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ORIGINAL ARTICLE

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Vitamin D Deficiency Is Associated With Increased Length
of Stay After Acute Burn Injury: A Multicenter Analysis
Sarah Zavala, PharmD, BCPS, BCCCP*,1, ; Kate O. Pape, PharmD, BCPS, BCCCP2;
Todd A. Walroth, PharmD, BCPS, BCCCP, FCCM3, ; Melissa Reger, PharmD, BCPS4, ;
Brittany Hoyte, PharmD, BCCCP5, ; Wendy Thomas, PharmD, BCCCP5;
Beatrice Adams, PharmD, BCPS, BCCCP, FCCM6, ; David M. Hill, PharmD, BCPS, BCCCP, FCCM7,

In burn patients, vitamin D deficiency has been associated with increased incidence of sepsis and infectious
complications. The objective of this study was to assess the impact of vitamin D deficiency in adult burn
patients on hospital length of stay (LOS). This was a multicenter retrospective study of adult patients at 7
burn centers admitted over a 3.5-year period, who had a 25-hydroxyvitamin D concentration drawn within
the first 7 days of injury. Of 1147 patients screened, 412 were included. Fifty-seven percent were vitamin D
deficient. Patients with vitamin D deficiency had longer LOS (18.0 vs 12.0 days, P < .001), acute kidney injury
(AKI) requiring renal replacement therapy (7.3 vs 1.7%, P = .009), more days requiring vasopressors (mean
1.24 vs 0.58 days, P = .008), and fewer ventilator-free days of the first 28 days (mean 22.9 vs 25.1, P < .001).
Univariable analysis identified burn center, AKI, TBSA, inhalation injury, admission concentration, days until
concentration drawn, days until initiating supplementation, and dose as significantly associated with LOS.
After controlling for center, TBSA, age, and inhalation injury, vitamin D deficiency was associated with longer
LOS. In conclusion, patients with thermal injuries and vitamin D deficiency on admission have increased LOS
and worsened clinical outcomes when compared with patients with nondeficient vitamin D concentrations.

Key words: vitamin D; length of stay; burn; nutrition; thermal injury.

INTRODUCTION receptors are found on the surface of nearly all cells, which
may explain the pleiotropic benefits of vitamin D as shown
Vitamin D is well known for its role in bone and calcium ho- in Figure 1.5–7 The hormonally activated form of vitamin D
meostasis, and several early studies in burn patients focused is calcitriol or 1,25-dihydroxvitamin D3 (1,25(OH)2D3), and
on this role, particularly in pediatric patients.1–4 Vitamin D it both inhibits the adaptive immune response (by decreasing
inflammatory cytokines) and promotes the innate immune
1
Department of Pharmacy, Jesse Brown VA Medical Center, Chicago, IL 60612, response (by stimulating the production IL-4 by Th2 cells,
USA; 2Department of Pharmacy, University of Iowa Health Care, Iowa City, enhancing T regulatory cells, and increasing differentiation
IA 52245, USA; 3Department of Pharmacy, Eskenazi Health, Indianapolis,
IN 46202, USA; 4Department of Pharmacy, Community Regional Medical
and phagocytic capacity of macrophages).5–7
Center, Fresno, CA 93721, USA; 5Department of Pharmacy, Corewell Health, The effect of 25-hydroxyvitamin D (25[OH]D) on clinical
Grand Rapids, MI 49503, USA; 6Department of Pharmacy, Tampa General outcomes has been studied in critically ill nonburn patients. In
Hospital, Tampa, FL 33606, USA; 7Department of Pharmacy, Regional One
Health, Memphis, TN 38103, USA one study of critically ill adult patients with traumatic injuries,
Author Contributions: Sarah Zavala (Conceptualization [Equal]; Data the majority (76%) were found to have either 25(OH)D de-
curation [Supporting]; Investigation [Lead]; Methodology [Supporting]; ficiency or severe deficiency.8 In critically ill surgical patients,
Project administration [Lead]; Supervision [Supporting]; Writing—
original draft [Lead]; Writing—review & editing [Lead]), Kate O Pape
admission 25(OH)D concentrations predicted the length of
(Investigation [Supporting]; Writing—review & editing [Supporting]), stay (LOS) in the intensive care unit (ICU), treatment cost,
Todd A Walroth (Investigation [Supporting]; Writing—review & editing and mortality.9,10 Low 25(OH)D concentrations were found
[Supporting]), Melissa Reger (Investigation [Supporting]; Writing—review &
editing [Supporting]), Brittany Hoyte (Investigation [Supporting]; Writing— to be a significant predictor of sepsis in a mixed surgical and
review & editing [Supporting]), Wendy Thomas (Investigation [Supporting]; medical ICU population.11 In medical ICU patients, 25(OH)
Writing—review & editing [Supporting]), Beatrice Adams (Investigation D deficiency is associated with in-hospital mortality.12
[Supporting]; Writing—review & editing [Supporting]), and David M Hill
(Conceptualization [Equal]; Data curation [Lead]; Formal analysis [Lead]; Most 25(OH)D studies in burn patients are small and
Investigation [Supporting]; Methodology [Lead]; Project administration from a single center. Few have studied 25(OH)D in adult
[Supporting]; Supervision [Supporting]; Validation [Supporting];
Visualization [Lead]; Writing—review & editing [Supporting])
burn patients.13–17 Several areas of future research have
Funding: None declared. been identified, including the role of 25(OH)D and clin-
Conflict Of Interest Statement: D.H. has received research funding and is a ical outcomes in burn patients, such as LOS and ventilator
consultant for Medline Industries, LP, Trevena, Inc, and Access Pro Medical.
*
Address correspondence to S.Z. (email: Sarah.zavala@va.gov) days.13,17,18 The objective of this multicenter study was to as-
sess the impact of vitamin D deficiency in patients admitted
© The Author(s) 2023. Published by Oxford University Press on behalf of the
American Burn Association. All rights reserved. For permissions, please e-mail: with burn injuries on hospital LOS. The authors hypothesized
journals.permissions@oup.com. patients with vitamin D deficiency on admission would have
https://doi.org/10.1093/jbcr/irad201 a longer LOS.
1
請遵守請遵守著作權法之規範：本館以電子檔案傳遞具有保全設定之文獻，僅供列印使用，請勿任意傳送與重製；應覽人供個人研究之要求，得重製已公開發表著作之一部分，或期刊或已公開發表之研討會論文集之單篇著作，每人以一份為限

