Nutritional Supplements
Intensivistendagen 2020
Heleen Oudemans-van Straaten, EmeritusDepartment of Intensive Care
2
Geen (potentiële) belangenverstrengeling
Voor bijeenkomst mogelijke relevante
relaties
Bedrijfsnamen
• Sponsoring of onderzoeksgeld
• Honorarium of andere (financiële)
vergoeding
• Aandeelhouder
• Andere relatie, namelijk…
• ZonMW Grant Vit C after
cardiac arrest
• non
• none
• none
Nutritional supplements are any dietary supplement
intended to provide nutrients that may otherwise not be
consumed in sufficient quantities; i.e.
vitamins, minerals, proteins, amino acids
or other nutritional substances
20 minutes!?!
Focus for today
• Thiamine
• Vitamin C
• Vitamin D
My first confrontation with micronutrients.
Hair loss
tufts of hair in her bed
1981
40-y old woman➢Exacerbation M Crohn
➢Parenteral nutrition for 3 weeks
Zinc deficiency
• Loss of taste and smell
• Anorexia
• Apathy, depression
• Ataxia
• Decreased immunity
• Poor wound healing
• Dermatitis
• Diarrhea
• Excessive hair loss
Zinc
Component of
• > 3000 zinc-associated transcription factors
• > 300 enzymes, including copper/zinc superoxide
dismutase (antioxidant defense)
• proteins involved in DNA repair
• 55 yrs old burn patient
• CRRT for weeks
• Unexplained repeated
Ventricular fibrillation
without coronary artery disease
Copper deficiency in the ICU
• major burns, after gastric and
bariatric surgery, CRRT,
prolonged enteral nutrition
Symptoms of acute deficiency
• cardiac arrhythmias,
myeloneuropathy, delayed wound
healing.
‘Supra-normal’ concentrations• Inflammation/infections
• Alzheimer, hemopathies,
hemochromatose,
hyperthyroidism, liver cirrhosis
and hepatitis.
Bound to ceruloplasmin
• a ferroxidase protein,
which increases in
inflammation.
Copper deficiency
Micronutrients are important
• Plasma concentrations often decline during
inflammation
Percentage change of micronutrients
increments of CRP
Vitamin C
Vitamin B6
Zinc
Selenium
Copper
A. Duncan, Am J Clin Nutr 2012;95:64–71The decline was greatest for selenium, vit A, B6, C and D
Micronutrients are important
• Concentration decline during inflammation➢ except for Copper and Vitamin E
• Concentrations of some increase during recovery
• Recommended doses are mostly higher during
disease than during health, but
• Some supplements should probably not be given
during the acute phase of illness: glutamine, arginine,
iron, copper …• Robust RCTs are not available for most
Crit Care 2016; 20: 356
• No positive or negative effect of iv selenium on
mortality, LOS, ventilator stay
• Reduction of infections in the subgroup of patients
without sepsis RR 0.88 (95% CI 0.78-0.98)
21 RCTs
anti-inflammatory
anti-oxidant
immune modulating
Thiamine
• Water soluble vitamine
• Enteral uptake: carrier mediated + passive diffusion
• Body stores: 25-30 mg➢ skeletal muscle, heart, brain, liver, and kidneys
• Urinary excretion
Short half life
Limited stores
Thiamine deficiency➢ Alcoholism
➢ Prolonged fasting, anorexia nervosa, unbalanced diet
➢ AIDS, malignancy, hyperemesis gravidarum
Intake LossMetabolism
➢ Sepsis/SIRS/Burns
➢ Cardiac surgery
➢ Chronic heart failure
➢ Iv glucose/parenteral nutrition
➢ REFEEDING
➢ GI surgery (bariatric)
➢ Prolonged hemodialysis, CRRT
➢ Critical illness!
