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Vitamin D deficiency on admission to the emergency department is a mortality predictor for patients with septic shock treated with early protocol-driven resuscitation bundle therapy

Published:October 17, 2022DOI:https://doi.org/10.1016/j.amjms.2022.10.005

      Abstract

      Background

      Vitamin D is an important immune modulator and is associated with susceptibility to infection. However, past studies have reported inconsistent results regarding the association between vitamin D deficiency and mortality in patients with sepsis, and early-stage data regarding septic shock are limited. This study aimed to determine the relationship between vitamin D deficiency on admission to the emergency department (ED) and mortality in patients with septic shock.

      Methods

      We analyzed prospectively collected data on adult patients with septic shock who were treated with protocol-driven resuscitation bundle therapy in the ED between September 2019 and February 2021. Septic shock was defined by the sepsis-3 definition and vitamin D deficiency was defined as a 25-hydroxyvitamin D <20 ng/ml. The primary outcome was 30-day mortality.

      Results

      A total of 302 patients were included, 236 (78.1%) patients had vitamin D deficiency; it was significantly higher in non-survivors than in survivors (89.3% vs. 73.9%, P = 0.004). Mortality was higher in vitamin D deficient patients than in non-deficient patients (31.8% vs. 13.6%, P = 0.004). In multivariate analysis, vitamin D deficiency (odds ratio [OR], 2.43; 95 % confidence interval [CI], 1.03–5.74), hyperlactatemia (OR, 3.65; 95 % CI, 1.95–6.83), Sequential Organ Failure Assessment scores (OR, 1.22; 95% CI, 1.09–1.36), and albumin levels (OR, 0.39; 95% CI, 0.21–0.73) were significantly associated with 30-day mortality.

      Conclusions

      Vitamin D deficiency was prevalent in patients with septic shock visiting the ED and was associated with mortality.

      Key Indexing Terms

      Introduction

      Sepsis is a life-threatening medical condition that results in significant morbidity and mortality. Each year, it affects over 750,000 patients in the United States and causes approximately 250,000 deaths.
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      Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.
      Septic shock, occurring in approximately 15% of sepsis cases, is a medical emergency that accounts for 10% of intensive care unit (ICU) admissions and has a mortality rate of > 50%.
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      Sepsis and septic shock: guideline-based management.
      The current guidelines for the management of sepsis and septic shock recommend urgent assessment and early application of protocol-driven resuscitation care bundle therapy. The management includes fluid resuscitation, performing blood cultures, and the administration of broad-spectrum antibiotics.
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      • Rhodes A.
      The surviving sepsis campaign bundle: 2018 update.
      Sepsis resuscitation generally focuses on macro-circulatory failures, such as decreased mean arterial pressure and cardiac output. However, a growing body of evidence suggests that the inability of the cell to consume oxygen may play a crucial role in the pathogenesis of sepsis. And that evidence entitled metabolic resuscitations for mitochondria such as the combination of vitamin C, thiamine, and corticosteroid. Vitamin D deficiency is prevalent in patients with critical illnesses
      • 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.
      and chronic diseases.
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      Vitamin D and cardiovascular disorders.
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      Prospective study of predictors of vitamin D status and cancer incidence and mortality in men.
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      Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study.
      • Pilz S
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      • Fischer JE
      • et al.
      Low vitamin D levels predict stroke in patients referred to coronary angiography.
      In addition to its role in regulating calcium and phosphate metabolisms, vitamin D plays a key role in immunity, endothelial functioning, and the optimal functioning of antimicrobial activity. Previous studies have evaluated vitamin D deficiency as a diagnostic or predictive marker for infections.
      • 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.
      ,
      • Lucidarme O
      • Messai E
      • Mazzoni T
      • et al.
      Incidence and risk factors of vitamin D deficiency in critically ill patients: results from a prospective observational study.
      Moreover, the association between vitamin D deficiency and the risk of infection has been reported in critically ill patients.
      • Braun A
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      • et al.
      Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill.
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      Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis.
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      • et al.
      Association between vitamin D deficiency and mortality in critically ill adult patients: a meta-analysis of cohort studies.
      A recent study has shown that vitamin D supplementation can reduce the risk of influenza and coronavirus disease (COVID-19).
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      • Hasan SS.
      Vitamin D Supplementation in Influenza and COVID-19 Infections Comment on:“Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths” Nutrients 2020, 12 (4), 988.
      Although vitamin D deficiency is prevalent in patients with sepsis, evidence of the association between vitamin D deficiency and sepsis mortality is limited and inconsistent. Considering the role of vitamin D in maintaining the innate and adaptive immune systems
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      Immunoregulation by 1, 25-dihydroxyvitamin D3: basic concepts.
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      Regulation of immune function by vitamin D and its use in diseases of immunity.
      , we hypothesized that vitamin D deficiency is a surrogate marker of disease severity and may be a modifiable risk factor that could be rapidly treated via supplementation. We believe this investigation will result in high yields as, currently, no proven metabolic therapy is available for septic shock treatment. However, the prevalence of vitamin D deficiency and the association between vitamin D levels and mortality needs to be clarified.
      Thus, this study aimed to determine the prevalence of vitamin D deficiency and investigate the relationship between vitamin D deficiency on admission to the emergency department (ED) and mortality in patients with septic shock treated with protocol-driven resuscitation bundle therapy.

