Randomized Clinical Trial of Hypovitaminosis D Treatment in the Neurocritical Care Unit
Phase: PHASE2
Conditions: Craniocerebral Trauma, Intracranial Aneurysm, Brain Neoplasms, Spinal Cord Injuries, Seizures, Meningitis, Stroke, Intracranial Hemorrhages, Critical Illness, Vitamin d Deficiency
Sponsor: University of Utah

Title: Randomized Clinical Trial of Hypovitaminosis D Treatment in the Neurocritical 
Care Unit 
IRB#:  IRB_00091541 
IND#: 131398 
Date: 8/30/17 
 

Randomized Clinical Trial of Hypovitaminosis D Treatment in the Neurocritical 
Care Unit 
 
Michael Karsy, MD, PhD1; Andrea Brock, MD, MSc1; Ilyas Eli, MD1; Jian Guan, MD1; 
Aatman Shah, MD1, Al-Wala Awad, MD1, Sarah Menacho, MD1; Min S Park, MD1 
 
1Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 
North Medical Dr. East, Salt Lake City, UT 84132, USA 
 
1. Abstract 
 
Vitamin D has been shown as an important marker of prognosis in a variety of 
clinical settings, including overall mortality, acute respiratory distress syndrome (ARDS), 
infection/sepsis, asthma, cardiovascular disease, diabetes, and 
pediatric/medical/surgical intensive care unit outcomes. Vitamin D not only plays a role 
in bone maintenance, but also a variety of extra-axial functions including immune-
dysregulation and systemic inflammation. In addition, a number of randomized clinical 
trials support the supplementation of vitamin D as improving outcome in critical care 
patients. While the evaluation of vitamin D levels remains a standard-of-care at our 
institution, the widespread use of vitamin D monitoring and impact on neurocritical care 
patients remains limited. Our recent prospective observational study of vitamin D levels 
in neurocritical patients showed that deficiency (<20ng/ml) was highly associated with 
prolonged hospital stay and increased in-hospital mortality for emergent patients. 
Moreover, a number of limitations arise from this study due to its observational nature. 
This study proposes a randomized, double-blinded, placebo-controlled, single 
center evaluation of vitamin D supplementation in the neurocritical care patient 
population (Table 1). Patients admitted to the neurocritical care unit for emergent 
cases and with vitamin D deficiency (<20ng/ml) will undergo vitamin D serum 
draw on admission and be randomized to receive cholecalciferol/vitamin D3 
supplementation (540,000 IU once orally) or placebo with the primary measured 
outcome being hospital length-of-stay. Secondary outcomes will include length of 
hospital course, length of ICU course, complications, adverse events, discharge 
Glasgow Outcome Score, in-hospital and 30-day mortality, as well as quality-of-life. 
Power analysis estimates 198 patients will be needed for each subgroup to determine a 
2 day difference in length-of-stay, and we plan to recruit 218 patients per treatment arm 
to account for dropout, which will take approximately 6-9 months to recruit. Interim 
analysis and safety monitoring will be performed. We hypothesize that vitamin D 
supplementation may make a significant impact on reducing morbidity and mortality in 
the neurocritical care population. The possibility of reducing hospital length of stay and 
mortality from a simple and cheap intervention such as vitamin D supplementation may 
be a useful adjuvant treatment in the neurocritical care population. 
 
2. Background/Rationale 
 
Hypovitaminosis D has a high prevalence among the general population, with 
some studies showing over half of the elderly population being affected (Chapuy 1997). 
Among critically ill patients, various studies have shown associations between 
hypovitaminosis D and multiple negative outcomes including mortality (De Haan 2014, 

Rech 2014), ARDS (Dancer 2015), and infection (Flynn 2012). Vitamin D deficiency has 
also been shown to have impacts on various neurological diseases such as stroke 
(Yalbuzdag 2015, Chung 2015), and dementia (Littlejohns 2014). While the mechanism 
between vitamin D deficiency and these diseases is not entirely known, evidence 
suggest that vitamin D can affect vascular reactivity, inflammation, and the immune 
system (Carthy 1989, Vargas-Vasserot 2011) (Table S1, Figure S1-2). 
 
