Kenneth B. Christopher

Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill

Objective:We hypothesized that deficiency in 25-hydroxyvitamin D before hospital admission would be associated with all-cause mortality in the critically ill. Design:Multicenter observational study of patients treated in medical and surgical intensive care units. Setting:A total of 209 medical and surgical intensive care beds in two teaching hospitals in Boston, MA. Patients:A total of 2399 patients, age ≥18 yrs, in whom 25-hydroxyvitamin D was measured before hospitalization between 1998 and 2009. Interventions:None. Measurements and Main Results:Preadmission 25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (≤15 ng/mL), insufficiency (16–29 ng/mL), and sufficiency (≥30 ng/mL). Logistic regression examined death by days 30, 90, and 365 post-intensive care unit admission, in-hospital mortality, and blood culture positivity. Adjusted odds ratios were estimated by multivariable logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive for short-term and long-term mortality. At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D deficiency have an odds ratio for mortality of 1.69 (95% confidence interval of 1.28–2.23, p < .0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of mortality at 30 days following intensive care unit admission following multivariable adjustment (adjusted odds ratio of 1.69, 95% confidence interval of 1.26–2.26, p < .0001). At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D insufficiency have an odds ratio of 1.32 (95% confidence interval of 1.02–1.72, p = .036) and an adjusted odds ratio of 1.36 (95% confidence interval of 1.03–1.79, p = .029) relative to patients with 25-hydroxyvitamin D sufficiency. Results were similar at 90 and 365 days following intensive care unit admission and for in-hospital mortality. In a subgroup analysis of patients who had blood cultures drawn (n = 1160), 25-hydroxyvitamin D deficiency was associated with increased risk of blood culture positivity. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for blood culture positivity of 1.64 (95% confidence interval of 1.05–2.55, p = .03) relative to patients with 25-hydroxyvitamin D sufficiency, which remains significant following multivariable adjustment (odds ratio of 1.58, 95% confidence interval of 1.01–2.49, p = .048). Conclusion:Deficiency of 25-hydroxyvitamin D before hospital admission is a significant predictor of short- and long-term all-cause patient mortality and blood culture positivity in a critically ill patient population.

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.

IMPORTANCE Low vitamin D status is linked to increased mortality and morbidity in patients who are critically ill. It is unknown if this association is causal. OBJECTIVE To investigate whether a vitamin D3 treatment regimen intended to restore and maintain normal vitamin D status over 6 months is of health benefit for patients in ICUs. DESIGN, SETTING, AND PARTICIPANTS A randomized double-blind, placebo-controlled, single-center trial, conducted from May 2010 through September 2012 at 5 ICUs that included a medical and surgical population of 492 critically ill adult white patients with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 (n = 249) or a placebo (n = 243). INTERVENTIONS Vitamin D3 or placebo was given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months. MAIN OUTCOMES AND MEASURES The primary outcome was hospital length of stay. Secondary outcomes included, among others, length of ICU stay, the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day 7, hospital mortality, and 6-month mortality. A predefined severe vitamin D deficiency (≤12 ng/mL) subgroup analysis was specified before data unblinding and analysis. RESULTS A total of 475 patients were included in the final analysis (237 in the vitamin D3 group and 238 in the placebo group). The median (IQR) length of hospital stay was not significantly different between groups (20.1 days [IQR, 11.1-33.3] for vitamin D3 vs 19.3 days [IQR, 11.1-34.9] for placebo; P = .98). Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28.3% [95% CI, 22.6%-34.5%] for vitamin D3 vs 35.3% [95% CI, 29.2%-41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58-1.11]; P = .18; 6-month mortality: 35.0% [95% CI, 29.0%-41.5%] for vitamin D3 vs 42.9% [95% CI, 36.5%-49.4%] for placebo; HR, 0.78 [95% CI, 0.58-1.04]; P = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 20.1 days (IQR, 12.9-39.1) for vitamin D3 vs 19.0 days (IQR, 11.6-33.8) for placebo. Hospital mortality was significantly lower with 28 deaths among 98 patients (28.6% [95% CI, 19.9%-38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%-56.2%]) for placebo (HR, 0.56 [95% CI, 0.35-0.90], P for interaction = .04), but not 6-month mortality (34.7% [95% CI, 25.4%-45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%-60.1%] for placebo; HR, 0.60 [95% CI, 0.39-0.93], P for interaction = .12). CONCLUSIONS AND RELEVANCE Among critically ill patients with vitamin D deficiency, administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130181.

Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality

Objective:We hypothesized that deficiency in 25-hydroxyvitamin D at critical care initiation would be associated with all-cause mortalities. Design:Two-center observational study. Setting:Two teaching hospitals in Boston, MA. Patients:The study included 1,325 patients, age ≥18 yrs, in whom 25-hydroxyvitamin D was measured 7 days before or after critical care initiation between 1998 and 2009. Measurements:25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (⩽15 ng/mL), insufficiency (16–29 ng/mL), and sufficiency (≥30 ng/mL). Logistic regression examined death by days 30, 90, and 365 postcritical care initiation and in-hospital mortality. Adjusted odds ratios were estimated by multivariable logistic regression models. Interventions:None. Key Results:25-hydroxyvitamin D deficiency is predictive for short-term and long-term mortality. Thirty days following critical care initiation, patients with 25-hydroxyvitamin D deficiency have an odds ratio for mortality of 1.85 (95% confidence interval 1.15–2.98; p = .01) relative to patients with 25-hydroxyvitamin D sufficiency. 25-hydroxyvitamin D deficiency remains a significant predictor of mortality at 30 days following critical care initiation following multivariable adjustment for age, gender, race, Deyo-Charlson index, sepsis, season, and surgical vs. medical patient type (adjusted odds ratio 1.94; 95% confidence interval 1.18–3.20; p = .01). Results were similarly significant at 90 and 365 days following critical care initiation and for in-hospital mortality. The association between vitamin D and mortality was not modified by sepsis, race, or neighborhood poverty rate, a proxy for socioeconomic status. Conclusion:Deficiency of 25-hydroxyvitamin D at the time of critical care initiation is a significant predictor of all-cause patient mortality in a critically ill patient population.