      Methods

      Study design and population

      This observational, single-center study using prospectively collected septic shock registry data was conducted in the ED of a tertiary referral academic center in Seoul, South Korea, which provides treatment to approximately 120,000 patients per year. This study included all adult patients aged ≥18 years with septic shock who were treated with protocol-driven resuscitation care bundle therapy and had data on 25-hydroxyvitamin D [25(OH)D] levels taken at the time of admission to the ED from September 2019 and February 2021. The requirement of informed consent was waived, and the study design was approved by the appropriate ethics review board of our hospital.
      Refractory hypotension was defined as persistent hypotension with systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg after adequate intravenous fluid challenge (20–30 mL/kg or at least ≧1 L of crystalloid solution administered over 30 min) or as the need for vasopressors after fluid resuscitation. Patients with septic shock were defined as those with refractory hypotension, hyperlactatemia (≧2 mmol/L), and suspected or confirmed infections by the sepsis-3 definition.
      • Singer M
      • Deutschman CS
      • Seymour CW
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      Patients who visited the ED multiple times during the study period were included only once. Transfer cases with do-not-resuscitate orders were excluded to eliminate the confounding effect on mortality as much as possible. (Supplementary S1)

      Data collection

      The septic shock registry retrieved data on demographic and clinical data on age, sex, previous medical history, initial vital signs, severity, laboratory test values on admission, and interventions. Sequential Organ Failure Assessment (SOFA) scores
      • Vincent J-L
      • Moreno R
      • Takala J
      • et al.
      The SOFA (Sepsis-related Organ Failure Assessment) score describes organ dysfunction/failure.
      were calculated based on physiological and laboratory data collected in the ED. Mental status was assessed according to the alert/responsive to voice/responsive to pain/unresponsive scale, and patients with Glasgow coma scale scores <15 were considered to have altered mental statuses.
      Serum 25(OH)D levels (reference value: 10.0–29.0 ng/mL) were analyzed using 3 mL of whole blood collected in a serum separating tube with radioimmunoassay (RIA) using Freedom EVO® (Tecan Schweiz AG, Switzerland) and Dream Gamma-10 with 25-OH-Vitamin D total-RIA-CT (DIAsource). Analyses of 25(OH)D levels were performed immediately after blood sample collection on weekdays and within 48 hours on weekends, until which the blood sample was stored in a refrigerator at 2°C–8°C. When the analysis was expected to be delayed for >48 hours, the blood samples were frozen at -20°C. Vitamin D deficiency was defined as 25(OH)D level <20 ng/ml (50 nmol/L) according to the Endocrine Society guidelines.
      • Holick MF
      • Binkley NC
      • Bischoff-Ferrari HA
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      All patients were followed up for >30 days as the primary study outcome was 30-day mortality.

      Statistical analysis

      Continuous variables are presented as mean ± standard deviation due to their normal distribution. Categorical variables are presented as numbers and percentages. To compare the difference among the variables, Student's t-test or the Wilcoxon rank-sum test was used for continuous variables and the chi-square test or Fisher's exact test was used for categorical variables. Univariate and multivariate logistic regression analyses were performed to assess the relationships between patient characteristics or laboratory data and the probability of 30-day mortality. Multivariate logistic regression analyses were performed to determine the predictors of 30-day mortality and the values were reported as odds ratios (ORs) of 30-day mortality. The logistic model of the goodness of fit was evaluated using the Hosmer–Lemeshow test. For all tests, P values were two-tailed and values <0.05 were considered statistically significant. All analyses were performed using IBM SPSS Statics for Windows, version 21.0 (IBM Corp., Armonk, NY, USA).