➢ If left untreated →• Korsakow syndrome
➢ Chronic amnestic syndrome
Thiamine deficiency
NEUROLOGICAL MANIFESTATIONS• Wernick syndrome: acute
➢ Confusion, disturbed eye movements, ataxia 1881
Only 20% presents
with the trias
CARDIAC MANIFESTATIONS‘Wet’ Beri Beri
Tachycardia, high CO, pulmonary and peripheral edema
Lactic acidosis
Wernicke encephalopathy: pathological substrate
NEJM 2005
Abnormal hyperintensity of the
mamillary bodies and
periaquaductal gray matter
21-y old women
Abdominal pain,
nausea, vomiting,
weight loss 13 kg
Tachycardia,
sleepy,
disoriented,
slurred speech,
ocular bobbing
Near complete
resolution after
7-days thiamine
Wernicke encephalopathy
NEJM 2005
Abnormal hyperintensity of the
mamillary bodies and
periaquaductal gray matter
Thiamin functions predominantly in one of its
phosphorylated forms, mainly TTP and TPP
The main role of T+ is being an antioxidant
2014;53: 821-35
Thiamine pyrophosphate (TPP)
Cofactor carbohydrate metabolism
Manzanares W. Curr Opin Clin Nutr Met Care
2011;14:610
NADPH
ATP• Production Energy
• # Oxidative damage
Production of
acetylcholine & myeline
Production of glucose-
derived neurotransmitters
(GABA, glutamate)
Recent clinical studies in intensive care
• Adult patients with septic shock and lactate>3 mmol/L
• Thiamine 200 mg or placebo for 7 days
• 88 patients enrolled
• No difference in primary outcome (lactate after 24-h)
Predefined subgroup: thiamine deficient (35%)
• Lower lactate concentrations
• Tendency to lower mortality; significant over time
• 77 patients
Thiamine Placebo P-value
Baseline
creatinine
1.2 [0.8 – 2.5] 1.8 [1.3 – 2.7] 0.3
Need of RRT 1 (3%) 8 (21%) 0.04
Repeated measures adjusted for baseline creatinine:
• worst creatine was higher in the placebo group (p=0.05)
Vitamin CHumans have lost the
capacity to synthesize
vitamin C
Most animals
synthetise vitamin
C under stress
Humans develop
deficiency under
extreme circumstances
Amrein K. et al.Intensive Care Med 2018
Critical illness: vitamin C deficiency is
common
Amrein K. et al.Intensive Care Med 2018
• Baseline comorbidity➢ smoking, elderly
• Enteral uptake ➢ carrier-mediated satiable transport
• Redistribution
Vitamin C
deficiency
Rozemeijer, S. Nutrients 2019
• Baseline comorbidity➢ smoking, elderly
• Enteral uptake ➢ carrier-mediated satiable transport
• Redistribution
• Metabolic needs ➢ oxidative stress
• Recycling (consumption)
• Renal loss ➢ glomerular hyperfiltration
Vitamin C
deficiency
Relation between vitamin C and
oxidative stress sORP)
Vitamin C deficiency
despite recommended enteral and parenteral intakes
Mean vit C intake 125 mg/d
Carr AC, Critical Care 2017:21(1):300.
Septic shock
Non-sepsis
Septic shockNon-sepsis
hypovitaminosis
Metaplus study: patients with sepsis
vitamin C in enteral nutrition
-5
5
15
25
35
45
55
65
75
Baseline Dag 4 Dag 8
Vit
am
in C
(µm
ol/
L)
Vitamine C plasma concentraties
690 mg/dag p.o.
195 mg/dag p.o.
Deficiency
Vitamin C plasma concentrations
Healthy volunteers
van Zanten, JAMA, 2014; 312: 514-524
Critical illness:
enteral supplementation is ìnsufficient
Day 4 Day 8
De Grooth, HJS. Intensive Care Med 2014;40 (Suppl 1), Abstract 0723
Vitamin C plama concentrations
ICU admission and day 3
Plasma vitamin C organ failure
De Grooth, HJS. Intensive Care Med 2014;40 (Suppl 1), Abstract 0723
SOFA
score
AKIN
stage
Plasma vitamin C ICU mortality
De Grooth, HJS. Intensive Care Med 2014;40 (Suppl 1), Abstract 0723
ICU mortality
Is deficiency
• Consequence of
severe illness?
• Contributes to
severity?
• Both?
• Vitamin C deficiency➢ goes unnoticed (the assay is complex)
➢ symptoms may mimic critical illness
Vitamin C: physiological role
• Cofactor in biosynthetic pathway➢ catecholamines, bioactive peptides and peptide hormones,
collagen
• Antioxidant➢ protects biomolecules and cells
➢ Recycles vitamin E
➢ Increases receptor sensitivity (catecholamines, glucocorticoids)
• Epigenetic role➢ gene transcription and cell signalling pathways (HIFs)
• Anti-inflammatory and immune-promoting
Supression of chronic
inflammation and dysoxia
Oxidative protection
Immune defence
Inflammatory response
Production of vasopressors
and collagen
Wound healing
Microcirculation
Vascular barrier
Mood
Pain perception
Vitamin C
is
crucial
> 500 peer-reviewed experimental and clinical studies
Carr, Critical Care 2015. Oudemans-van Straaten, Crit Care 2014. Mohammed, International Wound Journal
2015. Carr, Nutrients 2017. Wang Am J Clin Nutr 2000. Ang Biochemical Society Transactions 2018
Clinical trials in critically ill patients
• Supplementation
• Pharmacological dosing
Controlled
trials
Vit C
supplementation
0.5 – 3 g/day
Less organ failure
Less organ support
Lower mortality
No effect
J Surg Research 2003; 100: 144-148
Normal values
1.4-5 mg/dl
I.V.
3 g/d iv is needed to obtain normal plasma
concentrations
• 2 g/day iv is needed to obtain plasma
concentrations in the high-normal range
• Continued supplementation is needed to
prevent re-occurrence of hypovitaminosis
Vitamin C pharmacokinetic modeling
10 g bolus twice daily
2 g bolus twice daily
10 g continuously
2 g continuously
De Grooth et al.
