Karin Amrein, MD, MSc Assoziierte Professorin Medical University of Graz, Austria Division of Endocrinology and Metabolism

VITAMIN D Hilft es dem Intensivpatienten?

CONFLICTS OF INTEREST

• BBraun

• Fresenius Kabi

• MSD

• Novartis

• Novo Nordisk

• Nycomed

• Aguettant

• Sinapharm

VDR KNOCKOUT (KO) MAUS

Bouillon R et al. Endocrine Reviews 2008; 29:726-776

Keisala et al. Premature aging in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol. 2009 Jul;115(3-5):91-7

HD

NICHT KLASSISCHE WIRKUNG

KLASSISCHE WIRKUNG

BASICS VITAMIN D

• VITAMIN D IST EIN STEROIDHORMON (VDR!)

• VITAMIN D REGULIERT ~ 200 GENE •CALCITRIOL (AKTIVES VITAMIN D) WIRD NICHT NUR IN DER NIERE PRODUZIERT • VITAMIN D HAT NEBEN DER KALZIUMHOMÖOSTASE VIELE ANDERE FUNKTIONEN

BASICS VITAMIN D BEI KRITISCH KRANKEN

(ERWACHSENE UND KINDER)

• EIN VITAMIN D MANGEL

• IST HÄUFIG

• MIT SCHLECHTEM OUTCOME ASSOZIIERT

(MORTALITÄT, NIERENVERSAGEN, SEPSIS…)

• FRAGE:

IST VITAMIN D NUR EIN MARKER ODER MEHR?

DEFINITION

Defizienz < 20ng/ml <50nmol/L

Insuffizienz 20-30ng/ml 50-75nmol/L

Normal >30ng/ml >75nmol/L

Intoxikation > 150 ng/ml > 375nmol/L

Holick M., NEJM 2007

Herz

Lunge/Muskel

Infektionen

Allgemein- Bevölkerung

Atemwegsinfekte, Tuberkulose

COPD, Myopathie,

Myalgia

Herzinfarkt, Herzinsuffizienz,

Sudden Cardiac Death

Kritisch Kranke

Nosokomiale Infekte Sepsis, SIRS

Lungenversagen Prolong. Weaning,

Critical Illness Myopathy

Kardiogener Schock, Arrhythmie

Adaptiert von: Lee P. et al., Intensive Care Med. 2009 Dec;35(12):2028-32

MECHANISMEN VON VITAMIN D - ICU

• Vitamin D Council Podcast 03: Vitamin D in hospitalized patients

• Intensive Care Network

http://www.vitamindcouncil.org/blog/vitamin-d-council-podcast-03-vitamin-d-in-hospitalized-patients/#

• randomisiert, doppelblind, placebokontrolliert • 5 ICUs (Neuro, Med, Chirurgie 3x) • 480 Pat. > 48 Std. auf ICU; 25(OH)D ≤ 20 ng/ml

Setting

• 540,000 IU Vitamin D3 vs. Placebo 1x po/NGS • 90,000 IU/ Monat vs. Placebo 5x Intervention

Aufenthaltsdauer im Spital Primärer Endpunkt Sekundäre Endpunkte

Mortalität, Aufenthaltsdauer auf ICU, Labor, 6-Monats-Follow Up…

VITDAL@ICU Correction of Vitamin D Deficiency in Critically Ill Patients

ClinicalTrials: NCT01130181

Amrein BMC Disorders 2012, JAMA 2014

RECOMMENDED DAILY INTAKE & UPPER LIMIT – IOM (ALLGEMEINBEVÖLKERUNG!)