Journal of Burn Care & Research

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Figure 1. Vitamin D Receptors Have Been Found on Nearly All Cells. This Figure Shows the Proposed Mechanism of Action of Vitamin D on
Select Systems in the Body

MATERIALS AND METHODS infection, in-hospital mortality, ventilator-free days of the

first 28, acute kidney injury (AKI) requiring renal replace-
This retrospective, observational multicenter study of adult ment therapy (RRT), length of ICU stay, days requiring
patients included patients with acute burn injuries admitted vasopressors, form of vitamin D received during admission
to one of 7 burn centers between January 1, 2016 and July (ergocalciferol or cholecalciferol), vitamin D dosing during
25, 2019 who had a 25(OH)D concentration drawn within admission, and form of nutrition provided.19
the first 7 days of admission. Patients were excluded from
the study if they were admitted for a nonburn-related in-
jury, had TBSA burned of less than 5%, were a readmission Statistical analysis
after a previous initial admission for burn treatment, preg- Sample size was determined a priori.19 Dichotomous
nant, incarcerated, or made comfort care or expired within 48 variables were compared via chi-square test. Continuous
hours of admission. Institutional Review Board approval was data were compared via student t-test or Mann–Whitney U
obtained from each study site. test, depending on distribution. All collected variables were
Collected demographic data include patient demographics, subjected to univariable linear regression to identify variables
vitamin D levels, burn injury mechanism, % TBSA affected, associated with LOS to analyze further. Variables found to have
presence of inhalation injury, comorbid conditions as defined P < .10 during univariable analysis were considered further for
by the Charlson Comorbidity Index, vitamin D supplementa- multivariable analysis via an iterative process. In following the
tion prior to admission, month of admission, and degrees of primary hypothesis, center (i.e., control for differences among
latitude of the admitting burn center. treating facilities), % TBSA, age, and presence of inhalation
The primary end point was to compare hospital LOS be- injury were included in each iterative predictive model for
tween burn patients with vitamin D deficiency (defined as predicting LOS along with significant variable(s) identified
25[OH]D < 20 ng/mL) and nondeficiency (25[OH]D ≥ during univariable regression. Cox proportional hazard
20 ng/mL). Secondary end points included incidence of model was utilized to test the primary hypothesis that vitamin
請遵守請遵守著作權法之規範：本館以電子檔案傳遞具有保全設定之文獻，僅供列印使用，請勿任意傳送與重製；應覽人供個人研究之要求，得重製已公開發表著作之一部分，或期刊或已公開發表之研討會論文集之單篇著作，每人以一份為限