Vitamin D has been shown to impact prognosis in a variety of retrospective and 
randomized clinical trials within an intensive care unit (ICU) environment (Amrein 2011). 
Despite these findings, there have been no studies examining the impact of 
hypovitaminosis D in specialized neurocritical care units (NCCU).  Given the often 
significant differences in the management of patients in NCCU and more generalized 
intensive care units (Kurtz 2011) there is a need for further inquiries into the impact of 
low vitamin D levels in this specific environment. This study proposes a randomized, 
double-blinded, placebo-controlled, single center evaluation of vitamin D 
supplementation in the emergent NCCU patient population (Table 1). We have 
previously conducted a prospective, observational analysis of 823 NCCU patients and 
shown a significant reduction in hospital length-of-stay for all patients (7.14 vs. 5.97 
days, p=0.0018) and for emergent cases (8.21 vs. 6.36 days, p=0.038), as well as 
reduced in-hospital mortality for emergent patients with non-deficient vitamin D levels 
(26/203 vs. 22/321, p=0.021). Nevertheless, these results remain limited in being 
observational studies without randomization or controls. 
 
3. Study purposes and objectives 
1. Evaluate the impact of vitamin D supplementation on the length-of-stay of 
emergent neurocritical care patients (primary outcome) 
2. Evaluate the impact of vitamin D supplementation on in-hospital mortality, ICU 
length-of-stay, Glasgow Outcome Score on discharge, complications, and 
quality-of-life metrics (secondary outcome) 
3. Evaluate the impact of vitamin D supplementation on Glasgow Outcome score 
and quality-of-life metrics at 3 and 6 months post-discharge (secondary outcome) 
 
4. Methods 
 
4.1. Inclusion criteria 
• Patients >18 years of age 
• Patients admitted to the neurosurgery or neurology services 
• Patients admitted to a critical care unit 
• Informed consent  
• Expected to stay in the ICU for 48 hours or more 
• Vitamin D deficiency (<20ng/ml) 
 
4.2. Exclusion criteria 
• Patients where a vitamin D level was not drawn within 48 hours of admission 
• Patients not randomized within 48 hours of admission 
• Readmitted patients to the critical care unit 
• Lack of informed consent 

• Prior supplementation with vitamin D 
• Severely impaired gastrointestinal function 
• Other trial participation 
• Pregnant or lactating women 
• Hypercalcemia (total calcium of >10.6 mg/dL or ionized serum calcium of >5.4 
mg/dL  
• Tuberculosis history or clinical exam 
• Sarcoidosis history or clinical exam 
• Nephrolithiasis within the prior year 
• Patients not deemed suitable for study participation (ie, psychiatric disease, living 
remotely from the clinic, or prisoner status)  
• Pregnant or nursing women 
 
4.3. General protocol 
1. Patients will be identified through primary treatment teams, including the 
Departments of Neurosurgery and Neurology, and through screening of 
the electronic medical record for patients admitted to the NCCU at the 
University of Utah Health Sciences Center. Patients admitted for non-
elective indications as outlined in the inclusion criteria will be enrolled. 
The full inclusion and exclusion criteria are listed in Table 1. We expect 
most patients to be admitted to the neurosurgery service and NCCU. 
2. A Vitamin D level will be drawn on all non-electively admitted NCCU 
patients as part of our standard admission protocol. 
3. Patients with a Vitamin D level <20ng/ml, defined as deficient, will be 
consented for the trial. Patients that do not consent for the trial will be 
studied retrospectively as part of our standard-of-care similarly to our 
previous prospective trial. Women between 18-45 years of age will 
undergo a serum or urine pregnancy test to rule out pregnancy prior to 
enrollment. 
4. Patients will be randomized 1:1 to receive Cholecalciferol (Vitamin D3, 
540,000 IU once orally or by feeding) immediately or placebo by random 
number generator. Treatments will be blinded to the patient and physician 
care teams. Placebos will include similar tablets or liquid formulations that 
mimic the treatment drug but are indistinguishable.  
5. A subsequent Vitamin D level will be drawn 3 days after drug 
administration or on date of discharge if sooner than 3 days to evaluate 
the adequacy of vitamin D repletion. 
6. Primary outcomes will total hospital length-of-stay. Secondary outcomes 
will include in-hospital mortality, ICU length-of-stay, ICU complications 
(rates of sepsis/bacteremia, pneumonia, urinary tract infection), discharge 
Glasgow Outcome Score, medication adverse events, and quality-of-life 
metrics. Various patient demographic data will be acquired. 
7. Subsequent 30-day mortality will be measured on standard clinical follow-
up.  