      Results

      Study population

      During the study period, 337 patients with septic shock who had data on serum vitamin D levels were enrolled. After excluding 8 patients with multiple ED visits and 27 patients who were transferred to other hospitals with do-not-resuscitate orders, 302 patients were included. The mean patient age was 66.5 years, and 59.6% of the patients were men. The prevalence of vitamin D deficiency was 78.1%, and the overall 30-day mortality rate was 27.8%.

      Baseline characteristics

      The baseline characteristics, including demographic, clinical, and laboratory data, of patients in the 30-day survivor and non-survivor groups, are presented in Table 1. There was no significant difference between the two groups with regard to age, sex, and medical history, except for malignancy (61.5% vs. 77.4%, P = 0.009). The body temperature was lower (37.19 vs. 37.74 °C, P = 0.002) and changes in mental status were more common (27.4 % vs. 14.2%, P = 0.007) in the non-survivor group than in the survivor group. There were statistically significant differences between the two groups in the initial laboratory data including hemoglobin levels (10.74 vs. 9.91 g/dl, P = 0.006), platelet levels (169.8 vs. 127.7 × 103/µL, P = 0.003), prothrombin time (PT) (1.37 vs. 1.91 international normalized ratios (INR), P < 0.001), albumin levels (2.65 vs. 2.25 g/dL, P < 0.001), creatinine levels (1.82 vs. 2.38 mg/dL, P = 0.011), and lactate levels (3.35 vs. 6.01 mmol/L, P < 0.001). The mean SOFA score was significantly higher in the non-survivor group than that in the survivor group (10.16 vs. 7.41, P < 0.001).
      Table 1Baseline characteristics between 30-day survivors and 30-day non-survivors.
      Total (n = 302)Survivor (n = 218)Non-survivor (n = 84)P value
      Age (years)66.50 ± 11.5166.72 ± 11.5465.92 ± 11.480.585
      Male (%)180 (59.6)128 (58.7)52 (61.9)0.613
      Comorbidities (%)
       Hypertension107 (35.4)78 (35.8)29 (34.5)0.838
       Diabetes mellitus84 (27.8)65 (29.8)19 (22.6)0.211
       Chronic renal disease31 (10.3)23 (10.6)8 (9.5)0.792
       Coronary artery disease35 (11.6)21 (9.6)14 (16.7)0.087
       Malignancy199 (65.9)134 (61.5)65 (77.4)0.009
      Initial vital sign
       SBP (mmHg)87.12 ± 21.1987.11 ± 21.3987.13 ± 20.790.995
       DBP (mmHg)56.49 ± 13.2356.30 ± 12.8656.99 ± 14.190.685
       Heart rate (bpm)109.7 ± 23.65108.5 ± 23.15112.7 ± 24.790.173
       Body temperature (°C)37.58 ± 1.4237.74 ± 1.3737.19 ± 1.460.002
      Change of mental status (%)54 (17.9)31 (14.2)23 (27.4)0.007
      Vitamin D (ng/mL)14.44 ± 9.3515.59 ± 10.0811.43 ± 6.23<0.001
      Vitamin D Deficiency (%)236 (78.1)161 (73.9)75 (89.3)0.004
      Laboratory data
       WBC (x103/μL)10.90 ± 9.0810.67 ± 8.0711.50 ± 11.340.541
       Hemoglobin (g/dL)10.51 ± 2.3510.74 ± 2.349.91 ± 2.300.006
       Platelet (x103/μL)158.1 ± 109.8169.8 ± 105.7127.7 ± 115.00.003
       PT (INR)1.52 ± 0.801.37 ± 0.481.91 ± 1.24<0.001
       Albumin (g/dL)2.54 ± 0.592.65 ± 0.572.25 ± 0.53<0.001
       Creatinine (mg/dL)1.98 ± 1.701.82 ± 1.612.38 ± 1.850.011
       CRP (mg/dL)15.60 ± 10.7015.45 ± 10.8115.98 ± 10.430.701
       Procalcitonin (ng/dL)27.23 ± 43.2325.80 ± 40.3430.94 ± 50.050.364
       Lactate (mmol/L)4.09 ± 3.113.35 ± 2.536.01 ± 3.64<0.001
      SOFA score8.18 ± 3.247.41 ± 2.7810.16 ± 3.54<0.001
      ICU admission (%)101 (33.4)69 (31.7)32 (38.1)0.288
      Values are expressed as the mean ± standard deviation, the median [interquartile range], or the number (%).
      SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, white blood cells; PT, prothrombin time; INR, international normalized ratio; CRP, c-reactive protein; SOFA, sequential organ failure assessment; ICU, intensive care unit.
      The average 25(OH)D level was significantly higher in the survivor group than in the non-survivor group (15.59 ± 10.08 vs. 11.43 ± 6.23 ng/mL, P < 0.001). The prevalence of vitamin D deficiency as a categorical variable was significantly higher in the non-survivor group than in the survivor group (89.3% vs. 73.9%, P = 0.004).