• randomisiert, doppelblind, placebokontrolliert • 5 ICUs (Neuro, Med, Chirurgie 3x) • 480 Pat. > 48 Std. auf ICU; 25(OH)D ≤ 20 ng/ml

Setting

• 540,000 IU Vitamin D3 vs. Placebo 1x po/NGS • 90,000 IU/ Monat vs. Placebo 5x Intervention

Aufenthaltsdauer im Spital Primärer Endpunkt Sekundäre Endpunkte

Mortalität, Aufenthaltsdauer auf ICU, Labor, 6-Monats-Follow Up…

VITDAL@ICU Correction of Vitamin D Deficiency in Critically Ill Patients

ClinicalTrials: NCT01130181

Amrein BMC Disorders 2012, JAMA 2014

RESULTATE PRIMÄRER ENDPUNKT

SPITALAUFENTHALT (Tage)

Vitamin D3: 20.1 [IQR 11.1-33.3]

Placebo: 19.3 [IQR 11.1-34.9]

P=0.981

RESULTATE SEKUNDÄRER ENDPUNKT

% PATIENTEN MIT >30 NG/ML TAG 7

52% = KORREKTUR DES VITAMIN D - MANGELS

RESULTATE SEKUNDÄRER ENDPUNKT

SUBGRUPPE ≤ 12NG/ML (n=200; 42%)

SPITALSSTERBLICHKEIT

Vitamin D3: 28.6% Placebo: 46.1%

HR 0.56 [95%CI 0.35-0.90]

P=0.01 (log rank), 0.04 (for interaction)

RESULTATE SEKUNDÄRER ENDPUNKT

SUBGRUPPE ≤ 12NG/ML (n=200; 42%)

SPITALSSTERBLICHKEIT

Vitamin D3: 28.6% Placebo: 46.1%

HR 0.56 [95%CI 0.35-0.90]

P=0.01 (log rank), 0.04 (for interaction)

6 month mortality rate 42.9 vs. 35.0% P=0.087

6 month mortality rate 37.5 vs. 35.3%

6 month mortality rate 50.0 vs. 34.7%

VITAMIN D & MORTALITÄT

MENDELIAN RANDOMIZATION

Afzal, S.; Brøndum-Jacobsen, P.; Bojesen, S.E.; Nordestgaard, B.G. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ 2014

96,000 Dänen, Copenhagen

- Primary endpoint: overall mortality, cancer mortality and other mortalities. - genes associated with 25(OH)D levels <8 ng/mL (<20 nmol/L) caused a 30% higher mortality risk and a 40% higher risk of cancer deathsm no correlation with cardiovascular death.

- Genetic variants in DHCR7,CYP2R1!?

COCHRANE META-ANALYSE 2011

Bjelakovic 2011

COCHRANE META-ANALYSE 2014

Bjelakovic 2014

Main results We identified 159 trials, 56 randomised trials with 95,286 participants provided usable data on mortality. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).

.... only vitamin D3 decreased mortality: RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I2 = 0%; 75,927

participants; 38 trials). Trial sequential analysis supported our finding regarding vitamin D3, with the

cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials).

VITAMIN D & SUDDEN CARDIAC DEATH

Pilz S, et al. J Clin Endocrinol Metab 2008; 93: 3927-3935

Follow-up 7.7 Years

760 Deaths (188 Sudden Cardiac Deaths)

25(OH)D levels

>30 ng/ml

20-29.9 ng/ml

10-19.9 ng/ml

<10 ng/ml HR: 5.05 (2.13-11.97)

Severely deficient vs. normal

VITAMIN D AND HOSPITAL

MORTALITY

JCEM 2012

MORTALITY

Autier 2013

Bolland 2014

Heaney 2013

WELCHE INTERVENTIONEN HABEN JEMALS IM MULTICENTER DESIGN DIE MORTALITÄT REDUZIERT?

Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect*. Landoni, Giovanni et al. , Critical Care Medicine. 43(8):1559-1568, August 2015.

HELFEN ANTIBIOTIKA INTENSIVPATIENTEN?