8. 1, 3 month and 6 month Glasgow Outcome Scores and quality-of-life 
metrics will be obtained. Physical therapy gait distance measurements as 
well as modified Rankin scale on discharge will be obtained. 
 
4.4. Safety monitoring 
 
There are minimal risks related to the patient. Vitamin D treatment is a relatively 
safe procedure in properly selected individuals. There may be additional discomforts 
including close monitored by the research team in order to monitor the study and collect 
data. The risk and side effects for Vitamin D administration are minimal and discussed 
further in the drug description. We have outlined a detailed data and safety monitoring 
plan. 
 
We have previously shown Vitamin D administration in our prospective, 
observational study for patients with Vitamin D levels <10ng/ml to be safe and without 
any adverse effect at dosages of 50,000 IU Qweek of ergocalciferol/vitamin D2. The 
dosages used in this study are comparable to other studies evaluating Vitamin D 
efficacy and safety (Bacon 2009, Von Restorff 2009, Amrein 2011, Amrein 2014). There 
was no reported adverse event from ergocalciferol/vitamin D2 administration during our 
prospective, observational trial along with recent trials evaluating cholecalciferol/vitamin 
D3. 
 
For patient safety, we will continue daily monitoring of CBC, BMP, Calcium, 
Phosphate, and neurological examinations as per standard practice in the neurocritical 
care unit. Should risks be identified, modification of the protocol will be proposed. And 
should the trial prove unsafe, we plan to notify the IRB and terminate the study. The 
study principal investigator and co-investigators will be responsible for oversight of 
patient safety. In addition, an independent safety and data review committee of licensed 
physicians will evaluate the study data on a quarterly basis. Quarterly safety and data 
monitoring reports will be discussed among the investigators and safety committee. The 
study will remain double-blinded except in the case of possible safety issues warranting 
unblinding. 
 
Participants will be withdrawn from the study should they demonstrate >grade 3 
Common Terminology Criteria for Adverse Events (CTCAE) suggesting Severe or 
medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated. In addition, patients will be withdrawn from the study should 
they show other signs/symptoms of vitamin D toxicity including, hypercalcemia, 
anorexia, nausea, vomiting, as well as polyuria, polydipsia, weakness, nervousness, 
pruritus, laboratory studies suggesting renal injury or failure (proteinuria, urinary casts, 
azotemia, metastatic renal calcifications). A checklist will be used to monitor patients. 
These findings can be uncovered by routine neurological and laboratory exams as per 
the ICU standard. Should adverse events be identified at higher or clustered rates than 
expected statistically, the trial will be modified or terminated.  
 
4.5. Informed consent 
 
The goals of the study, including potential benefit and minimal risk, will be 
discussed. Patients will be told that not participating in the study will not affect their 
hospital care. We will provide patients with a copy of the informed consent containing 
contact information for the investigators. In addition, we will inform the critical care staff, 

including nursing and administration, regarding the study so patients can find the 
appropriate research staff should they have questions.  All interim and data safety 
analysis when analyzed will be immediately conveyed to all study participants in the 
event of potential adverse events or risks. 
 