      Characteristics of patients with Vitamin D deficiency

      The baseline characteristics, including demographic, clinical, and laboratory data, of patients in the vitamin D deficient and non-deficient groups, are summarized in Table 2. Overall, there were no statistically significant differences between the two groups except for age (70.77 vs. 65.31 years, P = 0.001). Among the laboratory test values, only PT (1.36 vs. 1.56 INR, P = 0.010) and serum lactate levels (4.31 vs. 3.34 mmol/L, P = 0.025) were significantly different between the two groups.
      Table 2Comparison of baseline characteristics of patients according to vitamin D deficiency and non-deficiency group.
      Total (n = 302)25(OH)D Non-deficiency group (n = 66)25(OH)D Deficiency group (n = 236)P value
      Age (years)66.50 ± 11.5170.77 ± 10.8065.31 ± 11.440.001
      Male (%)180 (59.6)39 (59.1)141 (59.7)0.924
      Comorbidities (%)
       Hypertension107 (35.4)23 (34.8)84 (35.6)0.911
       Diabetes mellitus84 (27.8)17 (25.8)67 (28.4)0.67 3
       Chronic renal disease31 (10.3)6 (9.1)25 (10.6)0.722
       Coronary artery disease35 (11.6)11 (16.7)24 (10.2)0.145
       Malignancy199 (65.9)38 (57.6)161 (68.2)0.107
      Initial vital sign
       SBP (mmHg)87.12 ± 21.1989.92 ± 22.5286.33 ± 20790.224
       DBP (mmHg)56.49 ± 13.2358.09 ± 14.1056.04 ± 12.970.267
       Heart rate (bpm)109.7 ± 23.65109.9 ± 22.06109.6 ± 24.120.936
       Body temperature (°C)37.58 ± 1.4237.95 ± 1.4237.48 ± 1.400.017
      Change of mental status (%)54 (17.9)9 (13.6)45 (19.1)0.309
      Laboratory data
       WBC (x103/μL)10.90 ± 9.089.57 ± 8.3711.28 ± 9.26 ±0.178
       Hemoglobin (g/dL)10.51 ± 2.3510.26 ± 2.2510.58 ± 2.380.317
       Platelet (x103/μL)158.1 ± 109.8165.9 ± 106.4155.9 ± 110.80.513
       PT (INR)1.52 ± 0.801.36 ± 0.421.56 ± 0.870.010
       Albumin (g/dL)2.54 ± 0.592.60 ± 5.112.52 ± 0.610.291
       Creatinine (mg/dL)1.98 ± 1.701.83 ± 1.742.02 ± 1.680.438
       CRP (mg/dL)15.60 ± 10.7016.10 ± 10.8615.46 ± 10.670.668
       Procalcitonin (ng/dL)27.23 ± 43.2331.07 ± 45.9826.17 ± 42.490.426
       Lactate (mmol/L)4.09 ± 3.113.34 ± 2.764.31 ± 3.180.025
      30-day mortality (%)84 (27.8)9 (13.6)75 (31.8)0.004
      Values are expressed as the mean ± standard deviation, the median [interquartile range], or number (%).
      SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, white blood cells; PT, prothrombin time; INR, international normalized ratio; CRP, c-reactive protein.

      Seasonal variation in vitamin D levels

      The variation in the prevalence of vitamin D deficiency and mean 25(OH)D level according to months is shown in Fig. 1. The prevalence of vitamin D deficiency was the lowest (71.7%) in autumn, whereas the prevalence of vitamin D deficiency was above 80.0% in spring, summer, and winter. However, there was no significant difference between the seasons (P = 0.209).
      Fig 1
      Fig. 1Seasonal variation of the prevalence of vitamin D deficiency and mean 25(OH) D values.
      The prevalence of vitamin D deficiency was the lowest (71.7%) in the autumn of September, October, and November, whereas the prevalence of vitamin D deficiency was above 80.0% in other spring, summer, and winter. However, there were no significant seasonal differences (P = 0.209).

