Vitamin D in Critical Illness

Vitamin D in Critical Illness

Iris Thiele Isip Tan MD, MScAssoc. Prof. 4, UP College of Medicine

Chief, UP Medical Informatics Unit

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7 Oct 2014

Tuesday, October 7, 14

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Vitamin D Metabolism

Image from http://www.well.ox.ac.uk/aug-10-vitamin-d-influences-over-200-genes

Vit D3cholecalciferoloily fish & egg yolk

Vit D2ergocalciferolplant sources


http://www.well.ox.ac.uk/aug-10-vitamin-d-influences-over-200-genes

http://www.well.ox.ac.uk/aug-10-vitamin-d-influences-over-200-genes

The vitamin D endocrine system.

Norman A W Am J Clin Nutr 2008;88:491S-499S

©2008 by American Society for Nutrition


Tissues that express the vitamin D receptor

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


Does vitamin D replacement improve outcomes in critical illness?

Does low vitamin D affect outcomes in critical illness?

Is there vitamin D deficiency in critical illness?

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Is there vitamin D deficiency in critical illness?





P: 42 critically ill patients referred for endocrinologic eval

I: 25(OH)D levelsO: MortalityM: prospective

Lee et al. NEJM 2009;360:18

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


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


n=24Critically ill in ICU diagnosed with sepsis*

n=25Critically ill in ICU without sepsis

n=21Healthy, non-hospitalized controls*

* As defined by the American College of Chest Physicians & Society of Critical Care Medicine consensus panel (2001)

1 2 3

* 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

Jeng et al. Journal of Translational Medicine 2009;7:28

Vit D insufficiency

25(OH)D < 30 ng/mL

Grp 1 (Sepsis): 100%Grp 2 (No sepsis): 92%Grp 3 (Controls): 66.5%


Subjects with sepsis had lower DBP levels vs those without sepsis



Vitamin D & ImmunomodulationLL-37

CathelicidinAdams 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





Is there vitamin D deficiency in critical illness? Yes







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P: Veterans in ICU n = 136 (42 SICU & 94 MICU) I: 25(OH)D levelsO: length of ICU stay, mortalityM: retrospective

McKinney et al, J Am Med Dir Assoc 2011;12:208-211



Average 25(OH)D level 24.6 +12.1 ng/mLVitamin D insufficiency (<30 ng/mL): 60%

Vitamin D deficiency (<20 ng/mL): 38%


ICU stay >3 daysVitamin D replete: 29%

Vitamin D deficient: 58%

Timing of vitamin D blood draw was unrelated to deficiency status

Vit D deficient: 16.2 daysVit D replete: 12.7 days

p=0.440




Survived n=81 (59%)Died in ICU n=16 (12%)

Died after discharge n=39 (29%)


SurvivalVitamin D replete: 69%

Vitamin D deficient: 44%p=0.004

Death after admission for vit D deficient RR =1.81McKinney et al, J Am Med Dir Assoc 2011;12:208-211


Low serum 25(OH)D & mortality in the critically illBraun 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


DEFICIENCY25(OH)D <15 ng/mL

30-day OR 1.69 [1.26–2.26]; p <0.0001

OR 1.0

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

INSUFFICIENCY25(OH)D <16-29

SUFFICIENCY25(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 costM: Prospective observational


0

5

10

15

20

MILD MODERATE SEVERE

13.33

7.295.17

Matthews et al, Am J Surg Juy 2012;204(1):37-43

Vit D deficiency & ICU outcomesDa

ys

n=96 (37.2%)27-39 ng/mL 14-26 ng/mL <13 ng/mLn=18 (7%) n=138 (53.5%)

25(OH)Ddeficiency

13.33 + 19.957.29 + 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

Mortality n=17 (12.3%)n=11 (11.5%)p = 0.047

Mild/normal vs moderate/severe


P: 130 hospitalized patients on mechanical ventilation I: 25(OH)DO: Mortality rateM: 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/mLn=23

Ave 24.9 ng/mL

Arnson et al, Q J Med 2012;105:633-639Tuesday, October 7, 14

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 admissionO: 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)Tuesday, October 7, 14

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

Long-xiang et al, Chinese Medical Journal 2013;126(14)

No difference in 28- and 90-day survival



Does low vitamin D affect outcomes in critical illness? Yes?









+ 100 IU oral vitamin D intake

= + 1 ng/mL (2.5 nmol/L)

serum 25(OH)D

Rule of ThumbPatient 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

Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41


Institute of MedicineTolerable 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 increaseM: randomized, double-blind placebo controlled


Limitations of Vit D administrationDosingContraindication for IM injection in most ICU patientsUnavailability of parenteral high-dose vit D formulationsUnreliable 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/dropdissolved 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 3Two patients in Vit D group demonstrated small (7 ng/mL) or no increase (1 ng/mL) in 25(OH)D levels


Does vitamin D replacement improve outcomes in critical illness? Don’t know

Does low vitamin D affect outcomes in critical illness? Yes?







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Vitamin D in Critical Illness