In some cases a legally authorized representative (LAR) will be used for informed 
consent of the patient. Many of the emergent patients admitted to the NCCU will not 
have the capacity for an informed consent. LARs may include spouses or patient 
children, as well as authorized legal healthcare proxies, depending on policies for 
informed consent at the University of Utah Health Sciences Center. As with studies of 
Vitamin D in other critical care settings, patient consent through a proxy may be 
possible. We will include a LAR signature block at the end of the consent document. 
 
Phone consents will be allowed as part of the trial to ensure timely consent. 
Similar, to surgical or procedural consents, phone consents will involve discussion with 
a LAR and informed consent will be documented by the study investigator as well as a 
witness, usually the patient’s nurse. Phone consents will be performed when the patient 
is incapacitated and family is unable to reach the hospital to sign the paper consent. 
 
4.6. Privacy protection 
 
Information about each participant, including the results of tests, will be 
confidential. Each participant will be assigned a study number and we will not use the 
participant's name in our study records. Paper records will be kept in a locked file 
cabinet in a secure room. Computerized records will be kept in a locked room on 
password-protected computers. The participant's name will not be used in any 
published reports. 
 
4.7. Facilities and staff 
 
 The principal investigator and co-investigators are all licensed physicians within 
the department of neurosurgery with experience in both basic and clinical science 
research. All investigators have had prior database research experience, including IRB 
submission as well as data acquisition and analysis. The faculty advisor, is a licensed 
physician as well as a board-certified neurosurgeon and Assistant Professor at the 
University of Utah, has also reviewed the protocol and will be involved in patient safety 
monitoring as well as quality control. He has been involved in our prior prospective, 
observational study on Vitamin D status of neurocritical care patients. The project will be 
discussed by meetings and by email as necessary to discuss results, patient safety 
issues, and data quality. All investigators are already trained in research methodology, 
have completed CITI certification, receive annual training on research bioethics through 
the Department of Neurosurgery, and have been trained on aspects of informed 
consent. 
 
The research will be primarily performed at the University of Utah Hospital. Some 
data analysis may be performed on computers within the Neurosciences Center at the 
University. The NCCU at the University Hospital will be the predominant facility used for 
research activity. Other ICUs will be used if neurosurgery or neurology patients are 
admitted. All information related to be data will be kept in a HIPAA-compliant database 
or locked cabinet units only accessed by the principal investigator. The University of 
Utah Neurocritical Care Unit (NCCU)  NCCU is a 23-bed intensive care unit which 

specializes in the treatment of patients with critical neurological illness, such as stroke, 
intracranial hemorrhage, status epilepticus, traumatic brain injury, and meningitis. The 
NCCU is the region’s largest and most technologically advanced critical care unit and 
the catchment are for the NCCU comprises 20% of the geographical area of the 
continental United States. Nurses specially trained in caring for neurological patients 
who require intensive care staff the NCCU in conjunction with 5 neurointensivists and a 
multidisciplinary team of neurologists and neurosurgeons.   
 
4.8. Selection of therapeutic agent 
 
Patients will be supplemented with cholecalciferol (vitamin D3) or placebo. Two 
major vitamin D compounds exist in humans, ergocalciiferol (vitamin D2) and 
cholecalciferol (vitamin D3) and recent guidelines suggest that either vitamin D2 or 
vitamin D3 can be supplemented in patients with hypovitaminosis D (Holick 2011). One 
study evaluating short-term supplementation with vitamin D2 in an critical care setting 
demonstrate that only 26% of patients receiving 50,000 IU three times per week 
achieved normal vitamin D levels (Dickerson 2015). Critically ill patients have been 
suggested to have a blunted response to vitamin D supplementation. Nonetheless, a 
number of randomized trials have shown the ability of high dose vitamin D3 to adequate 
replete critically ill patients with minimal toxicity, mostly mild hypercalcemia (Quraishi 
2015, Nair 2015, Amrein 2011, Amrein 2014). Intramuscular (200,000 IU) or oral 
(540,000 IU) have been shown to adequately replete vitamin D levels in the majority of 
patients by 2-7 days after treatment. For this reason we have chosen to supplement 
with cholecalciferol (540,000 IU orally). 
 