Journal of Burn Care & Research

Volume XX, Number XX Zavala et al.  3

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Figure 2. Screening Diagram

D deficiency is associated with longer LOS, while censoring Table 1. Baseline Demographics and Injury Characteristics
for death, and controlling for TBSA, age, presence of inhala-
Total cohort (n = 412)
tion injury, and potential for a center effect. All analyses were
performed using SPSS version 25.0 for Windows (SPSS, Inc., Age, median, y (IQR) 49.5 (34, 61.5)
Chicago, IL). Male, n (%) 304 (73.8)
Ethnicity, n (%)
 Caucasian 277 (67.2)
 African American 60 (14.6)
RESULTS  Hispanic 45 (10.9)
Of 1147 patients screened, 412 patients were included in  Other 30 (7.3)
the study (Figure 2). Baseline demographics are shown in Height, median, cm (IQR) 175.3 (167.6, 182.9)
Table 1. Patients were predominately middle-aged males with Weight, median, kg (IQR) 84.8 (70.8, 99.8)
few comorbidities. The median (IQR) TBSA of 13.4% (8.1, BMI, median (IQR) 27.7 (23.7, 32.7)
22.9) and the most frequent mechanism of injury was flame TBSA, median, % (IQR) 13.4 (8.1, 22.9)
burn. Mechanism, n (%)
Details regarding vitamin D supplementation are seen in  Flame 307 (74.5)
Table 2. Most patients had a 25(OH)D level drawn on day 1  Scald/grease 71 (17.2)
of admission, and our cohort had an average admission con-  Other 34 (8.3)
centration of 17.8 ng/mL. The median day of concentration Inhalation injury, n (%) 51 (12.4)
measurement was 1 (1, 2) day, while the median day to initi- Charlson Comorbidity Index, median (IQR) 1 (0, 3)
ation of vitamin D supplementation was 3 (2, 6) days. With
Abbreviations: BMI, body mass index; cm, centimeter; IQR, interquartile
regards to type of supplementation, 33% of patients in the range; n, number; TBSA, total body surface area.
cohort received ergocalciferol during their admission, 32% re-
ceived cholecalciferol, and the remainder did not receive any
supplementation. Patients received a median dose of 7142 in- Table 2. Vitamin D Supplementation
ternational units (IU) per day, or 50,000 IU weekly.
Total cohort (n = 412)
Univariable analysis identified AKI requiring RRT, %
TBSA, inhalation injury, admission concentration, days until Received vitamin D prior to admission, n (%) 18 (4.4)
concentration drawn, days until initiating supplementation, Admission concentration, median, ng/ 17.8 (12, 25)
and dose as significantly associated with LOS (Table 3). mL (IQR)
After censoring for death and controlling for burn center, % Day concentration drawn, median (IQR) 1 (1, 2)
TBSA, age, and inhalation injury, the presence of deficiency Supplementation used, n (%)
increased LOS. Table 4 displays the hazard ratios and confi-  Ergocalciferol 137 (33.3)
dence intervals.  Cholecalciferol 132 (32.0)
Figure 3 demonstrates that at 60 days and at any point Daily dose vitamin D received, median IU 7142 (2000, 7143)
throughout that time, patients with a deficient vitamin D level (IQR)
on admission were more likely to remain in the hospital when
compared with the nondeficient group. Abbreviations: IQR, interquartile range; IU, international units; n, number.
請遵守請遵守著作權法之規範：本館以電子檔案傳遞具有保全設定之文獻，僅供列印使用，請勿任意傳送與重製；應覽人供個人研究之要求，得重製已公開發表著作之一部分，或期刊或已公開發表之研討會論文集之單篇著作，每人以一份為限