      Risk factors for 30-day mortality in patients with septic shock

      The results of univariate and multivariate logistic regression analyses to explore and identify the risk factors for 30-day mortality in patients with septic shock are presented in Table 3. Variables with P < 0.10 in univariate analysis, such as malignancy, body temperature, hemoglobin levels, platelet counts, creatinine levels, albumin levels, hyperlactatemia, mental changes, SOFA scores, and vitamin D deficiency were considered as candidate variables in multivariable analyses. Variables that overlap in the representation of the same organ function, or have less clinical importance were excluded, malignancy, hemoglobin levels, albumin levels, hyperlactatemia, SOFA score, and vitamin D deficiency were analyzed as adjusted variables in multivariate analyses finally.
      Table 3Univariate and multivariate logistic regression analysis for the association of mortality in septic shock.
      UnivariateMultivariate
      OR (95% CI)P valueOR (95% CI)P value
      Vitamin D deficiency2.950 (1.387–6.274)0.0052.434 (1.032–5.739)0.042
      Malignancy2.145 (1.201–3.828)0.0101.847 (0.888–3.840)0.101
      Hemoglobin0.855 (0.763–0.958)0.0070.980 (0.836–1.150)0.806
      Albumin0.270 (0.162–0.450)<0.0010.387 (0.206–0.728)0.003
      Lactate ≧ 4mmol/L5.267 (3.062–9.059)<0.0013.648 (1.950–6.826)<0.001
      SOFA score1.337 (1.219–1.468)<0.0011.218 (1.093–1.358)<0.001
      OR, odds ratio; CI, confidence interval; SOFA, sequential organ failure assessment.
      Hosmer and Lemeshow Goodness of Fit test: χ2 = 2.637, df = 8, p-value 0.955.
      In multivariate analysis, the following factors were independently associated with 30-day mortality: vitamin D deficiency (OR, 2.43; 95% confidence interval [CI], 1.03–5.74, P = 0.042), albumin levels (OR, 0.39; 95% CI, 0.21–0.73, P = 0.003), hyperlactatemia (OR, 3.65; 95% CI, 1.95–6.83, P < 0.001), and SOFA scores (OR, 1.22; 95% CI, 1.09–1.36, P < 0.001).