4.9. Power analysis and statistical plan  
 
A variety of variables will be collected on patients (Table 2). We estimated 
various sample sizes based on our preliminary, prospective, observational trial. Using 
length-of-stay as a primary outcome, previously we detected a significant decrease in 
patients with sufficient vitamin D levels (>20ng/ml) (8.21 vs. 6.36 days, p=0.002). Using 
an effect size of 2, alpha of 0.05, 1:1 case/control sampling, we estimate 198 patients 
will be required per group for this study. We plan to recruit patients to account for a 10% 
dropout resulting in 218 patients per group, total 436. We also performed power 
calculations using various other outcomes including, in-hospital mortality, as well as 
evaluation of both emergent and non-emergent patients. Based on a 6-month timeframe 
needed to enroll 512 patients in our prospective, observational trial, we estimate the trial 
would take 12 months for enrollment and randomization in the proposed trial. The 
primary outcome (length-of-stay) will be measured by T-test as well as multivariate 
regression to adjust for potential confounders using SPSS (IBM, Armonk, NY). 
Secondary outcomes will be evaluated by a variety of statistical methods. 
 
4.10. Funding source 
 
Planned sources of funding for this study are from internal departmental grants 
without potential for conflicts-of-interest. No submission for additional funding sources is 
planned at this time. 
 
5. Anticipated results and potential public health impact 

 
The potential benefit of this study would include knowledge about the success of 
vitamin D supplementation on various critical care outcomes. While they may not 
directly apply to a patient, they can be useful to additional critical care patients admitted 
an ICU in the future. The societal benefit will include reduced patient morbidity and 
mortality, as well as shorter hospital stays and therefore reduced ICU expenditure. 
Vitamin D is a relatively cost-effective  medication that is well-tolerated. Its potential 
impact to reduce hospital stays, by even 1 day would play a significant role in reducing 
patient cost, disease morbidity, and risk from hospitalization. Future research directions 
can involve a multi-center randomized clinical trial to validate the effect of vitamin D in 
the neurocritical care patient as well as further molecular studies evaluating the non-
skeletal effects of vitamin D. Additional, studies on vitamin D as a biomarker and effects 
on a cellular level can also be forthcoming if a potential benefit is identified clinically. 
Identification of the molecular mechanisms by which vitamin D may alter disease 
pathology may serve as a method for the development of additional treatments. 
 
6. Protocol amendments 
 
6.1. 1/10/17, Addition of phone consents as well as two study co-investigators, 
Aatman Shah, MD and Al-Wala Awad, MD was performed. Repeat vitamin D 
levels at 3 days following administration of study drug or placebo was modified 
from prior planned repeat vitamin D at 7 days.  
 
6.2. 8/6/17, Addition of physical therapy assessment and modified Rankin scale 
as secondary outcomes of the study. Change of study faculty sponsor from Dr. 
Min S. Park to Dr. Sarah T. Menacho as Dr. Park is leaving the University of 
Utah.  
  
 
 
 

