Microsoft PowerPoint - 06_Patel_ASPEN_Micronutrient_2020_HindiJayshil (Jay) Patel, MD Associate Professor of Medicine Medical College of Wisconsin
Micronutrient Therapy in Critically ill Patients with
COVID-19 Disease: Promising Paradigm or Fleeting Fiction?
Micronutrient Therapy in Critically ill Patients with
COVID-19 Disease: Promising Paradigm or Fleeting Fiction?
COVID-19 -
SCCM
1
Consider this case…Consider this case… • 50-year-old woman with diabetes, hypertension, and obesity presents to your
emergency department with 5 days of shortness of breath with exertion, cough, fever, anorexia, and fatigue.
• In the ED, she’s confused, tachypneic, hypoxemic with oxygen saturation 80% despite 6 liters high-flow nasal cannula and febrile to 101° F
• Endotracheally intubated and becomes hypotensive given 2 liters crystalloid and started on a NE infusion
• CT chest with dense bilateral lower lobe infiltrates
• Transferred to your ICU under strict isolation
, , , , , , , , ICU RDS , , ,
2
1.What is the pathophysiology of oxidative stress in critical illness (and COVID-19 infection)?
2.What are the mechanisms for zinc, selenium, vitamin C, and vitamin D in critically ill patients with COVID-19 disease?
3.What is the evidentiary base for zinc, selenium, vitamin C, and vitamin D in critically ill patients with and without COVID-19 disease?
What questions will this talk seek to answer?
What questions will this talk seek to answer?
, COVID-19 ? COVID-19 ? ? COVID-19 , ,
3
Homeostasis
AntioxidantsPro-oxidants
Vitamins Enzyme cofactors Endogenous compounds
ROS RNS
, , , -
4
1. Increased utilization 2. Increased loss 3. Redistribution
Antioxidants
ARDS , - , ,
5
Back to our case…Back to our case… • 50 year old woman with diabetes, hypertension, and obesity
presents to your emergency department with 5 days of shortness of breath with exertion, cough, fever, anorexia, and fatigue.
• In the ED, she’s confused, tachypneic, hypoxemic with oxygen saturation 80% despite 6 liters high-flow nasal cannula and febrile to 101° F
• Endotracheally intubated and becomes hypotensive given 2 liters crystalloid and started on a NE infusion
• CT chest with dense bilateral lower lobe infiltrates
• Transferred to your ICU under strict isolation
Testing for SARS-CoV-2 virus returns positive
Huang C et al. Lancet 2020;395:497-506 Stokes EK et al. MMWR 2020;69:759-765
Wu Z et al. JAMA 2020 2020;323:1239-1242
SARS- CoV-2 ?
6
Wu J. Nitric Oxide 2020;102:39-41 Zhou F. Lancet 2020;395:1054-1062
SARS-CoV-2 - , , , , ,
7
Wu J. Nitric Oxide 2020;102:39-41 Zhou F. Lancet 2020;395:1054-1062
Variable Total (n=191) Non-survivor (n=54) Survivor (n=137) P-value D-dimer 0.8 (0.4-3.2) 5.2 (1.5-21.1) 0.6 (0.3-1.0) <0.0001 LDH 300 (234-407) 521 (363-669) 253 (219-318) <0.0001 Ferritin 722 (377-1435) 1435 (728-2000) 503 (264-921) <0.0001 IL-6 7.4 (5.3-10.8) 11 (7.5-14.4) 6.3 (5-7.9) <0.0001 Lymphocyte 1.0 (0.6-1.3) 0.6 (0.5-0.8) 1.1 (0.8-1.5) <0.0001
Why is SARS-CoV-2 different than other viruses?
Why is SARS-CoV-2 different than other viruses?
