 [95% CI 0.04-0.48, p=0.02] Marik PE, et al. Chest 2017; 151(6):1229-1238.
Clinical Outcomes Between Antioxidanttreated Patients vs No Antioxidant Parameters Treatment group Control group Age 58.3 ± 14.1 yr 62.2 ± 14.3 yr APACHE II Score 22.1 ± 6.3 22.6 ± 5.7 Hospital mortality 8.5 % 40.4 % Median ICU LOS 4 (3-5) days 4 (4-10) days Duration of vasopressors 18.3 ± 9.8 hrs 54.9 ± 28.4 hrs Need for CRRT 10 % 33 % SOFA score, 72 h 4.8 ± 2.4 0.9 ± 2.7 Marik PE, et al. Chest 2017; 151(6):1229-1238.
Summary- Antioxidant Therapy in ICU Patients Current Dilemma 1. Antioxidant concentrations appear to be decreased in ICU patients 2. Replacing the deficiencies does not appear to improve clinical outcomes in most trials 3. It is unclear what treatment goals or antioxidant targets to aim for
Factors Contributing to the Dilemmas 1. The blood test- Is it prognostic? 2. Selection of regimen- which one to use? The dose The salt and dosage form The duration of therapy The route of administration 3. Patient types 4. What is the goal?
Clinical Outcomes According to Plasma Vit. C Clinical Outcomes Normal >0.46 mg/dl (n=37) Severely Low 0-0.12 mg/dl (n=8) Plasma Vitamin C (mg/dl) 1.17 ± 0.69 0.07 ± 0.04 ICU Length of Stay (days) 13.6 ± 11.9 9.25 ± 5 Hospital Length of Stay (days) 23.3 ± 17.4 24.5 ± 21.2 Respiratory Failure 91% 100% Renal Failure 39% 0 Liver Failure 11% 12.5% Mortality 21% 37% Hoge E, et al. J Parentr Ent Nutr (JPEN) 2009
Comparison of Regimens Among the Three Selenium Trials Clinical Trial Treatment Control SIC Liverpool French 1000 µg loading; 41.67 µg/hr x 14 days 474 µg x 3 days; 316 µg x 3 days; 158 µg x 3 days; 31.6 µg/day 167 µg/hr x 24hr; 41.67 µg/hr x 9 days Saline 31.6 µg/day Saline Angstwurm MWA et al. Crit Care Med 2007;35:118-26. Mishra V et al. Clin Nutr 2007;26:41-50. Forceville X et al. Crit Care 2007;11:R73
Selenium Supplementation: Kinetic Consideration Selenium has a complex kinetic profile in the body Distribute to different compartments with highly variable rates and elimination half-lives Peak time in plasma: PO: 10-11 hrs IV: 1-2 hrs Mean residence times (staying in the body): Plasma: ~ 2 d Liver/Pancreas: ~20 d Tissues: > 200 d Urine excretion within hours Sustained, provision of selenium is needed to fully treat clinical deficiency and restore tissue deficits
Comparison of plasma concentration profile of a single 3-gram dose of vitamin C IV bolus 3 grams, single dose PO Padayatty SJ et al. Ann Intern Med 2004;140:533-7.
Nathens AB et al. Ann Surg 2002;236(6):814-22.
Implication A dose response relationship was mostly absent in these interventional trials Where did the vitamins go??? Possible scenarios: Antioxidant vitamins were not absorbed enterally (at high doses) saturation of absorption Antioxidants were used up in the GI tract, by the liver, or wasted through enterohepatic re-circulation Antioxidants were absorbed but sent to depots (e.g., other organs); thus the plasma concentrations did not increase proportionately.
Cooperative Actions LOOH Tocopheroxyl radical Ascorbate GSSG NADPH + tocopherol Dehydroascorbate GSH NADP LOO
Key Takeaways. > Critical illness is associated with reduced antioxidant concentrations in the plasma > For most antioxidants, it remains unclear whether this is a true deficiency or an acute phase response > Replacing the observed deficiencies has NOT been associated with improved clinical outcomes > More research should be dedicated to understand the kinetics of these micronutrients > Provide detailed doses, delivery technique, infusion time because the kinetics matter > Allow the results to be replicated
How Inflammatory Responses Affect the Clinical Assessment of Micronutrients Micronutrient Sample Changes with acute phase reaction (e.g., CRP) Chromium Plasma Copper Serum Ceruloplasmin Serum Selenium Plasma Zinc Serum/plasma 25(OH) vitamin D Plasma Retinol Serum Folate Serum Iron (total) Serum Ferritin Serum Vitamin C (total) Serum/Leukocyte Thurnham DI, McCabe GP. Geneva, Switzerland: World Health Organization; 2012. Tomkins A. J Nutr 2003:133: 1649S 1655S.
The IRONMAN Trial Eligibility criteria: Hemoglobin < 10 g/dl Exclusion: Ferritin > 1,200 ng/ml TSAT > 50% Intervention: Ferric carboxymaltose 0.5 g/100 ml of NaCl 0.9% May repeat in 4 days based on lab results The IRONMAN Investigators. Intensive Care Med (2016) 42:1715 1722
The IRONMAN Trial Primary outcome- Total RBC Unit transfused per patient Total number of pts received transfusion Not different between 2 groups Other outcomes No difference in mortality, LOS No difference in incidence of nosocomial infections and bacteremia No difference in thromboembolic events More patients with Hgb > 10 g/dl at discharge with IV iron The IRONMAN Investigators. Intensive Care Med (2016) 42:1715 1722
Impact of Iron Supplementation by Any Route on Mortality and Infection Risk in ICU Adult Patients with Anemia Mortality risk In-hospital infections risk Shah et al. Critical Care (2016) 20:306
Key Takeaways. > Critical illness is associated with reduced antioxidant concentrations in the plasma > For most antioxidants, it remains unclear whether this is a true deficiency or an acute phase response > Replacing the observed deficiencies has NOT been associated with improved clinical outcomes > Empirical IV iron supplementation does not appear to alter clinical outcomes, nor does it lead to harms > Additional research is needed to determine when iron therapy is warranted in ICU patients