 
Table 1: Summary of Study Characteristics 
Title 
Randomized Clinical Trial of Hypovitaminosis D Treatment in 
the Neurocritical Care Unit 
Methodology 
Randomized, double-blinded, placebo-controlled clinical trial 
Study Duration 
1-1.5 years (12 months recruitment, 3-6 month analysis) 
Study Center(s) 
University of Utah Health Sciences Center 
Objectives 
1. Evaluate the impact of vitamin D supplementation on the 
length-of-stay of emergent neurocritical care patients (primary 
outcome) 
2. Evaluate the impact of vitamin D supplementation on in-
hospital mortality, ICU length-of-stay, Glasgow Outcome Score 
on 
discharge, 
complications, 
and 
quality-of-life 
metrics 
(secondary outcome) 
Primary Aims 
Length-of-stay 
Secondary Aims 
ICU length-of stay, in-hospital mortality, 30-day mortality, ICU 
complications (sepsis, pneumonia, urinary tract infection), 
Glasgow Outcome Score, medication adverse events , modified 
Rankin Scale, physical therapy assessments 
Number of 
Subjects 
218 per treatment arm, total 436 
Intervention 
Vitamin D3 540,000 IU oral vs. placebo 
Diagnosis and 
Main Inclusion 
Criteria 
Patients >18 years of age 
Patients admitted to the neurosurgery or neurology services 
Patients admitted to a critical care unit 
Informed consent  
Expected to stay in the ICU for 48 hours or more 
Vitamin D deficiency (<20ng/ml) 
Exclusion criteria Patients where a vitamin D level was not drawn within 48 hours of 
admission 
Patients not randomized within 48 hours of admission 
Readmitted patients to the critical care unit 
Lack of informed consent 
Prior supplementation with vitamin D 
Severely impaired gastrointestinal function 
Other trial participation 
Pregnant or lactating women 
Hypercalcemia (total calcium of >10.6 mg/dL or ionized serum 
calcium of >5.4 mg/dL  
Tuberculosis history on clinical exam 
Sarcoidosis history on clinical exam 
Nephrolithiasis within the prior year 
Patients not deemed suitable for study participation (ie, psychiatric 
disease, living remotely from the clinic, or prisoner status)  
Pregnant or nursing women 
Data and safety 
Monthly review of data entry 

monitoring 
Quarterly independent review of data safety metrics 
Daily review of patient neurological exam, and laboratory values 
(CBC, BMP, calcium, phosphate) 
Interim 6-month data analysis 
Statistical 
Methodology 
T-test (parametric), Chi-square (non-parametric), univariate 
regression, multivariate linear regression, logistic regression, 
Kaplan-Meier survival, Cox proportional hazards modeling, interim 
analysis 
SPSS (IBM, Armonk, NY) 
 
 
 
 

Table 2: Demographic, Clinical, and Safety Variables 
 
Demographic Variables 
• Name 
• Medical record number 
• Date of birth 
• Gender 
• Diagnosis 
• Ethnicity/race 
 
Clinical Variables 
• Date of admission to NCCU 
• Disease category (tumors, trauma, vascular, other) 
• Disease severity: Glasgow Coma Scale, Simplified Acute Physiology Score II 
• Medical comorbidities: diabetes, hypertension, heart disease, cancer history 
• Any surgeries during hospitalization 
• Randomization – vitamin D or placebo  
• Vitamin D level on admission 
• Date vitamin D level 
• Vitamin D level 3 days post treatment  
• Date vitamin D level 3 days post treatment 
• Date ICU discharge 
• Date hospital discharge 
• Date deceased 
• Glasgow Outcome Score on discharge 
• EQ-5D on discharge 
• Discharge disposition 
• Hospital complications (specifically: deep vein thrombosis, bacteremia, urinary 
tract infection, pneumonia, readmission to NCCU) 
• Glasgow Outcome Score at 3 and 6 months 
• EQ-5D at 1, 3 and 6 months 
• Physical therapy assessments at discharge 
• Modified Rankin Scale on discharge  
 
Safety Monitoring  
• Common Terminology Criteria for Adverse Events (CTAE) V4.0 
• Daily ICU laboratory studies (CBC, BMP, calcium, phosphate) 
• Daily neurological exam 
• Quarterly independent review of safety and data 
• Monitoring of adverse events 
 
 
 