Pharmacological dosing: controlled studies
15 mg/day
Journal of Translational Medicin 2014;12:32
Vit C 50 mg/kg/day vs. Vit C 200 mg/kg/day iv vs Placebo
24 patientsCRP
Procalcitonin
3.75 mg/day
• RCT
• 2 x 14 patients
• Surgical septic shock
• Placebo vs. Vit C 4 x 25 mg/kg/day iv
Zabet J Res Pharm Pract 2016 ;5: 94-100
Dose and duration of noradrenalin
28 day mortality 14.3% vs. 64.3%, p = 0.009
75 kg
7.5 g/day
g/day
• Before-after study
• Patients➢ severe sepsis/septic shock
➢ procalcitonin > 2 ng/L
Standard treatment
• No vitamin C
• Hydrocortisone (guidelines)
• No thiamine
Intervention
• Vitamin C 4 dd 1.5 g iv
• Hydrocortisone 4 dd 50 mg iv
• Thiamine 2 dd 200 mg
Chest 2017; 151(6):1229-1238
6 g/day
Marik, P. Chest 2017; 151(6):1229-1238
• Multicenter RCT
Patients
• 167 patients with sepsis and ARDS
Intervention
• Vitamin C 50 mg/kg iv every 6-h OR placebo for 96h
Primary endpoint
• Delta SOFA
JAMA 2019 322; 1261
875 g
15 g/day
No difference in delta SOFA
Sofa scores of the deceased patients were not accounted for
• Multicenter open label RCT
Patients
• Sepsis-3 definition of septic shock
Primary endpoint
• Duration of time alive + free of vasopressors day-7
Intervention• iv vitamin C 1.5 g
• iv thiamine 200 mg
• iv hydrocortisone 50 mg OR
every 6-h
• iv hydrocortisone 50 mg
every 6-h
until cessation of vasopressors or for 10-d
JAMA 2020, 17 Jan online
6 g/day
Results
216 patients were randomized
211 patients completed the primary outcome
No difference between groups of duration of time alive and
free of vasopressor support and other outcomes, except for
Change in SOFA score
Intervention Control-2 [-4 to 0] -1 [-3 to 0]n=82 n=75
VITAMINS vs. Marik
• All patients in the contol group received hydrocortisone
• Strikingly low mortality compared to SOFA admission
➢ 98% survived the first week
• Low reported comorbidity (only diabetes and pre GFR< 30 ml)
• Late administration of vitamin C
• Estimated median 15-h after admission (compared to < 6-hours
in the Marik study)
8.5
Time to needle may be important
Hydrocortisone-Ascorbic Acid-Thiamine Use Associated with
Lower Mortality in Pediatric Septic Shock
E.L. Wald et al.; Am J Resp Crit Care 2020 online
Retrospective propensitiy matched cohort study in patients
with septic shock admitted to the PICU 2014-2019
HR for death 0.3 (95 CI 0.1 – 0.9)
Pharmacological dosing: vitamin C
• Promising, but not all trials are positive
Maybe related to
➢ Timing
➢ Type of patients
➢ …….?
• No adverse events
Vitamin D
Vit D deficiency
• In 30-60% of ICU patients
• Associated with excess morbidity and mortality
Putzu A. J Crit Care 2017;38:109-114
≤15 ng/mlincreased
risk of sepsis
RCTs on Vit D
in critically ill patients
Mortality benefit in
the predefined
subgroup with severe
vitamin D deficiency
(25OHD) < 12
Cathelicidin
Quadriceps strength
Less inflammation
J Crit Care 2017; 38: 109-114
• Vitamin D might reduce mortality
• No major adverse events
NEJM 2019 (dec) online
Patients
• Critically ill vitamin D deficient patients
• 1087 patients: baseline 25OH < 50 nmol/L confirmed
Intervention
• 540.000 IU vit D3 (single oral dose) vs. Placebo < 12-h of
randomization
trial was stopped after the 1st interim analysis
VIOLET
Primary endpoint
90-day mortality
No interaction between
treatment group and vitamin D
statusNEJM 2019 (dec) online
Higher mortality in
• patients with
sepsis/infection (primary
analysis group)
• Prehospital facility
residence, pneumonia,
infection,
prerandomization ARDS
(screened deficient
population)
Differences between the two large RCTs
VIOLET VITdAL-ICU
2019 2014
Multi center, -national Austria
Inclusion < 12 h vs. < 3 d
Type of patient medical > 2/3 surgical/neuro
Dosing once loading + follow up
Ethnic mixed > 99% white
Potential confounder:
Enzymes
that synthesize and metabolize
vitamin D
are magnesium dependent!
to normal
• Deficiency is common but often goes unnoticed
Micronutrients
Pharmacological
dosing
• Needs may be increased and supplementation
may be beneficial
• Controlled studies: controversial
Timing
Population
Concomitant deficiency of other micronutrients
Supplementation: target is a high normal dose
Supplementation
dose
Thiamin 100 - 400 mg /day
In patients at riskVitamin C 2 - 3 g /day i.v.
Vitamin D 1500 - 2000 IU /day
???
Trace elements/
Multivitamins
1 PN vial / day
Higher doses Specific compounds
Patients at risk