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Journal of Parenteral and Enteral

http://pen.sagepub.com/content/36/6/713The online version of this article can be found at:

DOI: 10.1177/0148607112444449

2012 36: 713 originally published online 20 April 2012JPEN J Parenter Enteral Nutravid M. Higgins, Paul E. Wischmeyer, Kelly M. Queensland, Stefan H. Sillau, Alexandra J. Sufit and Daren K. Hey

Relationship of Vitamin D Deficiency to Clinical Outcomes in Critically Ill Patients

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Journal of Parenteral and Enteral

Nutrition

Volume 36 Number 6

November 2012 713-720

2012 American Society

for Parenteral and Enteral Nutrition

DOI: 10.1177/0148607112444449

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Original Communication

Clinical Relevancy Statement

Vitamin D deficiency has been associated with a myriad of

disease conditions in the general population. However, the

impact of vitamin D deficiency on outcome in critically ill

patients remains unclear. Although studies have described a

high burden of vitamin D deficiency in this population and

suggested a correlation with adverse outcomes, few studies

have addressed specific outcomes. Furthermore, the useful-

ness of obtaining vitamin D levels in critically ill patients is

not clear because most studies have evaluated preintensive

care unit (ICU) vitamin D levels, and no large studies to date

have trended vitamin D levels during the ICU stay. We con-

firm in this study that vitamin D deficiency is common in this

population and is associated with a longer ICU length of stay,

may increase the risk of ICU-acquired infections and pneumo-nia, and may be associated with elevated organ failure scores.

In addition, we describe the trend of vitamin D status during

the stay of patients in the ICU and demonstrate that there is a

statistically significant decrease in the levels of vitamin D.

These results add to the growing fund of knowledge concern-

ing the association of vitamin D deficiency with adverse out-

comes in the critical care population and indicate that further

research is warranted in defining whether vitamin D supple-

mentation is beneficial and what is the optimal dose and tim-

ing of vitamin D in this population.

. / i i

From the 1Department of Anesthesiology, University of Colorado

School of Medicine, Aurora, Colorado; 2Department of Biostatistics and

Informatics, Colorado School of Public Health, University of Colorado,

Aurora, Colorado; and3Clinical Evaluation Research Unit, Kingston

General Hospital, Kingston, Ontario, Canada;4Department of Medicine,

Queens University, Kingston, Ontario, Canada.

This work was presented at the following meetings: Society for Critical

Care Medicine, San Diego, California, January 16, 2011; American

Society for Parenteral and Enteral Nutrition, Vancouver, Canada, January

30, 2011; and SHOCK society, Norfolk, Virginia, January 12, 2011.

Financial disclosure: This study was a secondary analysis of an existing

database.

Received for publication December 7, 2011; accepted for publication

January 6, 2012.

Corresponding Author: Paul Wischmeyer, MD, University of ColoradoSchool of Medicine, Department of Anesthesiology, RC-2, Mail Stop

8602, 12700 E 19th Ave, Aurora, CO 80045; e-mail: Paul.Wischmeyer@

ucdenver.edu

Relationship of Vitamin D Deficiency to Clinical Outcomes in

Critically Ill Patients

David M. Higgins, MS1; Paul E. Wischmeyer, MD

1; Kelly M. Queensland, BA

1;

Stefan H. Sillau, MS2; Alexandra J. Sufit, BA1; and Daren K. Heyland, MD3, 4

Abstract

Background: Despite the numerous disease conditions associated with vitamin D deficiency in the general population, the relationship

of this deficiency to outcome in critically ill patients remains unclear. The objective of this study is to determine the burden of vitamin

D deficiency in intensive care unit (ICU) patients and determine if it is associated with poor patient outcomes. Methods: The authors

conducted an analysis of samples collected from a prospective study of 196 patients admitted to a medical/surgical ICU in a tertiary

care hospital. They measured serum 25-hydroxyvitamin D at admission and up to 10 days following admission and followed patients

prospectively for 28-day outcomes.Results: Of analyzable patients, 50 (26%) were deficient (30 nmol/L) and 109 (56%) were insufficient

(>30 and 60 nmol/L). Baseline 25(OH)D levels decreased significantly in all patients after 3 days in the ICU and remained significantly

lower through 10 days (P< .001). 25(OH)D status was not significantly associated with 28-day all-cause mortality (hazard ratio [HR],

0.89; 95% confidence interval, [CI] 0.372.24). Higher levels of 25(OH)D were associated with a shorter time-to-alive ICU discharge(HR, 2.11; 95% CI, 1.273.51). 25(OH)D-deficient patients showed a nonstatistically significant trend toward a higher infection rate

(odds ratio [OR], 3.20; 95% CI, 0.78413.07;P= .11) compared with patients with sufficient levels of 25(OH)D. Conclusions: This study

demonstrates significant decreases in vitamin D status over the duration of the patients ICU stay. Low levels of vitamin D are associated

with longer time to ICU discharge alive and a trend toward increased risk of ICU-acquired infection. (JPEN J Parenter Enteral Nutr.