 
Table S1: Clinical Studies Evaluating Vitamin D in a Critical Care Environment 
Reference 
Study type 
Participants/ 
groups 
Summary 
Van den 
Berghe 
2003 
RCT 
22 
200 IU vs. 500IU 
Minimal change in serum 
markers 
Ostermann 
2007 
Retrospective 
cohort 
100 
Normal vs. 
insufficient vs. 
deficient 
Hospital-free days were 
significantly different between 
patients with deficiency and 
sufficiency 
No significant relationship 
between 25(OH)D 
concentrations and mortality 
Lucidarme 
2010 
Retrospective 
cohort 
100 
Normal vs. 
insufficient vs. 
deficient vs. 
undetectable 
28-day mortality was significantly 
different between the four groups 
No significant association 
between 25(OH)D 
concentrations and length of ICU 
stay. 79% of patients had low 
25(OH)D concentrations 
 
Mata-
Granados 
2010 
RCT 
33 
Placebo vs. 60,000 
IU PO, vs. 2mcg IV 
vit D3 
97% of critically ill patients were 
vitamin D deficient. Group B 
(60,000 IU) showed a statistically 
significant increase in 25(OH)D 
concentrations. 
Cecchi 2011 Retrospective 
cohort 
170 
Severe sepsis vs. 
non-septic trauma 
28-day mortality was not 
statically different between the 
two groups with rates of 27.9% in 
severe septic patients and 11.1% 
in trauma patients 
Braun 2011 
Retrospective 
cohort 
2,399 
Normal vs. 
insufficient vs. 
deficient 
Preadmission 25(OH)D 
deficiency is associated with 
mortality 
Adjusted 30-day morality odds 
ratio was 1.00, 1.36, and 1.69, 
respectively 
Amrein 2011 RCT 
25 
Placebo vs. 
540,000 IU enteral 
The mean serum 25(OH)D 
increased in the treatment group 
25 ng/mL. Deficiency was 
corrected in 2 days with 
 
Venkatram 
2011 
Retrospective 
cohort 
437 
Normal vs. 
insufficient vs. 
Higher hospital mortality for 
patients with vitamin D deficiency 
but not insufficiency 

deficient 
Braun 
2012a 
Retrospective 
cohort 
1,325 
Normal vs. 
insufficient vs. 
deficient 
Adjusted 30-day mortality odds 
ratio was 1.00, 1.35, and 1.94 b 
respectively 
Braun 
2012b 
Retrospective 
cohort 
2,075 
Normal vs. 
insufficient vs. 
deficient 
Adjusted 30-day mortality odds 
ratio was 1.00, 1.41, and 1.61, 
respectively 
Preadmission 25(OH)D 
deficiency is significantly 
associated with acute kidney 
injury 
Arnson 2012 Prospective 
cohort 
130 
Normal vs. 
insufficient 
Mortality was lower for vitamin D 
deficient patients (15±12.4 days 
vs. 24.2 ± 16.5 days) 
Vitamin D levels correlated with 
WBC count 
Flynn 2012 
Prospective 
cohort 
66 
Normal vs. deficient 
Longer length of stay, infection 
rates and rates of sepsis in 
patients with vitamin D deficiency 
Higgins 
2012 
Prospective 
cohort 
196 
Normal vs. deficient 
vs. insufficient 
Vitamin D levels decreased 3 
days after admission and 
remained through 10 days 
Higher vitamin D levels were 
associated with shorter time to 
ICU discharge (HR 2.11) 
Vitamin D not associated with 
mortality or infection rate  
Nair 2012 
Prospective 
cohort 
100 
Normal vs. deficient 
vs. insufficient 
Vitamin D deficiency associated 
with fewer hospital-free days.  
Secondary hyperparathyroidism 
was highly prevalent in the 
critically ill population 
Remmelts 
2012 
Prospective 
cohort 
272 
Normal vs. deficient 
vs. insufficient 
Vitamin D deficiency associated 
with increased risk of ICU 
admission and 30-day mortality 
in patients with community-
acquired pneumonia 
Nair 2013 
Retrospective 
cohort, RCT 
196 
Normal vs. 
insufficient vs. 
deficient 
Placebo vs. low 
(200IU) vs. high 
(500IU) supplement  
Mean time-to-alive at ICU 
discharge was 5.9 ± 5.4, 6.8 ± 
6.0, and 10.6 ±8.4 respectively 
25(OH)D insufficiency was not 
associated with mortality 
25(OH)D levels were higher in 
the high dose group on days 2, 
6, and 7. Doses studied did not 