, - , COVID
8
Consequences of Oxidative StressConsequences of Oxidative Stress
Koekkoek W et al. NCP 206;31:457-474 Infusino F et al. Nutrients 2020;12:1718
1
Consequences of Oxidative StressConsequences of Oxidative Stress
Koekkoek W et al. NCP 206;31:457-474 Infusino F et al. Nutrients 2020;12:1718
2 1
Impaired microcirculatory
blood flow
Endothelial dysfunction
Consequences of Oxidative StressConsequences of Oxidative Stress
Koekkoek W et al. NCP 206;31:457-474 Infusino F et al. Nutrients 2020;12:1718
3
2 1
Impaired microcirculatory
blood flow
Endothelial dysfunction
Altered coagulation
, COVID-19 , , , , ,
11
Key Micronutrients in COVID-19Key Micronutrients in COVID-19
Koekkoek W et al. NCP 206;31:457-474 Infusino F et al. Nutrients 2020;12:1718
Micronutrient Antioxidant Endothelial Function
2. Selenium X X X Editorials, observational
3. Vitamin D X X X Editorials, observational
4. Vitamin C X X X X Editorials, case report, observational
? ,
, , , , , , , SARS-CoV-2 SARS-CoV-2 ?
12
SR
RCT
SR = systematic review
Guyatt G et al. Users’ Guide to the Medical Literature, 3rd edition. 2015, McGraw Hill:New York.
, - , , , , ,
13
Key Micronutrients in COVID-19Key Micronutrients in COVID-19
Koekkoek W et al. NCP 206;31:457-474 Infusino F et al. Nutrients 2020;12:1718
Micronutrient Antioxidant Endothelial Function
2. Selenium X X X Editorials, observational
3. Vitamin D X X X Editorials, observational
4. Vitamin C X X X X Editorials, case report, observational
COVID-19 , COVID-19 -COVID , , COVID -COVID
14
Case series for COVID-19 patients
Four outpatients Two patients without laboratory confirmation Hourly to every 4 hour use of zinc lozenge Subjective reporting No comparison group
Finzi E. Int J Infect Dis. 2020
, COVID , COVID-19
15
Heyland DK. JPEN 2008;32:509-519
Small studies Burn and head trauma patients Zinc dose varied (2.5 to 26.5 grams) Three of four studies gave selenium or copper with zinc
-COVID ? ? IV , , 68 - , -COVID COVID-19
16
2 SELENIUM Observational data for COVID-19 patients
Moghaddam A. Nutrients 2020;12:2098 Zhang J. Am J Clin Nutr. 2020;111:1297-1303

COVID-19 , , 200 COVID-19 , , , - , -
COVID-19 166 , ,
17
www.criticalcarenutrition.com
mortality No difference in
nosocomial infection
-COVID ? ICU 22 - , , 22 12 , , COVID-19 -COVID 19 COVID-19
18
3 VITAMIN D Observational data for COVID-19 patients
Feehan SH et al. Maturitas 2020 Panagiotou G. et al. Clin Endocrinol (Oxford). 2020
Author Type of Study Outcome D’Avolio Cohort Correlation between vitamin D level and outcomes
Merzon Cohort Correlation between vitamin D level and outcomes Meltzer Cohort Correlation between vitamin D level and outcomes Hastie Cross-sectional No correlation between vitamin D level and outcomes Lau Cross-sectional Correlation between vitamin D level and outcomes Rais-Estabragh Cross-sectional Racial disparities not explained by vitamin D level Panagiotou Cross sectional Higher prevalence of vitamin D deficiency and