2012;36:713-720)

Keywords

immunonutrition; research and diseases; vitamins; nutrition; critical care; research and diseases

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714 Journal of Parenteral and Enteral Nutrition36(6)

Introduction

Vitamin D deficiency is a common disorder that is associated

with excess morbidity and mortality in general population

studies.1-4 The role of vitamin D in the regulation of calcium,

phosphorus, and skeletal growth has been extensively

described.5,6

Evidence is mounting that vitamin D deficiencyalso has an association with the immune system, affecting

cancer, multiple sclerosis, diabetes, and autoimmune disor-

ders.7-13 The recent discovery that many cells of the immune

system express both the enzyme 25-hydroxyvitamin D-1-

hydroxylase to convert circulating 25(OH)D to hormonally

active 1,25(OH)2D and vitamin D receptors may reveal a new

and significant function of vitamin D on immune system regu-

lation.10,14 Specifically, vitamin D may play a key physiologic

role in attenuating potentially pathogenic cell-mediated

immune responses and thus has been linked to an increased

incidence of autoimmune disorders.7-13 Vitamin D may also be

important for optimizing host defense against infection as

children with rickets are more susceptible to infection,15 and

vitamin D has been implicated in the pathogenesis of infec-

tions such as tuberculosis.16

Vitamin D deficiency in the critically ill patient was

observed more than 20 years ago, primarily in hypocalcemic

patients.17 Recent studies in normocalcemic critically ill

patients have suggested a very high burden of vitamin D defi-

ciency in this population and suggested a previously unrecog-

nized contribution of deficient states to non-calcium-related

consequences.18-24 However, to our knowledge, no large stud-

ies have specifically addressed vitamin D status trends through

the duration of stay in the intensive care unit (ICU). Critically

ill patients are at an especially high risk for many of the disor-ders that vitamin D deficiency may be associated with. Yet,

evaluation of 25(OH)D status is rarely performed in the critical

care setting.25

The hypothesis of this study is that vitamin D status in ICU

patients is significantly decreased at admission and continues

to decrease throughout their hospital stay. Furthermore, we

hypothesize that vitamin D deficiency is associated with poor

patient outcomes, particularly longer ICU stay and greater risk

of infection.

Materials and Methods

The original purpose of the prospective observational study was

to evaluate a diagnostic marker for sepsis in critical illness. This

trial was conducted at the Kingston General Hospital, a tertiary

care, mixed medical-surgical ICU,26 and 2 other hospitals. In the

original study, 597 patients were enrolled at the 3 sites.

However, additional blood was collected and available for

analysis only from patients at the Kingston General Hospital

site, which included 203 total patients, and this is the cohort

studied in this report. Here we report a secondary analysis of the

serum samples collected in this study evaluating the relationship

between 25(OH)D levels and clinical outcomes. The patients

were enrolled over the period of 1 year from October 2002 to

October 2003. Research ethics boards from Queens University

approved the protocol for the original study; informed consent

was obtained from next of kin before enrollment. The inclusion

criteria of the patients included all consecutive patients 18 years

and older who were expected to stay more than 24 hours in the

ICU and were enrolled within the first 24 hours of ICU admis-sion. Only patients admitted for overdoses were excluded from

the study. The study protocol at Kingston General Hospital

included blood sample collection daily for a maximum of 10

days. Serum samples were also collected and stored at 80C

prior to analysis.

Data Collection

Demographics, past medical history, and medications were

obtained from the patients charts and included age, race, sex,

body mass index (BMI; determined prior to ICU admission or

estimated as pre-ICU dry weight [in kg] divided by height [in

cm] squared in the ICU on admission), season of admission

(summer admission was defined as admission between June 21

and September 22 of the year of the study), admission category

(cardiovascular, respiratory, neurological, metabolic, gastroin-

testinal, hematologic, sepsis, postoperative), and comorbidities

(coronary artery disease, hypertension, chronic obstructive pul-

monary disease, diabetes, renal disease, liver disease, cancer).

Necessary variables were recorded to calculate Acute Physiology

and Chronic Health Evaluation II (APACHE II)27 and Sequential

Organ Failure Assessment (SOFA) scores28 at admission.

Clinical outcomes were assessed at 14 and 28 days. No patients

were lost to follow up for the 14- or 28-day clinical end points.

Outcomes recorded included mortality, time-to-alive ICU dis-charge, and infection status. The diagnosis of ICU-acquired

infection was defined as infection present after 48 hours of ICU

admission. Suspected infection was defined by the presence of

a new positive culture result or initiation of new antibiotics after

48 hours of ICU admission. The charts of all patients with sus-

pected infections were reviewed by 2 independent blinded

physicians using standardized definitions.29 Adjudicators then

met to determine the presence or absence of infection. In case of

discrepancy, the physicians would meet and resolve the issue by

reanalyzing the chart. Given the uncertainty around the absolute

diagnosis of a new infection, we used standard definitions of

probable and possible for each type of infection, where

probable reflected a higher degree of probability, in the opinion

of the adjudicator, that infection was present compared with pos-

sible infection. This adjudication technique has been validated

and published in previous large clinical ICU trials.30,31 The max

SOFA score was calculated as the worse score for each organ

component over the patients ICU stay. The delta SOFA score

was determined by subtracting the maximum SOFA score from

the admission total SOFA score. As vitamin D insufficiency has

been associated with an increased susceptibility to pulmonary

infections,32 the subgroup of patients with ICU-acquired pneu-

monia >48 hours after admission was analyzed separately.


