Vitamin D in critical illness: A literature review

Iris Thiele Isip Tan MD, MSc
Assoc. Prof. 4, UP College of Medicine
Chief, UP Medical Informatics Unit
Sunlight by Rishi Bandopadhay
https://flic.kr/p/7wrAGT
Vitamin D in Critical Illness
7 Oct 2014
Tuesday, October 7, 14

Image from http://www.well.ox.ac.uk/aug-10-vitamin-d-influences-over-200-genes
Vitamin D Metabolism
Vit D3
cholecalciferol
oily fish & egg yolk
Vit D2
ergocalciferol
plant sources

The vitamin D endocrine system.
Norman A W Am J Clin Nutr 2008;88:491S-499S
©2008 by American Society for Nutrition

Adipose Adrenal Bone Bone Marrow
Brain Breast Cancer cells
Cartilage Colon Eggshell gland Epididymis
Hair follicle Intestine Kidney Liver (fetal) Lung
Lymphocytes (B & T) Muscle, embryonic
Muscle, smooth Osteoblast Ovary Pancreas B cell
Parathyroid Parotid Pituitary Placenta Prostate
Retina Skin Stomach Testis Thymus
Thyroid Uterus Yolk sac (bird)
Norman A W Am J Clin Nutr 2008;88:491S-499S
Tissues that express the vitamin D receptor

Is there vitamin D deficiency
in critical illness?
Sunset by Maria Rosaria Sannino,
https://flic.kr/p/tQ7S2
Does low vitamin D affect
outcomes in critical illness?
Toronto General Hospital interior by mars_discovery _district
https://flic.kr/p/2A3Taj
Does vitamin D replacement
improve outcomes in critical
illness?

Sunset by Maria Rosaria Sannino, https://flic.kr/p/tQ7S2

P: 42 critically ill patients
referred for endocrinologic eval
I: 25(OH)D levels
O: Mortality
M: prospective
All patients who died had
undetectable 25(OH)D
Consider vit D status in
critically ill: hypocalcemia as
reason for referral only 5%
Lee et al. NEJM 2009;360:18

SAPS II* score & predicted mortality
and vitamin D status
Sufficient: 34+11; 16%
Insufficient: 45+13; 35%
Deficient: 51+13; 45%
* Simplified Acute Physiology Score II
Lee et al. NEJM 2009;360:18

Cross-sectional study of vitamin D status
[25(OH)D & DBP] & systemic LL-37 (cathelicidin)
levels in critically ill patients
(with and without sepsis)
Journal of Translational Medicine 2009;7:28

1 2 3
n=24
Critically ill in
ICU diagnosed
with sepsis*
n=25
Critically ill in
ICU without
sepsis
n=21
Healthy, non-hospitalized
controls*
* As defined by the
American College of
Chest Physicians &
Society of Critical Care
Medicine consensus
panel (2001)
* Adults without known
acute or chronic diseases,
no hospitalizations for any
illness previous 12
months, not taking any
medications or vitamin
supplements
Journal of Translational Medicine 2009;7:28

Lower 25(OH)D
levels in critically ill
vs healthy controls
Vit D insufficiency
25(OH)D < 30 ng/mL
Grp 1 (Sepsis): 100%
Grp 2 (No sepsis): 92%
Grp 3 (Controls): 66.5%
Jeng et al. Journal of Translational Medicine 2009;7:28

Subjects with
sepsis had
lower DBP
levels vs those
without sepsis

Vitamin D & Immunomodulation LL-37
Cathelicidin
Adams JS & Hewison M. Nat Clin Pract Endocrinol Metab 2008 Feb;4(2):80-90.

Lower LL-37
levels in critically ill
vs healthy
controls

Positive relationship
between 25(OH)D
and LL-37 levels in
all three groups

in critical illness? Yes
illness?

Toronto General Hospital interior by mars_discovery _district https://flic.kr/p/2A3Taj
Does low vitamin D affect outcomes

P: Veterans in ICU n = 136 (42 SICU & 94 MICU)
I: 25(OH)D levels
O: length of ICU stay, mortality
M: retrospective
McKinney et al, J Am Med Dir Assoc 2011;12:208-211

Average 25(OH)D level 24.6 +12.1 ng/mL
Vitamin D insufficiency (<30 ng/mL): 60%
Vitamin D deficiency (<20 ng/mL): 38%

ICU stay >3 days
Vitamin D replete: 29%
Vitamin D deficient: 58%
Timing of vitamin D blood draw
was unrelated to deficiency status
Vit D deficient: 16.2 days
Vit D replete: 12.7 days
p=0.440

Survived n=81 (59%)
Died in ICU n=16 (12%)
Died after discharge n=39 (29%)

Survival
Vitamin D replete: 69%
Vitamin D deficient: 44%
p=0.004
Death after admission for vit D deficient RR =1.81