Journal of Burn Care & Research

4  Zavala et al. XXXX/XXXX 2024

Table 3. Univariable Linear Regression

Variable Coefficient P value r2

Age 0.004 0.944 0.00001

Ethnicity 1.601 0.174 0.005

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BMI −0.17 0.289 0.003
Charlson Comorbidity 0.092 0.866 0.00007
Index
Received vitamin D prior −8.604 0.115 0.006
to admission
TBSA % 0.908 <0.001 0.305
Burn injury mechanism −1.937 0.115 0.006
Inhalation injury 14.349 <0.001 0.044
Burn center −0.974 0.04 0.01
Admission concentration −0.519 <0.001 0.062
Days until concentration 3.35 <0.001 0.042
drawn
Presence of vitamin D 10.363 <0.001 0.052
deficiency
Supplementation used 10.964 <0.001 0.053
Days until supplementa- 1.136 <0.001 0.053
tion initiation
Figure 3. Admission Vitamin D Level and Length of Stay. Length
Received cholecalciferol −3.139 0.297 0.004
of Stay Analysis Stratified by the Presence of Vitamin D Deficiency
Vitamin D dose 0.001 0.016 0.022 (Defined as 25[OH]D < 20 ng/mL) on Admission, Censored
AKI requiring RRT 25.779 <0.001 0.06 by Death and Including Percent TBSA Burned, Age, Presence
MV free days in the first −0.953 <0.001 0.118 of Inhalation Injury, and Burn Center as Covariates. Patients
28 days Demonstrating Vitamin D Deficiency on Admission Were Less Likely
Days requiring 1.898 <0.001 0.151 to be Discharged by Hospital Day 60
vasopressors
Infection 22.654 <0.001 0.244
regression analysis, as the dilution is most likely to occur with
Abbreviations: AKI, acute kidney injury; BMI, body mass index; MV, mechan- larger %TBSA receiving fluid resuscitation. Additionally, the
ical ventilator; RRT, renal replacement therapy; TBSA, total body surface area. %TBSA was larger in the 25(OH)D nondeficient group, which
would be bias in favor of the control group (ie, a longer LOS).
Table 4. Cox Proportional Hazards Model (Censored for Interestingly, a post hoc multivariable regression demonstrated
Death) deficiency to be significantly associated with LOS independent
of death, % TBSA, days requiring vasopressors, and presence of
Coefficient HR LCI UCI P value
infection (r2 = .513). In fact, this multivariable model proved
Burn center 0.088 1.092 1.045 1.141 <0.001 to be most predictive after including each collected variable
TBSA 0.072 0.93 0.92 0.941 <0.001 one at a time to find the best fit (Table 5).
Age 0.021 0.979 0.973 0.985 <0.001 The demographics performed as expected in the univariate
Inhalation injury 0.543 0.581 0.405 0.833 0.003 analysis based on previous literature (i.e., % TBSA contributes to
Vitamin D deficient 0.589 0.555 0.447 0.688 <0.001 LOS, as does inhalation injury and mechanism of injury). Age
did not contribute to an increased LOS, likely due to the higher
Abbreviations: HR, hazard ratio; LCI, lower limit (95% confidence interval); risk of mortality associated with increased age. The specific details
TBSA, total body surface area; UCI, upper limit (95% confidence interval). regarding vitamin D mattered, including the admission concen-
tration, timing of the level, whether supplementation was used,
DISCUSSION the dose used, and the time until supplementation was started.
Lastly, because burn center did have an effect in the univariable
In burn patients, 25(OH)D has primarily been studied in regression, it was added to ensure against confounding in the
pediatric patients, but several single-center studies in adults model. Limitations to our study include its retrospective nature,
have recently been published.13–17,20–22 One study of patients no data collected regarding calcium supplementation, and not
admitted to a rehabilitation center evaluated vitamin D levels having a standard protocol between burn centers for monitoring
and factors such as wound healing time and LOS according and supplementation; however, this was somewhat controlled
to burn mechanism.23 To our knowledge, this is the first by including center in the regression. Additionally, this real-
multicenter study to evaluate the association between vitamin world approach increases the external validity of our findings.
D concentrations and LOS in burn patients. In addition to the multicenter design, the robust number of
The concern for the dilutional effect surrounding the observations (n = 412) is a strength of the study.
drawing of 25(OH)D concentrations on admission should The effect on LOS in the study may be due to the pleiotropic
be adequately controlled for by including %TBSA in the effects of vitamin D, including its known impact on immune
請遵守請遵守著作權法之規範：本館以電子檔案傳遞具有保全設定之文獻，僅供列印使用，請勿任意傳送與重製；應覽人供個人研究之要求，得重製已公開發表著作之一部分，或期刊或已公開發表之研討會論文集之單篇著作，每人以一份為限

Journal of Burn Care & Research

Volume XX, Number XX Zavala et al.  5

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