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Vitamin D Deficiency in Critically Ill Patients/ Higgins et al 715

Serum was collected on the day of ICU admission (within

24 hours of ICU admittance) and daily for 10 days while in the

ICU. All samples were stored at 80C for future analysis and

did not undergo more than 1 freeze-thaw cycle before running

assays. Serum 25(OH)D levels were assessed using a radioim-

munoassay (RIA) method (DiaSorin, Antony, France) at The

Childrens Hospital Clinical and Translational Research CenterCore Lab in Denver, Colorado, at baseline and with samples

from days 3, 5, 7, and 10 (when available). This laboratory

participates biannually in the Vitamin D External Quality

Assessment Scheme to ensure the analytical reliability of the

25(OH)D assay. The coefficient of variation for the 25(OH)D

RIA assay is 0.046. Samples were run in 4 batches according

to the day after admission. The following 25(OH)D values

were used for deficient, insufficient, and sufficient patients

according to previously reported subgroups: sufficient, >60

nmol/L; insufficient, >30 to 60 nmol/L; and deficient, 30

nmol/L,19 which are similar to the recent Institute of Medicine

report cutoffs.33

Statistics

For baseline SOFA scores, multiple regression was used to

calculate adjusted least squares means using PROC GLM in

SAS Version 9.2 (SAS Institute, Inc, Cary, NC) between

25(OH)D groups. In all multivariate models, we controlled for

age, gender, BMI, and APACHE II score. Ethnicity was not

included in the analysis because 201 of the 203 patients were

white. Except for gender, all covariates were continuous.

Logistic and proportional hazards models used Wald tests and

confidence intervals. To assess the change in 25(OH)D status

over the patients stay in the ICU, the PROC MIXED functionwas used in SAS to run a mixed model regression. 25(OH)D

status was expressed as a categorical variable, and a multi-

variate Cox proportional hazard ratio model was used to iden-

tify variable association with time to ICU discharge or

mortality. The PROC PHREG function in SAS was used to

calculate the hazard ratios for time-to-alive ICU discharge and

mortality variables. Patients who died were censored because

their time to recovery was unknown. Because a 1-nmol/L

increase in 25(OH)D is not clinically relevant, we represented

a 1-unit increase as a 30-nmol/L increase in 25(OH)D levels

for hazard ratio estimates. This unit selection scales the hazard

ratio estimates but does not have any effect on the statistical

significance. The P value for this analysis was determined

using a type 3 Wald test. Logistic regression was used to

model probable and possible ICU-acquired infections in the

25(OH)D groups using the PROC LOGISTIC function in SAS

Version 9.2. The Student ttest (unpooled [Satterthwaite]) was

used to compare the means of baseline 25(OH)D between

patients with and without pneumonia. The SAS Version 9.2

statistical package was used for all analyses. Means (SD) are

reported. All tests were 2-sided, and P< .05 was considered

significant. A statistical trend was consideredP< .20.

Results

Patients and 25(OH)D Status

In the original study, 203 patients were enrolled at Kingston

General Hospital. However, baseline serum samples were not

available for analysis in 7 patients. Thus, a total of 196 patients

on admission day were included in this analysis. Of the 196patients analyzed, 66 (33.7%) were admitted as postoperative

patients and 130 (66.3%) were admitted for medical reasons.

The primary admission categories, including cardiovascular,

respiratory, neurological, metabolic, gastrointestinal, and

hematologic disorders, were not statistically different between

the groups (see Table 1). Comorbid conditions existing prior to

ICU admission, including coronary artery disease, hyperten-

sion, diabetes, renal disease, liver disease, or cancer, were not

significantly different between the groups. In addition,

APACHE II scores, presence of sepsis on admission, and base-

line SOFA scores were similar between the 25(OH)D groups

(see Table 1). Furthermore, there were no significant differ-

ences in mean parenteral nutrition (PN) and enteral nutrition

(EN) over ICU length of stay between the groups.