JA!?!!! ABER NUR WENN EINE INFEKTION VORLIEGT

LARGE ONGOING RCT‘s

• VITAL Study:

• 25,000 pat > 50/55 yrs, US, 2010 – 2016

• FIND Study

• 18,000 pat, Finland

• Vida Study:

• > 5,000 elderly pat., NZ

• DO HEALTH Study:

• 2152 pat. > 70; 7 europ. Centers

LEITLINIEN

• ZIEL 25(OH)D > 20ng/ml

• IOM (ALLGEMEINBEVÖLKERUNG)

• 600-800 IU/d, max. 4000 IU/d

• ENDOCRINE SOCIETY (RISIKOPAT.)

• 1500 – 2000 IU PRO TAG!!!

• SICHERES LIMIT 10,000 IU/d Ross 2011 Holick 2011

CONCLUSIO

• ZIELSPIEGEL > 20 ng/ml (zumindest Knochen)

• ERFORDERLICHE DOSIS oft 2000 IU/d oder mehr

• LINK VITAMIN D UND ICU - Outcome

• VITdAL-ICU: Signifikant niedrigere Spitalssterblichkeit bei

prädefinierter Subgruppe mit schwerem Vitamin D

Mangel (NNT 6; absolute Differenz 17.5%, relative 44%)

KNOCHEN RELEVANT?

SCHENKEL HALSFRAKTUR

HUMERUS FRAKTUR

FRAGILITY FRACTURES (fx)

• Fragility fx are associated with – increased morbidity – Increased mortality

• One year after hip fx – Institutionalization and death is a major

problem (up to 50%!)

Pasco 2005, Edwards 2009, Papaioannou 2010

FRACTURES AFTER ICU?

• MEN: 2.41 fx per 100 patient years • WOMEN: 3.84 fx per 100 patient years

• 65% increased risk compared with age-

matched random population sample • (HR 1.65, 95% 1.08-2.52, p=0.02, elderly

women) Orford CCM 2011

DANKE!

SIX-MONTH FOLLOW UP (eTABLE 5)

Prespecified Subgroup Population Severe Vitamin D Deficiencya Less Severe Vitamin D Deficiencyb

Placebo (n=51)

Vitamin D3 (n=64) P-value

Placebo (n=85)

Vitamin D3 (n=89)

P-value

Number of readmissions 20 (39.2%) 24 (37.5%) 0.85 39 (45.9%) 31 (34.8%) 0.14 No. of pat with respiratory tract infections 8 (15.7%) 6 (9.4%) 0.39 8 (9.4%) 3 (3.4%) 0.13

Quality of life (SF-12), points

Physical

Mental

37.6±10.3

46.9±9.4

37.8±11.8

47.1±10.6

0.90

0.85

38.4±10.7

49.2±10.2

42.4±10.6

49.2±9.8

0.02

0.95

Hand grip strength, mmHg

Left

Right

(n=13)

81.9±30.5

88.7±32.1

(n=13)

77.5±27.0

81.9±28.8

0.61

0.88

(n=27)

78.7±35.5

79.9±30.8

(n=23)

90.1±34.0

98.4±26.6

0.23

0.03

Falls (no. of pat) 14 (27.5%) 16 (25.0%) 0.77 19 (22.4%) 11 (12.4%) 0.08

Fractures (no. of pat) 1 (2.0%) 1 (1.6%) - 1 (1.2%) 1 (1.1%) -

Timed up & go test, seconds

(n=13)

10 (6-15)

(n=13)

11 (5-90) 0.64

(n=27)

9 (4-17)

(n=22)

8.5 (6-14) 0.11

BMD, T-Score

lumbar spine

femoral neck

(n=13-14)

-0.22±1.42

- 0.74±1.27

(n=14)

-0.23±1.30

-0.89±1.30

0.98

0.77

(n=25-26)

-0.75±1.23

-0.96±0.88

(n=22-23)

-0.12±1.60

-0.85±1.34

0.13

0.74

17 deaths less n=80 personal follow up