Impact of Vitamin D supplementation in critically ill patients Paul Lee (Dept. of Endocrinology) Garvan Institute Claire Reynolds & Priya Nair (Dept. of Intensive Care) St. Vincents Hospital, Sydney
UVB 7-dehydrocholesterol Previtamin D 3 Heat Chylomicrons <30% Vitamin D 3 24(OH)D 3 24-OHase 25(OH)D 3 1,25(OH) 2 D 3 1 -OHase 25-OHase Liver DBP Target tissues 1 -OHase 1,25(OH) 2 D 3 Local tissue actions
Rickets Osteomalacia Maintenance of mineral homeostasis Osteoporosis Ca reabsorption insulin secretion & synthesis Diabetes Inflammatory bowel diseaes Mucosal integrity Vitamin D Metabolic syndrome Cardiovacular Endothelial function diseaes Ca absorption Autoimmunity Cancer Immune modulation Infection Microbial defence
Neurologist Multiple sclerosis & stroke Cardiologist Pulmonologist Gastroenterologist ID physician Oncologist Ischaemic heart disease COPD Inflammatory bowel disease TB Breast & colon cancer Can vitamin D deficiency cause multi-organ dysfunction?
Aim: To determine the prevalence & impact of vitamin D deficiency in critically ill patients
Number of patients 42 Sex 47.6% M Age (years) 51.4 (16.8) Diagnosis Cardiac 10.5% Neurological 7.8% Trauma 2.6% Metabolic 13% Sepsis 36.8% Respiratory 31.3% Steroid user 66.7% Transplant recipients 52.3% % on Ca supplement 28.5% % on vitamin D supplement 23.8%
Prevalence of vitamin D insufficiency % % of patients 60 50 40 30 20 10 0 Severe Severe deficiency deficiency (<15 nmol/l) (<15 nmol/l) Deficiency (15-30 (15-30 nmol/l) nmol/l) Insufficiency (30-60 (31-60 nmol/l) nmol/l) Sufficiency (>60 nmol/l)
Relationship between vitamin D status & calcium 1.4 1.3 1.2 1.1 Normal 24% 76% 1 0.9 0.8 0.7 0 20 40 60 80 25-OH D (nmol/l) r=0.78 p<0.01
Vitamin D & disease severity SAPS 70 60 50 40 30 20 10 * Predicted mortality rate (%) 60 50 40 30 20 10 * 0 Sufficient Insufficient Deficient 0 Sufficient Insufficient Deficient *p=0.04 compared with sufficient group *p<0.01 compared with sufficient group 3 deaths all with undetectable vitamin D
Predictors of SAPS Age Sex Creatinine Albumin Ionised calcium 25-OH vitamin D X X X X p=0.02 p<0.001
Summary There is a high prevalence of vitamin D deficiency amongst critically ill patients Vitamin D deficiency is associated with hypocalcaemia & disease severity
Vitamin D deficiency/insufficiency is common A marker of ill-health?? Causality vs Association Vitamin D receptor is found in all mammalian cells Deficiency leads to multi-organ dysfunction?
Proposed Programme Step 1 To investigate changes in calcium-vitamin D- parathyroid hormone levels during admission in intensive care unit. Step 2 To investigate the impact of vitamin D supplementation on calcium-vitamin D homeostasis and on outcome in critically ill patients.
STUDY DESIGN Prospective observational study (Step 1) to investigate changes in calcium-vitamin D- parathyroid hormone levels during admission in intensive care unit. Randomised, double-blinded, placebocontrolled study (Step 2) to investigate the impact of vitamin D repletion on critically ill patients.
Study Groups Step 1 Consecutive patients admitted to the intensive care unit Step 2 Patients will be randomised to either active treatment or placebo: Active: Intramuscular vitamin D3 100,000 units (Vicotrat, Heyl Chem-pharm, Berlin, 2.5 mg (100,000 units)/1 ml vials) Placebo Intramuscular saline 1 ml
Step 1: 100 pts with expected ICU LOS>3d (2-3 centres) Step 2:??200 pts (100 in each group) with ICU LOS >3d (multi-centre)
Inclusion Criteria Age >18 years Expected ICU length of stay (as determined by treating intensive care physician) >3 days
Exclusion Criteria Patients who are deemed unsuitable for active treatment or not expected to survive for the next 24 hours. Pregnancy Hypercalcaemia Renal replacement therapy Patients at risk of bleeding from intramuscular injections (thromobocytopaenia (platelet count<50), coagulopathy (INR>2) and those on anti-coagulants) Known allergic reaction to vitamin D injection Patients with disorders characterized by pathologic 1 hydroxylase activity (sarcoidosis, granulomatous and lymphoproliferative disorder).
Blood tests In addition to those ordered in standard clinical care of intensive care patients: serum 25-OH vitamin D, 1,25-(OH) 2 vitamin D, parathyroid hormone level Extra sera and plasma will also be stored for measurements of other inflammatory markers at the end of the study.
Intervention Within 24 hours Day 3 Day 7 ICU discharge Consent Enrolment Blood Tests Severity score Injection Adverse events vitamind/(saline)
Primary Outcome Measures?? To investigate the impact of vitamin D supplementation on calcium-vitamin D homeostasis, inflammation, sepsis and metabolic function in critically ill patients. Measures- Ionized calcium, vitamin D metabolites (25- hydroxyvitamin D and 1,25-dihydroxyvitamin D) and parathyroid hormone levels, inflammatory markers (C-reactive protein and total white cell count), glucose and insulin levels in non-diabetic patients.
Secondary Outcome measures To investigate the impact of vitamin D supplementation on disease severity, cardiac and endothelial function, and outcome in critically ill patients: Measures- Length of stay, disease severity (APACHE score), day 90 mortality, functional status 1 week post-discharge from intensive care unit, (ejection fraction by echocardiography, flowmediated dilatation of the brachial artery by Doppler ultrasonography).
Specific points for discussion Large pragmatic phase 3 or phase 2b? Relevant outcome measures Primary Secondary Stratification/ pre-defined subgroups medical/surgical steroid use diabetes disease severity seasonal variation