Upon admission to the ICU, a low baseline serum 25(OH)

D (60 nmol/L) level was observed in 159 patients (82% of

total cohort), as seen in Figure 1. Of analyzable patients, 50

(26%) were deficient (30 nmol/L), 109 (56%) were insuffi-

cient (>30 and 60 nmol/L), and 37 (18%) were sufficient

(>60 nmol/L) at baseline. At baseline, the mean 25(OH)D level

was 47.0 nmol/L. The mean dropped significantly by post

admission day 3 to 44.4 nmol/L (n = 138, P < .001) and

remained significantly decreased compared with baseline in

patients who stayed 10 days or longer (45 nmol/L at baseline to

39 nmol/L on day 10, n = 44,P< .001). The mean 25(OH)Dfor patients who stayed at least 10 days (n = 44) in the insuffi-

cient or sufficient groups significantly decreased compared

with the baseline on days 3, 7, and 10, as seen in Figure 2. Of

the 23 patients who were sufficient at ICU admission and

stayed longer than 3 days (14 patients excluded), 9 of 23 suf-

ficient patients (39.1%) developed insufficiency at some point

during their stay.

Effect of 25(OH)D Level on Mortality and

Time-to-Alive ICU Discharge

All-cause 28-day mortality in the study population was 26.2%.

The mortality rates and average time to death for 25(OH)D

sufficient, insufficient, and deficient groups were 27.0% and

8.0 7.0 days, 27.5% and 8.8 7.2 days, and 22.0% and 9.0

8.8 days, respectively. Using a multivariate Cox proportional

hazard ratio (HR) model, 25(OH)D category was not associ-

ated with 28-day all-cause mortality (HR, sufficient vs defi-

cient groups: 0.89; 95% confidence interval [CI], 0.372.24),

as shown in Table 2.

The mean SD time-to-alive ICU discharge for all patients

in the study population was 7.5 8.5 days. The mean time-to-

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alive ICU discharge for 25(OH)D sufficient, insufficient, and

deficient groups was 5.9 5.4, 6.8 6.0, and 10.6 8.4,

respectively. Sufficient levels of 25(OH)D were significantly

associated with a shorter time-to-alive ICU discharge (HR,

1.74 per 30 nmol/L; 95% CI, 1.192.53 at 14 days and HR,

3.49; 95% CI, 1.368.95 at 28 days). Using the multivariate

Cox proportional hazards model with 25(OH)D represented as

a categorical variable, we found that 25(OH)D sufficient or

insufficient patients left the ICU sooner than patients with defi-

cient levels of 25(OH)D, as shown in Table 2.

Max SOFA scores were calculated and showed nonsignifi-

cantly higher SOFA scores in deficient patients compared with

the other groups (deficient max SOFA 9.7 4.2, insufficient

max SOFA 8.4 4.2, and sufficient max SOFA 8.4 3.3; P=

.12). Delta SOFA scores were 1.3 1.7, 1.6 2.1, and 2.1 2.3

in sufficient, insufficient, and deficient groups, respectively

(P= .29).

In addition, the mean duration of ventilation was deter-

mined and found to be 141.5 18.1 hours in vitamin

Ddeficient patients compared with 138 16.9 hours in insuf-

ficient and 120 20.9 hours in sufficient groups (P= .49), as

shown in Table 3.

Infection StatusPatients were followed for infection status, and the relationship

of baseline 25(OH)D status to new infections diagnosed after 48

hours in the ICU is summarized in Table 3. 25(OH)D-deficient

and insufficient patients had a higher rate of at least 1 probable

infection compared with patients with sufficient levels of

25(OH)D, but this was not statistically significant (odds ratio

[OR], 3.20; 95% CI, 0.78413.07,P= .11). There was no rela-

tionship between rate of culture-confirmed infections and pos-

sible infections and 25(OH)D levels (Table 3).

Table 1. Comparison of Demographics Between 25(OH)D Groups

Sufficient

(>60 nmol/L)

Insufficient

(>30 to 60 nmol/L)

Deficient (30

nmol/L) PValue

25(OH)D status, No. (%) 37 (18.5) 109 (55.9) 50 (25.6)

Age, y, mean SD 65.0 13.3 64.3 14.4 62.9 14.1 .41

Male sex, No. (%) 17 (46) 72 (66) 32 (64) .09b

Body mass index, mean SD 26.7 5.0 30.1 6.9 29.8 8.8 .76a

Summer admission, No. (%) 7 (26) 28 (36) 18 (36) .19a

APACHE II, mean SD 20.8 8.4 19.7 7.8 20.8 7.4 .47a

Baseline SOFA, mean SD 7.1 2.9 6.8 3.6 7.6 3.7 .45a

Sepsis, No. (%)c

15 (40) 52 (48) 22 (44) .29b

Parenteral + enteral nutrition, kcal/d,

mean SDd

485.5 82.5 613.3 57.7 573.5 73.4 .49a

Comorbidity, No. (%)

CAD 6 (17) 23 (21) 8 (16) .74b

Hypertension 12 (33) 50 (46) 21 (42) .35b

COPD 7 (19) 18 (17) 12 (24) .44b

Diabetes 8 (22) 29 (27) 14 (28) .93b

Renal disease 4 (11) 9 (8) 10 (20) .15b

Liver disease 3 (8) 1 (1) 3 (6) .15b

Cancer 3 (8) 9 (8) 4 (8) .99b

Admission category, No. (%)