normalize 25(OH)D serum 
concentrations 
Aygencel 
2013 
Prospective 
cohort 
201 
Increased mortality in vitamin D 
deficient (<20ng/mL) patients (43 
vs. 26%) 
Increase rates of severe acute 
disease, worsened laboratory 
studies on admission, morbidity 
and exposure to invasive therapy 
in deficient patients. 
Su 2013 
Prospective 
cohort 
206 (105 ICU) 
Normal vs. ICU 
sepsis 
 
Lower vitamin D seen in patients 
with ICU sepsis compared to 
normal patients 
No difference in mortality with 
vitamin D levels 
Amrein 2014 RCT 
475, (patients with 
deficiency ≤20 
ng/ml) 
Placebo vs. 
540,000 IU x1, 
monthly 90,000 IU 
for 5 month 
No difference in mean hospital 
stay (19.3 vs. 20.1), hospital 
mortality (35.3% vs. 28.3%), 6-
month mortality (42.9% vs. 
35.0%) 
Severe vitamin D subgroup 
(n=200) showed no difference in 
hospital stay (19 vs 20.1 days) 
and 6-month mortality (50% vs. 
34.7%)  
Severe vitamin D subgroup 
showed significantly lower 
hospital mortality (46.1% vs. 
28.6%, p=0.04),  
Moromizato 
2014 
Retrospective 
cohort, two-
center 
3,386 
Normal vs. 
insufficiency vs. 
deficiency 
Preadmission vitamin D 
deficiency was predictive for risk 
of sepsis including after 
adjustement for other variables 
90-day mortality was 1.6x higher 
in patients with preadmission 
vitamin D insufficiency and 
deficiency (HR. 1.63) 
Dickerson 
2015 
Retrospective 
cohort 
65 
50,000 IU qweek, 
BIweek, TIweek for 
4 weeks 
Normal vitamin D levels achieved 
in 6%, 11% and 26% of patients 
Brook 2015 
Retrospective 
cohort 
300 
Normal vs. deficient 
Vitamin D levels showed an 
inverse correlation with non-
home discharge destination 
Nair 2015 
RCT 
50 
150,000 IU vs. 
65% vs. 67% of patients 
normalized vitamin D levels by 7 

300,000 IU vitamin 
D3 IM 
days 
80% vs. 83% of patients 
normalized vitamin D levels by 
14 days  
Secondary hyperparathyroidism 
manifest in 25% of patients 
Alizadeh 
2015 
Retrospective 
cohort 
70 
Normal vs. deficient 
Longer length of stay (7.8 vs. 
4.05 days) with deficient patients 
but no difference in hospital 
mortality 
Quraishi 
2015 
RCT 
30 
Placebo vs. 
200,000 IU 
cholecalciferol vs. 
400,000 IU 
cholecalciferol 
Plasma levels of vitamin D 
peaked on day 5 of treatment 
CRP levels did not differ between 
groups 
Verceles 
2015 
Retrospective 
cohort 
183 
Normal vs. deficient 
Deficiency was common (61% 
patients) and not associated with 
days to wean from ventillation  
 
 
 

 
Figure S1: Forest plot of 30-day mortality in studies with univariate analysis of 
vitamin D sufficiency vs. deficiency. Adapted from de Haan et al. 2014. 
 
 
 
Figure S2: Forest plot of in hospital mortality in studies with univariate analysis 
of vitamin D sufficiency vs. deficiency. Adapted from de Haan et al. 2014. 
 
 
 
 

7. Reference 
 
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