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