Cardiovascular 5 (14) 14 (13) 8 (16) .77b

Respiratory 13 (36) 24 (22) 20 (40) .66b

Neurological 3 (8) 8 (7) 3 (6) .99b

Metabolic 2 (6) 9 (8) 3 (6) .99b

Gastrointestinal 0 (0) 2 (2) 3 (6)6 .26b

Sepsis 2 (6) 4 (4) 0 (0) .18b

Postoperative 8 (22) 45 (41) 13 (30) .81b

APACHE II, Acute Physiology and Chronic Health Evaluation II; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; SOFA,

Sequential Organ Failure Assessment. A total of 196 patient blood specimens were available for analysis.Pvalues are from univariate analysis.aAnalysis of variance testPvalue.

b2 testPvalue.cPatients were classified as having sepsis if at any time during their stay they met systemic inflammatory response syndrome criteria and had a source of

infection.dMean parenteral and enteral nutrition per day.


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Pneumonia rates were 5%, 10%, and 16% in sufficient,

insufficient, and deficient patients, respectively. Although the

rate of culture-positive and probable pneumonia between the

groups was higher in the 25(OH)D-deficient group, these

results were not significant (culture confirmed: OR, 4.24; 95%

CI, 0.5038.8, P= .21; probable pneumonia: OR, 3.07; 95%

CI, 0.76312.36,P= .11). Patients with a probable pulmonary

infection or pneumonia from documented infection or culture-

confirmed pneumonia diagnosed >48 hours after admission

had significantly lower levels of baseline 25(OH)D compared

with those who did not have pneumonia, as seen in Figure 3.

Discussion

Here we report an observational study evaluating the relation-

ship between vitamin D deficiency and clinical outcomes in an

unselected, heterogeneous critically ill patient population.

This study showed that a significant number of ICU patients

had inadequate vitamin D status (82% of patients were insuf-

ficient or deficient) on admission. In addition, this is the first

study to describe a significant decrease in 25(OH)D levelsfrom admission 25(OH)D levels as early as 3 days after admis-

sion and as late as 10 days. Our data also demonstrate a high

incidence (39.1%) of sufficient patients becoming insufficient

during their stay. We did not observe an association between

baseline 25(OH)D status and 28-day all-cause mortality, but

25(OH)D-deficient patients stayed significantly longer in the

ICU, tended to develop more organ failure, and tended to

experience a higher number of infections, particularly pneu-

monia, compared with sufficient patients.

The outcomes associated with inadequate 25(OH)D status

seen in this study corroborate the findings of a recent smaller

study (n = 41) by Lee et al19 that showed that 93% of patients

had inadequate baseline 25(OH)D levels. However, little is

known about the measurement of 25(OH)D status during a

patients duration of stay. Only 1 smaller study21 (12 patients)

indirectly evaluated 25(OH)D status beyond admission levels

in the ICU, and to our knowledge, no studies have demonstrated

a significant decrease in 25(OH)D status during the patients

stay. In our study, we show a significant decrease in 25(OH)D

levels over the first 310 days in the ICU in the sufficient and

insufficient groups but no changes in patients who are already

deficient. The explanation for this acute decrease in 25(OH)D

0

20

40

60

80

100

120

140

160

180

200

1-002

1-008

1-014

1-020

1-026

1-032

1-038

1-045

1-051

1-057

1-063

1-069

1-075

1-081

1-087

1-093

1-099

1-105

1-111

1-117

1-123

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1-135

1-141

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1-153

1-159

1-165

1-171

1-177

1-183

1-189

1-195

1-201

Admission25(OH

)D(nmol/L)levels

Paents

Figure 1. Admission levels of 25(OH)D (nmol/L) in 196

intensive care unit (ICU) patients. The following 25(OH)

D values were used for deficient, insufficient, and sufficient

patients according to previously reported subgroups: sufficient,

>60 nmol/L; insufficient, >30 to 60 nmol/L; and deficient, 30

nmol/L.

15

35

55

75

95

1 3 7 10

25(OH)D(nmol/L)

Days aer admission

All paents (n=44)

Deficient (n=15)

Insufficient (n=21)

Sufficient (n=8)

****

**

****

** **

****

Figure 2. Levels of 25(OH)D decreased over intensive care unit

(ICU) patient stay. Levels of 25(OH)D on days 1, 3, 7, and 10

following admission were assayed from patient serum samples. A

total of 44 patients (only patients who stayed 10 days or longer)

are displayed in this figure. The data represent the mean SE

bars. The All patients line represents all patients who stayed 10

days or longer. The Sufficient, Insufficient, and Deficient

lines represent patients in the respective group who stayed at

least 10 days or longer. **Pvalues

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in the sufficient and insufficient groups is not clear but could be

due to changes in vitamin D binding protein (VDBP), which

approximately 85% of 25(OH)D is bound to.34 VDBP is

decreased in ICU patients and has been shown to be a predictor

of ICU mortality.35 Another recent study demonstrated that ICU

patients with sepsis and worse outcomes had significantly

lower levels of VDBP compared with those without sepsis.20 A

decrease in VDBP may be due to decreased protein synthesis or

increased clearance of VDBP in ICU patients with liver, renal,

or intestinal diseases. However, because VDBP concentrations

are much higher than 25(OH)D and VDBP has a high affinity

for vitamin D metabolites, reduced levels of VDBP often result

in lower total 25(OH)D but do not affect free concentrations.36

The VDBP relationship should be considered in any future

studies examining the acute changes in 25(OH)D observed in

this study.