association between level and outcome
?
COVID-19 - SARS- CoV-2 ,
19
3 VITAMIN D Supplementation in non-COVID critically ill
Putzu A et al. J Crit Care 2017;38:109-114 Weng H et al. Inten Care Med 2017.43:277-278
Mortality benefit: OR 0.70 (95% CI 0.50-0.98)
No mortality benefit: OR 0.77 (95% CI 0.58-1.03)
-COVID ? , - , 2017 , - 716
- 602 , , 95%
20
Ginde AA et al. NEJM 2019;381:2529-2540
Vitamin D (540,000 IU enteral dose)
Placebo R 90-day mortalityPrimary
outcome
VIOLET , 20
540,000 , 90 , , SOFA

21
RCT in non-COVID critically ill
Variable Vitamin D Placebo p-value or difference 25-OH-D on day 0 11.2 (±4.8) 11.0 (±4.7) NR 25-OH-D on day 3 46.9 (±23.2) 11.4 (±5.6) 35.5 (31.5 to 39.6) 90-day mortality (%) 23.5 20.6 0.26 Ventilator-free days 21.3 (±11.3) 22.1 (±10.5) -0.8 (-2.1 to 0.5) New ARDS to day 7 (%) 4.9 4.1% 0.7 (-2.1 to 3.6) Hyper-Ca to day 14 (%) 2.7 2.1 0.51 Kidney stones to day 90 (%) 7.1 5.3 0.24
Ginde AA et al. NEJM 2019;381:2529-2540
22
RCT in non-COVID critically ill
Variable Vitamin D Placebo p-value or difference 25-OH-D on day 0 11.2 (±4.8) 11.0 (±4.7) NR 25-OH-D on day 3 46.9 (±23.2) 11.4 (±5.6) 35.5 (31.5 to 39.6) 90-day mortality (%) 23.5 20.6 0.26 Ventilator-free days 21.3 (±11.3) 22.1 (±10.5) -0.8 (-2.1 to 0.5) New ARDS to day 7 (%) 4.9 4.1% 0.7 (-2.1 to 3.6) Hyper-Ca to day 14 (%) 2.7 2.1 0.51 Kidney stones to day 90 (%) 7.1 5.3 0.24
Ginde AA et al. NEJM 2019;381:2529-2540
23
RCT in non-COVID critically ill
Variable Vitamin D Placebo p-value or difference 25-OH-D on day 0 11.2 (±4.8) 11.0 (±4.7) NR 25-OH-D on day 3 46.9 (±23.2) 11.4 (±5.6) 35.5 (31.5 to 39.6) 90-day mortality (%) 23.5 20.6 0.26 Ventilator-free days 21.3 (±11.3) 22.1 (±10.5) -0.8 (-2.1 to 0.5) New ARDS to day 7 (%) 4.9 4.1% 0.7 (-2.1 to 3.6) Hyper-Ca to day 14 (%) 2.7 2.1 0.51 Kidney stones to day 90 (%) 7.1 5.3 0.24
Ginde AA et al. NEJM 2019;381:2529-2540
24
RCT in non-COVID critically ill
Variable Vitamin D Placebo p-value or difference 25-OH-D on day 0 11.2 (±4.8) 11.0 (±4.7) NR 25-OH-D on day 3 46.9 (±23.2) 11.4 (±5.6) 35.5 (31.5 to 39.6) 90-day mortality (%) 23.5 20.6 0.26 Ventilator-free days 21.3 (±11.3) 22.1 (±10.5) -0.8 (-2.1 to 0.5) New ARDS to day 7 (%) 4.9 4.1% 0.7 (-2.1 to 3.6) Hyper-Ca to day 14 (%) 2.7 2.1 0.51 Kidney stones to day 90 (%) 7.1 5.3 0.24
Ginde AA et al. NEJM 2019;381:2529-2540
25 11 , , 47 , 11 , 90 - , , , 7 ARDS , - , -, ARDS , ,
25
Amrein K et al. BMJ Open 2019;12:e031083
Vitamin D (540,000 IU enteral dose + 4000 IU in MCT)
37.5 mg MCT solution R Primary
outcome 28-day mortality
>20 vitamin D and COVID-19 studies registered in clinicaltrials.gov
trials.gov 20 COVID-19
, VITDALIZE , COVID-19 , -COVID - - ,
26
Hiedra R et al. Expert Rev Anti Infect Ther. 2020.