Low serum 25(OH)D &
mortality in the critically ill
Braun et al. Crit Care Med 2011 April; 39(4):671-7
P: 2,399 patients in 209 medical & surgical
ICU beds
I: 25(OH)D measured prior to hospitalization
between 1998 & 2009
O: 30, 90 and 365-day post ICU admission
mortality, in hospital mortality
M: multicenter observational study

Low pre-admission 25(OH)D is a
significant predictor of mortality in
the critically ill Braun et al. Crit Care Med 2011 April; 39(4):671-7
DEFICIENCY
INSUFFICIENCY
25(OH)D <15 ng/mL
25(OH)D <16-29
30-day OR 1.69
OR 1.0
[1.26–2.26]; p <0.0001 SUFFICIENCY
25(OH)D >30 ng/mL
Adjusted OR
90-day OR 1.67
[1.28–2.17]; p=0.001
365-day OR 1.72
[1.35–2.19]; p=0.001
In-hospital OR 1.67
[1.27–2.33]; p=0.001
30-day OR 1.36
[1.03–1.79]; p =0.029
90-day OR 1.51
[1.19–1.93]; p=0.001
365-day OR 1.44
[1.15–1.79]; p=0.001
In-hospital OR 1.34
[1.01–1.79]; p=0.04

P: 258 consecutive patients admitted to SICU
I: 25(OH)D by HPLC and tandem mass spectrometry
O: length of stay, mortality rate and cost
M: Prospective observational

20
15
10
5
0
Vit D deficiency & ICU outcomes
13.33
7.29
5.17
MILD MODERATE SEVERE
27-39 ng/mL 14-26 ng/mL <13 ng/mL
n=18 (7%) n=138 (53.5%)
Matthews et al, Am J Surg Juy 2012;204(1):37-43
Days
n=96 (37.2%)
25(OH)D
deficiency
13.33 + 19.95
7.29 + 15.3
5.17 + 6.5
COSTS
p = 0.002
$51,413.33 +
75,123.00
$28,123.65 +
59,752.00
$20,414.11 +
25,714.3
p = 0.027
p = 0.047
Mortality n=11 (11.5%) n=17 (12.3%)
Mild/normal vs
moderate/severe

P: 130 hospitalized patients on mechanical ventilation
I: 25(OH)D
O: Mortality rate
M: Prospective observational single center study

Average vit D
14.0 + 6.9 ng/mL
Vit D deficient
(<20 ng/mL)
n=107
Ave 11.7 ng/mL
Vit D >20 ng/mL
n=23
Ave 24.9 ng/mL
Arnson et al, Q J Med 2012;105:633-639

P: 50 healthy controls, 51 ICU controls, 105 ICU
patients with sepsis
I: 25(OH)D by HPLC and tandem mass spectrometry within
first 24 h of ICU admission
O: Correlation with disease severity (APACHE II, SAPS II, SOFA)
M: Prospective observational single center study
Long-xiang et al, Chinese Medical Journal 2013;126(14)

APACHE II SAPS II
SOFA Very low negative correlations
between 25(OH)D
& scoring systems
No difference in
28- and 90-day survival

Yes?
illness?

Does vitamin D replacement improve

Rule of Thumb
+ 100 IU oral
vitamin D intake
= + 1 ng/mL
(2.5 nmol/L)
serum 25(OH)D
Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41
Patient with a starting serum
25(OH)D of 15 ng/mL would
require 1,500 IU/d to bring
his level to 30 ng/mL

Institute of Medicine
Tolerable Upper
Intake Level (TUIL)
2,000 IU/day No-observed-adverse-effect-
level (NOAEL)
10,000 IU/day
Heaney R. J Musculoskelet Neuronal Interact 2006:6(4):334
Serum 25(OH)D
32 ng/mL = minimum
daily intake of
2,600 IU vitamin D
(US residents)

P: 25 patients with 25(OH)D < 20 ng/mL
I: Single dose 540,000 IU (13.5 mg) of cholecalciferol
dissolved in 45 ml herbal oil vs placebo via feeding tube;
200 IU cholecalciferol daily for placebo group
O: mean 25(OH)D increase
M: randomized, double-blind placebo controlled

Limitations of
Vit D administration
Dosing
Contraindication for IM
injection in most ICU patients
Unavailability of parenteral
high-dose vit D formulations
Unreliable GI absorption after
oral dosing due to multifactorial GI
dysfunction, changes in GI blood
supply & motility, sepsis and
multiorgan failure
Amrein et al, Critical Care 2011;15:R104

540,000 IU of Vit D3
3 bottles of Oleovit D3
solution (commercially available,
Austria)
400 IU vitamin D3/drop
dissolved in 45 ml of herbal oil

8/10 had normalization of 25(OH)D levels (>30 ng/mL)
Highest achieved was 64 ng/mL on day 3
Two patients in Vit D group demonstrated small (7 ng/mL)
or no increase (1 ng/mL) in 25(OH)D levels

Yes?
illness? Don’t know

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Vitamin D in critical illness: A literature review

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