In our study, we did not observe an association with 28-day

all-cause mortality and 25(OH)D status. This is in contrast to

a recent study by Braun et al24 that evaluated preadmission

vitamin D levels and found vitamin D deficiency to be

significantly associated with 30-, 90-, and 365-day mortality.

However, the prior study was limited by selection bias and

measurement of vitamin D status up to 365 days prior to ICU

admission. The lack of association of vitamin D status with

mortality in our study may be due to our study being under-powered. We were not able to run a power analysis a priori

because the relationship of vitamin D to mortality was not the

initial end point of the trial at conception, but post hoc power

analysis suggests that this study did not have the power to

detect small differences in mortality or infection rates between

the groups (data not shown). Therefore, the failure to demon-

strate statistically significant differences in mortality as well as

infection rates in this study should not be interpreted as evi-

dence for lack of a true difference. In fact, the magnitude of the

association with infection and vitamin D levels is quite large

(OR, 1.73.2), but we lacked statistical precision because of

our limited sample size.

The data presented here are the largest thus far to report an

increased time-to-alive ICU discharge associated with admis-

sion vitamin D deficiency. Our study also suggests a hypothe-

sis for the observed increased time-to-alive ICU discharge. We

used a very rigorous adjudication process to determine the

presence or absence of infection and a rigorous definition of

pneumonia. Our observation of increased infection rates and

decreased organ function may be factors associated with vita-

min D deficiency that could contribute to prolonged time-to-

alive ICU discharge and poorer outcomes in ICU patients. This

potentially could be due to the role vitamin D has on the

immune system. In line with this, a recent report found

Table 3. Infection Outcomes in 25(OH)D Groups

Sufficient, No. (%)

Insufficient,

No. (%)

Deficient,

No. (%)

Deficient vs

Sufficient OR PValue

Possible ICU infection 5 (13%) 19 (17%) 12 (24%) 1.7 (0.48, 2.7) .35

Probable ICU infection 4 (11%) 15 (14%) 9 (18%) 3.2 (0.78, 13.0) .11

Probable pneumonia 2 (5%) 10 (10%) 8 (16%) 4.2 (0.46, 38.8) .11Culture-positive pneumonia 2 (5%) 8 (7%) 6 (12%) 3.0 (0.76, 12.3) .20

Duration of ventilation, h,

mean SD

120 20.9 138 16.9 141 18.1 .49

Intensive care unit (ICU) infections were defined as infections diagnosed >48 hours after ICU admission. Possible/probable infection or probable pneu-

monia status was adjudicated by 2 independent clinicians. OR, odds ratio.

0

10

20

30

40

50

0

10

20

30

40

50

60

No infecon Infecon

25(OH)D(nmol/L)

25(

OH)D(nmol/L)

A)

B)

* p=0.01

No pneumonia

(n=176)

* p=0.01 *p=0.05

Culture posive

(n=16)

No infecon (n=160) Infecon (n=36)

Pneumonia

(n=20)

Figure 3. (A) Baseline levels of 25(OH)D in patients with a

probable new infection vs no new infection diagnosed >48

hours after admittance to the intensive care unit (ICU). The

data represent the mean SD andPvalues compared with

no infection. (B) Baseline levels of 25(OH)D in patients with

new culture-positive pneumonia, probable pneumonia, and no

pneumonia diagnosed >48 hours after admission to the ICU. The

probable pneumonia group included culture-positive pneumonia

patients in addition to 4 patients without culture positivity butclinical presentation of pneumonia. The data represent the mean

SD andPvalues compared with patients with no pneumonia.

*P < 0.05.


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significantly lower levels of the endogenous antimicrobial

peptide cathelicidin (LL-37) in critically ill patients who were

vitamin D deficient, suggesting a role for vitamin D in main-

taining innate immunity to infection in the ICU.20 Furthermore,

1,25(OH)D has been shown to have a stimulatory effect on the

innate immune system by increasing interleukin-1 (IL-1) pro-

duction and stimulating monocyte proliferation.37

Withoutthese important innate immune system stimulating effects,

patients may be more susceptible to ICU infections. On the

other hand, sufficient levels of vitamin D have been associated

with lower rates of autoimmune disorders, and it may be that

adequate levels of vitamin D are necessary to regulate overac-

tive, pathologic inflammatory immune responses.10,14 Therefore

patients may be more susceptible to pathologic, overactive

immune responses to common ICU infections.