Variable Value Age, mean year (SD) 63.2 (14.2) Female, n (%) 7 (41) Intubation, n (%) 3 (18) In-patient mortality 12%
17 consecutive patients No control group Unclear timing of vitamin C Variable steroid, HCQ, tocilizumab use
Variable Value p-value Pre-treatment D-dimer 2169
0.022 Post-treatment D-dimer 1728 Pre-treatment ferritin 1393
0.006 Post-treatment ferritin 1031

COVID-19 ? , , 17 , - 17 ,
27
4 VITAMIN C ALONE
Fowler AA et al. J Transl Med.2014;12:32 Fisher BJ et al. Crit Care Med 2011;39:1454-1460
26 patients in 3 groups:
--Placebo --Low dose vitamin C --High dose vitamin C
No patients withdrawn
RCT data in critically ill non-COVID-19
-COVID ? , : , , , 30 , 96 , SOFA
28
Vitamin C
SOFA score
Primary outcome
CITRIS-ALI , 167 SOFA
29
No difference in 43 of 46 secondary outcomes
Vitamin C and placebo 28- day mortality 46.3 and 29.8% (p=0.03), respectively
, , 96 SOFA , 46 43 28 , ICU , 168 ICU ,
30
4 VITAMIN C, THIAMINE, AND HYDROCORTISONE
Observational data in critically ill non-COVID-19
VARIABLE HAT (n=47) Control (n=47) p-value Hospital mortality, % 8.5 40.4 <0.001 Duration of vasopressor, mean h (SD) 18.3 (±9.8) 54.9 (±28.4) <0.001 Delta SOFA, 72 hours 4.8 (±2.4) 0.9 (±2.7) <0.001
Marik P et al. CHEST 2017; 151:1229-1238
, HAT ? , - , HAT , 47 , HAT , SOFA ,
31
3 VITAMIN C, THIAMINE, AND HYDROCORTISONE
RCT data in critically ill non-COVID-19
1. Hwang SY et al. Intensive Care Med. 2020;11:1-11. 2. Iglesias J. Chest. 2020;158:164-173. 3. Fujii T et al JAMA 2020;323:423-431. 4. Wani SJ et al. Infect Dis (London). 2020;52:271-278 5. Chang P et al. CHEST 2020;158:174-182 6. Moskowitz A et al JAMA 2020;324:642-650
Author (study) Study Population Intervention (n) Placebo (n) Time (h) to
intervention Primary outcome Comments
Hwang (ATESS)1 Septic shock AT (58) 0.9% (58) 1.0 vs 3.3 No difference in SOFA:0-72 hours
No difference in 7-, 28-, or 90-day mortality
Iglesias (ORANGES) 2 Septic shock HAT (68) 0.9% (69) 9.9 (±4.5) 27 vs 53 hours on vasopressor*
No difference in hospital- or ICU- mortality
Fujii (VITAMINS) 3 Septic shock HAT (109) H (107) 12.1 vs 8.9 No difference in alive and vasopressor free at 7-days
No difference in 28- or 90-day, ICU-, or hospital mortality
Wani4 Septic shock HAT (50) 0.9% (50) <24 hours No difference in 28- day mortality
57 vs 42% lactate clearance *
Chang (HYVCTTSSS)5 Septic shock HAT (40) 0.9% (40) <24 hours No difference in 28- day mortality
Greater SOFA score between day 0-3
Moskovitz (ACTS) 6 Septic shock HAT (101) 0.9% (99) <24 hours No difference in SOFA:0-72 hours
No difference in 30-day mortality
*significant (p<0.05) favoring intervention H=hydrocortisone, A=ascorbic acid, T= thiamine
HAT , 2020 , HAT ,

HAT ?
, , SOFA ACTS - ,
,
32
>30 vitamin C studies registered in clinicaltrials.gov
STUDY Intervention/Comparator Expected Enrollment Primary outcome Country LOVIT* Vitamin C to placebo 800 hospitalized COVID PODS at 28-days Canada ASCOT* Vitamin C to placebo 200 ICU COVID Ventilator-free days USA A-TO-Z* Vitamin C and zinc to placebo 520 COVID Symptom reduction USA VICTAS^ HAT to placebo 501 sepsis VVFD at 30-days USA *Recruiting patients with COVID19 disease ^Completed recruitment (non-COVID-19)
www.clinicaltrials.gov (accessed 08.18.2020)
trials.gov 30 SARS-CoV-2 , COVID-19 , VICTAS , -COVID COVID-19 -COVID , COVID-19
33
1. What is the pathophysiology of oxidative stress in critical illness (and COVID-19 infection)? Usual mechanisms related to critical illness promote oxidative stress but a cytokine storm observed in COVID-19 may lead to heightened inflammation and accentuate oxidative stress.
2. What are the mechanisms for zinc, selenium, vitamin C, and vitamin D in critically ill patients with COVID-19 disease? Micronutrients have pleomorphic mechanisms for benefit. The discussed micronutrients are postulated to have antiviral effects.
3. What is the evidentiary base for zinc, selenium, vitamin C, and vitamin D in critically ill patients with and without COVID-19 disease? Mechanistic, expert opinion, case reports, and observational level data inform micronutrient use in critically ill patients with COVID-19 disease. RCT level data inform micronutrient use in critically ill without COVID-19 disease. RCT level data for selenium, zinc, vitamin C, and D do not show mortality benefit.
In Summary…In Summary…
, ,
34
Thank you for your attention
SARS-CoV-2 , , , ,
-
35