      Discussion

      This study found that vitamin D deficiency was prevalent (78.1%) in patients with septic shock who were treated with protocol-driven resuscitation bundle therapy in the ED and that the prevalence of vitamin D deficiency was higher in non-survivors than in survivors (89.3% vs. 73.9%, P = 0.004). After adjusting for significant variables such as malignancy, hemoglobin levels, albumin levels, hyperlactatemia, and SOFA scores, vitamin D deficiency was found to be an independent predictor of 30-day mortality (OR, 2.43; 95% CI, 1.03–5.74).
      Vitamin D deficiency is common in critically ill patients and is associated with mortality.
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      The prevalence of vitamin D deficiency (78.1%) in our study was higher than that reported in other studies. The higher prevalence might be due to the application of different definitions. Septic shock defined according to the sepsis-3 definition may enroll more severe patients than that defined according to the sepsis-2 definition. The prevalence of vitamin D deficiency in patients with septic shock defined according to the sepsis-3 definition has been reported for the first time in our study. The sepsis-3 definition was used to make the study population more homogenous in terms of severity and disease entity because sepsis is a heterogenous clinical syndrome
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      The mean age was significantly lower (65.31 vs. 70.77 years, P = 0.001) in the vitamin D-deficient group than the vitamin D non-deficient group in this study.
      In addition, most studies showed notable associations of all severity scoring criteria,
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      Therefore, as predicted, higher severity scores and a higher number of comorbidities were associated with vitamin D deficiency. This is supported by our results that higher serum lactate levels and a higher prevalence of active cancer were found in vitamin D-deficient patients than in vitamin D non-deficient patients.
      We found that mortality was higher in vitamin D-deficient patients (31.8%) than in non-deficient patients (13.6%). Additionally, vitamin D deficiency was independently associated with increased 30-day mortality. In line with our study, previous studies have reported that vitamin D deficiency was correlated with mortality in patients with sepsis. Amrein et al.
      • Amrein K
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      reported that vitamin D deficiency was associated with in-hospital mortality of patients with sepsis and a hazard ratio of 2.05. Another study including 135 patients admitted to the ICU
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      • et al.
      Vitamin D deficiency is independently associated with mortality among critically ill patients.
      reported that the mortality rates were higher among patients with vitamin D deficiency than in those without vitamin D deficiency, with an adjusted relative risk of 2.2. Although there are inconsistencies in the conclusions on the association between vitamin D deficiency and mortality, the hypothesis that they are associated is gaining more strength.
      However, there are limited data and inconsistent results regarding vitamin D deficiency in patients with septic shock presenting to the ED. Ginde et al.
      • Ginde AA
      • Camargo Jr CA
      • Shapiro NI
      Vitamin D insufficiency and sepsis severity in emergency department patients with suspected infection.
      established that vitamin D deficiency was not associated with mortality in patients with severe sepsis; however, Shojaei, et al.
      • Shojaei M
      • Sabzeghabaei A
      • Barhagh HV
      • Soltani S.
      The Correlation between serum level of Vitamin D and outcome of sepsis patients; a cross-sectional study.
      showed that vitamin D levels can predict 30-day mortality with an area under a receiver operating characteristic curve of 0.701. The present study adds to the current understanding regarding the association between vitamin D deficiency and mortality in patients with septic shock and can be a starting point for more extensive research based on the ED. Moreover, it can provide a basis for early treatment for patients with septic shock who need prompt intervention.
      The incidence of sepsis and serum vitamin D levels decrease in the winter season
      • Amrein K
      • Zajic P
      • Schnedl C
      • et al.
      Vitamin D status and its association with season, hospital and sepsis mortality in critical illness.
      ,
      • Danai PA
      • Sinha S
      • Moss M
      • et al.
      Seasonal variation in the epidemiology of sepsis.
      because both outdoor activities and exposure to ultraviolet B rays needed to synthesize vitamin D are lower in winter. Therefore, the prevalence of vitamin D deficiency was generally higher in winter and lower in summer, similar to the results of this study; however, our study did not show the general distribution and any significant difference between seasons. Marked decreases in outdoor activities due to the COVID-19 pandemic during the study period could have resulted in increased vitamin D deficiencies. Especially, the number of COVID-19 confirmed cases increased dramatically last autumn in Korea, so restrictions on social and outdoor activities had been stronger. This could have contributed to the study results.
      With consistent findings on the prevalence of vitamin D deficiency in patients with sepsis or septic shock, many previous reports, along with our study, have provided answers to the question of whether vitamin D deficiency is correlated with mortality. Therefore, our findings need to be applied to providing metabolic resuscitation in patients with septic shock. Several studies have reported that vitamin D supplementation lowered the severity of organ dysfunction
      • Alves FS
      • Freitas FGR
      • Bafi AT
      • et al.
      Serum concentrations of vitamin D and organ dysfunction in patients with severe sepsis and septic shock.
      and raised the serum vitamin D levels; however, it failed to decrease the mortality rate in patients admitted to the ICU.
      • Amrein K
      • Schnedl C
      • Holl A
      • et al.
      Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial.
      ,
      • Ding F
      • Zang B
      • Fu J
      • Ji K
      Effect of vitamin D3 on the severity and prognosis of patients with sepsis: a prospective randomized double-blind placebo study.
      To date, there have been no randomized controlled trials involving patients in the ED. Early recognition and intervention are being increasingly emphasized for septic shock; moreover, the time lost up to intervention after hospitalization may hamper improving outcomes. Therefore, randomized controlled trials of routine large-dose loading of vitamin D supplementation in the ED can be proposed to improve mortality rates in patients with septic shock as a novel metabolic resuscitation concept.
      The limitation of this study was that it was a single-center study that included many patients with local patterns of illness. Moreover, geopolitical and racial differences should also be considered. Furthermore, patients with chronic renal failure, chronic liver disease, and malignancy were included. These comorbidities can affect vitamin D metabolism and serum vitamin D levels and add to the heterogeneity of the study population; hence the possibility of their confounding effect cannot be ruled out. Also, there would be the possibility of selection bias from the time scale (middle of the year) because of the effect of vitamin D levels which has seasonal variation.

      Conclusions

      The prevalence of vitamin D deficiency was high in patients with septic shock visiting the ED, and vitamin D deficiency was associated with 30-day mortality. Further studies are needed to determine whether a routine supplement of vitamin D in case of septic shock is warranted.

      Authors Contributions

      Y.W.K. and Y-J.K. conceived and designed the analysis; Y.S.S., S.M.K., and S-I.H. collected the data; J-S.K. and S.M.R contributed data or analysis tools; B.C. performed the analysis; B.C. and W.Y.K. wrote and edited the paper.

      Source of Funding

      None declared.

      Declaration of Competing Interest

      None declared.

      Appendix. SUPPLEMENTARY MATERIALS

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