Limitations to this study include a relatively small sample

size and confounding variables that could not be accounted for

in our multivariate analysis. For instance, the observed vitamin

D deficiency in this study could be due to a number of con-

founding causes, including the fact that many patients have

limited exposure to UV-B light during chronic disease and

often have significant dietary alterations, and the calcium

parathyroidvitamin D axis may be disrupted in critical illness,

so a consideration of PTH and Ca levels should be considered

in future studies.25,38 Although our study suggests an associa-

tion between inadequate vitamin D levels and poor patient out-

comes, this does not mean vitamin D is the direct cause of the

poor outcomes. It is possible that the conditions leading to

poor outcomes cause a decrease in vitamin D levels, which are

reactionary and not causal. More studies are needed to deter-

mine if there is direct causality between admission vitamin D

status and patient outcomes. Furthermore, although there wasnot a statistically significant difference in the rates of infection

and pneumonia, the significant differences in baseline levels of

25(OH)D between infected and noninfected patients suggest

an association that this study may not have had the power to

observe in actual infection rates.

A recent report from the Institute of Medicine (IOM) points

out that cutoffs for vitamin D deficiency have not been system-

atically developed.33 The cutoffs used for this study to define

sufficient, insufficient, and deficient groups were selected

according to recently published articles on vitamin D in ICU

patients to allow for across-study comparison in ICU patients.

Our cutoffs, although not exactly matching, are similar to the

IOM report that suggests 25(OH)D levels

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Acknowledgments

The authors thank the Childrens Hospital Clinical and Transla-

tional Research Center Core Lab in Denver, Colorado, for techni-

cal support in analyzing vitamin D levels from serum.

References

1. Holick MF. High prevalence of vitamin D inadequacy and implications for

health.Mayo Clin Proc. 2006;81(3):353-373.

2. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR.

Serum 25-hydroxyvitamin D status of adolescents and adults in two sea-

sonal subpopulations from NHANES III.Bone. May 2002;30(5):771-777.

3. Rosen CJ. Clinical practice: vitamin D insufficiency. N Engl J Med.

2011;364(3):248-254.

4. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary refer-

ence intakes for calcium and vitamin D from the Institute of Medicine:

what clinicians need to know.J Clin Endocrinol Metab. 2011;96(1):53-58.

5. DeLuca HF. Overview of general physiologic features and functions of

vitamin D.Am J Clin Nutr. 2004;80(6)(suppl):1689S-1696S.

6. Holick MF. Vitamin D deficiency.N Engl J Med. 2007;357(3):266-281.

7. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum

25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA.

2006;296(23):2832-2838.

8. Holick MF. Sunlight and vitamin D for bone health and prevention of auto-

immune diseases, cancers, and cardiovascular disease. Am J Clin Nutr.

2004;80(6)(suppl):1678S-1688S.

9. Holick MF. Vitamin D: importance in the prevention of cancers, type 1

diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):

362-371.

10. Moro JR, Iwata M, von Andriano UH. Vitamin effects on the immune system:

vitamins A and D take centre stage.Nat Rev Immunol. 2008;8(9):685-698.

11. Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin D metabolites and

risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev.

2004;13(9):1502-1508.

12. Holick MF. Calcium plus vitamin D and the risk of colorectal cancer.N

Engl J Med. 2006;354(21):2287-2288; author reply 2287-2288.

13. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vita-

min D intake is inversely associated with rheumatoid arthritis: results from

the Iowa Womens Health Study.Arthritis Rheum. 2004;50(1):72-77.

14. DeLuca HF. Evolution of our understanding of vitamin D.Nutr Rev. Oct

2008;66(10)(suppl 2):S73-S87.

15. van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3:

basic concepts.J Steroid Biochem Mol Biol. 2005;97(1-2):93-101.

16. Shapira Y, Agmon-Levin N, Shoenfeld Y. Mycobacterium tuberculosis,

autoimmunity, and vitamin D. Clin Rev Allergy Immunol. 2010;38(2-

3):169-177.

17. Zaloga GP, Chernow B. The multifactorial basis for hypocalcemia dur-

ing sepsis: studies of the parathyroid hormonevitamin D axis.Ann Intern

Med. 1987;107(1):36-41.

18. Lucidarme O, Messai E, Mazzoni T, Arcade M, du Cheyron D. Incidence and

risk factors of vitamin D deficiency in critically ill patients: results from a

prospective observational study.Intensive Care Med. 2010;36(9):1609-1611.

19. Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients.

N Engl J Med. 2009;360(18):1912-1914.

20. Jeng L, Yamshchikov AV, Judd SE, et al. Alterations in vitamin D status

and anti-microbial peptide levels in patients in the intensive care unit with

sepsis.J Transl Med. 2009;7:28.

21. Mata-Granados JM, Vargas-Vasserot J, Ferreiro-Vera C, Luque de Castro

MD, Pavon RG, Quesada Gomez JM. Evaluation of vitamin D endocrine

system (VDES) status and response to treatment of patients in intensive

care units (ICUs) using an on-line SPE-LC-MS/MS method.J Steroid Bio-

chem Mol Biol. 2010;121(1-2):452-455.

