The present study aimed to determine whether pre-admission 25(OH)D was associated with all cause mortality following ICU admission. This large 11-year multicenter observational study illustrates the all cause mortality risk of pre-admission 25(OH)D deficiency. Pre-admission 25(OH)D deficiency was a significant predictor of 30, 90, 365 post ICU day mortality as well as in-hospital mortality and remained a significant predictor of survival following multivariable adjustments for relevant comorbidities. In addition, our subset analysis suggests an increased susceptibility to blood culture positivity in patients with vitamin D deficiency.
The mechanism for increased mortality following ICU admission in patients with hypovitaminosis D may be related to the pleiotropic functions of vitamin D. Vitamin D inhibits vascular smooth-muscle cell proliferation,(24
) protects normal endotheilial function,(25
) and modulates inflammatory processes.(26
D primarily has inhibitory effects on the adaptive immune response, some of its effects on innate immune cells are stimulatory. Studies provide evidence for defects in macrophage functions, such as chemotaxis, phagocytosis and the production of proinflammatory cytokines, in vitamin D deficient conditions.(28
) Vitamin D is a key link between Toll Like Receptor (TLR) activation and antibacterial responses in innate immunity.(29
) TLR stimulation of human macrophages induces conversion of 25(OH)D to active 1,25(OH)2D; expression of the vitamin D receptor; and, production of cathelicidin a downstream target of the vitamin D receptor capable of promoting innate immunity.(30
Our data is consistent with an analysis of the NHANES (National Health and Nutrition Examination Survey) data in which low vitamin D levels were associated with an increased incidence of upper respiratory tract infections.(33
) In another study, patients with severe vitamin D deficiency were abnormally susceptible to infections such as tuberculosis(34
) and infection in general.(35
) Similarly, in a Meta-analysis of 18 trials involving 57,311 randomly assigned subjects, Autier found that vitamin D supplementation reduced all-cause mortality by 7% (CI, 1% to 13%).(5
) These observations and others suggest that hypovitaminosis D is likely to play a key role in infection, and cardiac and metabolic dysfunctions in critically ill patients.
The present study has limitations. Selection bias may exist as the patient cohort under study had their vitamin D status investigated for a particular reason that may be absent in other patients treated with critical care. This is demonstrated by the significant differences in the total ICU population and the 25(OH)D cohort (). These noted differences may decrease the generalizability of our results to all critically ill patients. We cannot exclude the possibility that other unmeasured variables influence mortality independently of vitamin D, which may have biased estimates. Despite adjustment for multiple potential confounders, there may be residual confounding variables leading to observed differences in outcomes.
In a prior study of an outpatient population, the intra-person Pearson correlation coefficient for 25(OH)D is demonstrated to be 0.70 at three years between blood draws following adjustments for age, race, and season.(37
) The majority of our cohort had 25(OH)D levels drawn 3 months prior to ICU admission. Our sensitivity analysis demonstrates preservation of the observed vitamin D-mortality association with less than 90 days between 25(OH)D level and ICU admission. Despite this observation, vitamin D levels at the time of critical care initiation are not available in this cohort and may have changed since pre-admission values were determined. We do not have data available on over the counter supplementation or vitamin D prescribed by providers outside of clinics related to the hospitals under study. Such supplementation may have altered the true 25(OH)D-mortality association.
We define sepsis and comorbidity based on administrative ICD-9-CM coding. Administrative coding has been evaluated for particular disease states(38
) and comorbidity profiles.(43
) The accuracy of ICD-9-CM coding for the identification of medical conditions remains controversial.(19
) The several steps and participants required to assign ICD-9-CM codes introduce potential for error.(45
) Despite these shortcomings, the ICD-9-CM code 038.x is reported to have a high positive predictive value for the identification of true cases of sepsis(46
), and a high sensitivity(47
) and negative predictive value.(19
) Algorithms developed to recode ICD-9-CM coded data into a Deyo-Charlson index are well studied, validated and well suited for use in administrative datasets.(48
Our finding that pre-admission 25(OH)D is a significant predictor of mortality does not include physiologic data. In the administrative database used in this study, temperature, blood pressure, heart rate, respiratory rate and Glasgow Coma scale data is not available and thus APACHE scores are absent. Scoring systems inclusive of physiological data including APACHE are strong predictors of mortality in ICU patients.(50
) Further, it is not known if illness severity influences vitamin D levels at time of ICU admission. It is possible that inclusion of a physiologic score in the analysis may materially alter the 25(OH)D-mortality association. With the addition of age and gender data, the Deyo-Charlson comorbidity index can be considered an alternative method of risk adjustment in the absence of physiologic data.(51
) However, despite multivariable adjustment the absence of physiologic data remains a limitation of our study. Finally, we are also unable to adjust for body mass index, immobilization, lack of sun exposure and smoking status, factors that can alter 25(OH)D.
The present study has several strengths. As other chronic medical conditions may affect the attributed cause of death, all-cause mortality is considered an unbiased and clinically relevant outcome in long-term observational studies.(52
) Utilization of the Social Security Death Index allows for long term follow up of the cohort following hospital discharge. Our study is a relatively large regional multicenter study with sufficient numbers of patients to ensure the adequate reliability of our mortality estimates (N=2,399, hospital mortality rate =15.6%). We employed previous records to define comorbidities which increase prevalence of these conditions, resulting in a better risk adjustment.(40
) Measurements of 25(OH)D prior to ICU admission allow for the inference of the potential importance of vitamin D sufficiency prior to the onset of critical illness.
In aggregate, these data demonstrate that pre-admission 25(OH)D deficiency is strongly associated with the risk of death in critical illness and that this risk is independent of other risk factors. In addition, in patients with blood cultures drawn, 25(OH)D deficiency is strongly associated with the risk of blood culture positivity. In concert with the basic science evidence, we believe that these results provide clinical evidence of a potential link between vitamin D and outcomes of critical illness. However, studies of this relationship in a cohort with uniform methods for the measurement of vitamin D and a uniform timing of measurement relative to the onset of critical illness are clearly warranted to further elucidate the role of vitamin D in critical illness. Positive findings in prospective studies may establish 25(OH)D as an important and modifiable risk factor for ICU mortality. Given the safety profile of vitamin D, positive results would provide strong motivation for examining the utility of activated vitamin D as a novel therapeutic agent designed to improve survival in critical illness.