22. McKinney JD, Bailey BA, Garrett LH, Peiris P, Manning T, Peiris AN.

Relationship between vitamin D status and ICU outcomes in veterans. J

Am Med Directors Assoc. 2011;12(3):208-211.

23. Cecchi A, Bonizzoli M, Douar S, et al. Vitamin D deficiency in septic

patients at ICU admission is not a mortality predictor.Minerva Anestesiol.

2011;77(12):1184-1189.

24. Braun A, Chang D, Mahadevappa K, et al. Association of low serum

25-hydroxyvitamin D levels and mortality in the critically ill. Crit Care

Med. 2011;39(4):671-677.

25. Lee P, Nair P, Eisman JA, Center JR. Vitamin D deficiency in the intensive

care unit: an invisible accomplice to morbidity and mortality? IntensiveCare Med. 2009;35(12):2028-2032.

26. Heyland DK, Govert, J, Garrard C. Waveform abnormalities of APPT in

critically ill hospitalized patients: the WATTCH study. Crit Care Med.

2006;34(12):A100.

27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a sever-

ity of disease classification system. Crit Care Med. 1985;13(10):818-829.

28. Moreno R, Vincent JL, Matos R, et al. The use of maximum SOFA score to

quantify organ dysfunction/failure in intensive care: results of a prospec-

tive, multicentre study. Working Group on Sepsis related Problems of the

ESICM.Intensive Care Med. 1999;25(7):686-696.

29. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of

health careassociated infection and criteria for specific types of infections

in the acute care setting.Am J Infect Control. 2008;36(5):309-332.

30. Heyland DK, Dodek P, Muscedere J, Day A, Cook D. Randomized trial of

combination versus monotherapy for the empiric treatment of suspected

ventilator-associated pneumonia. Crit Care Med. 2008;36(3):737-744.

31. A randomized trial of diagnostic techniques for ventilator-associated pneu-

monia.N Engl J Med. 2006;355(25):2619-2630.

32. Ginde AA, Mansbach JM, Camargo CA Jr. Vitamin D, respiratory infec-

tions, and asthma. Curr Allergy Asthma Rep. 2009;9(1):81-87.

33. Ross AC, Institute of Medicine Committee to Review Dietary Reference

Intakes for Vitamin D and Calcium.Dietary Reference Intakes for Calcium

and Vitamin D. Washington, DC: National Academies Press; 2011.

34. Jafri L, Khan AH, Siddiqui AA, et al. Comparison of high performance

liquid chromatography, radio immunoassay and electrochemilumines-

cence immunoassay for quantification of serum 25 hydroxy vitamin D.

Clin Biochem. 2011;44(10-11):864-868.

35. Dahl B, Schiodt FV, Nielsen M, Kiaer T, Williams JG, Ott P. Admis-

sion level of Gc-globulin predicts outcome after multiple trauma. Injury.

1999;30(4):275-281.

36. Bikle DD, Halloran BP, Gee E, Ryzen E, Haddad JG. Free 25-

hydroxyvitamin D levels are normal in subjects with liver disease and reduced

total 25-hydroxyvitamin D levels.J Clin Invest. 1986;78(3):748-752.

37. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system:

vitamins A and D take centre stage.Nat Rev Immunol. 2008;8(9):685-698.

38. Kelly A, Levine MA. Hypocalcemia in the critically ill patient.J Intensive

Care Med. 2011 Aug 12. [Epub ahead of print]

39. Binkley N, Krueger D, Gemar D, Drezner MK. Correlation among

25-hydroxy-vitamin D assays. J Clin Endocrinol Metabolism. 2008;93

(5):1804-1808.

40. Leino A, Turpeinen U, Koskinen P. Automated measurement of

25-OH vitamin D3 on the Roche Modular E170 analyzer. Clin Chem.

2008;54(12):2059-2062.

41. Ersfeld DL, Rao DS, Body JJ, et al. Analytical and clinical validation of

the 25 OH vitamin D assay for the LIAISON automated analyzer. Clin

Biochem. 2004;37(10):867-874.

42. Antoniucci DM, Black DM, Sellmeyer DE. Serum 25-hydroxyvitamin

D is unaffected by multiple freeze-thaw cycles. Clin Chem. 2005;51(1):

258-261.

43. A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force.

Guidelines for the use of parenteral and enteral nutrition in adult and pediat-

ric patients.JPEN J Parenter Enteral Nutr. 2002;26(1)(suppl):1SA-138SA.

44. Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq

L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin

D.J Clin Endocrinol Metab. 2003;88(10):4623-4632.

45. Amrein K, Sourij H, Wagner G, et al. Short-term effects of high-dose oral

vitamin D3 in critically ill vitamin D deficient patients: a randomized,

double-blind, placebo-controlled pilot study. Crit Care. 2011;15(2):R104.


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