Red Cell Distribution Width and all cause mortality in critically ill patients

Objective:Red cell distribution width is a predictor of mortality in the general population. The prevalence of increased red cell distribution width and its significance in the intensive care unit are unknown. The objective of this study was to investigate the association between red cell distribution width at the initiation of critical care and all cause mortality. Design:Multicenter observational study. Setting:Two tertiary academic hospitals in Boston, MA. Patients:A total of 51,413 patients, aged ≥18 yrs, who received critical care between 1997 and 2007. Interventions:None. Measurements and Main Results:The exposure of interest was red cell distribution width as a predictor of mortality in the general population. The prevalence of increased red cell distribution width and its significance in the intensive care unit are unknown and categorized a priori in quintiles as ≤13.3%, 13.3% to 14.0%, 14.0% to 14.7%, 14.7% to 15.8%, and >15.8%. Logistic regression examined death by days 30, 90, and 365 postcritical care initiation, inhospital mortality, and bloodstream infection. Adjusted odds ratios were estimated by multivariable logistic regression models. Adjustment included age, sex, race, Deyo–Charlson index, coronary artery bypass grafting, myocardial infarction, congestive heart failure, hematocrit, white blood cell count, mean corpuscular volume, blood urea nitrogen, red blood cell transfusion, sepsis, and creatinine. Red cell distribution width was a particularly strong predictor of all-cause mortality 30 days after critical care initiation with a significant risk gradient across red cell distribution width quintiles after multivariable adjustment: red cell distribution width 13.3% to 14.0% (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.08–1.30; p <.001); red cell distribution width 14.0% to 14.7% (OR, 1.28; 95% CI, 1.16–1.42; p <.001); red cell distribution width 14.7% to 15.8% (OR, 1.69; 95% CI, 1.52–1.86; p <.001); red cell distribution width >15.8% (OR, 2.61; 95% CI, 2.37–2.86; p <.001), all relative to patients with red cell distribution width ≤13.3%. Similar significant robust associations postmultivariable adjustments are seen with death by days 90 and 365 postcritical care initiation as well as inhospital mortality. In a subanalysis of patients with blood cultures drawn (n = 18,525), red cell distribution width at critical care initiation was associated with the risk of bloodstream infection and remained significant after multivariable adjustment. The adjusted risk of bloodstream infection was 1.40- and 1.44-fold higher in patients with red cell distribution width values in the 14.7% to 15.8% and >15.8% quintiles, respectively, compared with those with red cell distribution width ≤13.3%. Estimating the receiver operating characteristic area under the curve shows that red cell distribution width has moderate discriminative power for 30-day mortality (area under the curve = 0.67). Conclusion:Red cell distribution width is a robust predictor of the risk of all-cause patient mortality and bloodstream infection in the critically ill. Red cell distribution width is commonly measured, inexpensive, and widely available and may reflect overall inflammation, oxidative stress, or arterial underfilling in the critically ill.

The relationship among obesity, nutritional status, and mortality in the critically ill.

Introduction:The association between obesity and mortality in critically ill patients is unclear based on the current literature. To clarify this relationship, we analyzed the association between obesity and mortality in a large population of critically ill patients and hypothesized that mortality would be impacted by nutritional status. Methods:We performed a single-center observational study of 6,518 adult patients treated in medical and surgical ICUs between 2004 and 2011. All patients received a formal, in-person, and standardized evaluation by a registered dietitian. Body mass index was determined at the time of dietitian consultation from the estimated dry weight or hospital admission weight and categorized a priori as less than 18.5 kg/m2 (underweight), 18.5–24.9 kg/m2 (normal/referent), 25–29.9 kg/m2 (overweight), 30–39.9 kg/m2 (obesity class I and II), and more than or equal to 40.0 kg/m2 (obesity class III). Malnutrition diagnoses were categorized as nonspecific malnutrition, protein-energy malnutrition, or well nourished. The primary outcome was all-cause 30-day mortality determined by the Social Security Death Master File. Associations between body mass index groups and mortality were estimated by bivariable and multivariable logistic regression models. Adjusted odds ratios were estimated with inclusion of covariate terms thought to plausibly interact with both body mass index and mortality. We utilized propensity score matching on baseline characteristics and nutrition status to reduce residual confounding of the body mass index category assignment. Results:In the cohort, 5% were underweight, 36% were normal weight, 31% were overweight, 23% had class I/II obesity, and 5% had class III obesity. Nonspecific malnutrition was present in 56%, protein-energy malnutrition was present in 12%, and 32% were well nourished. The 30-day and 90-day mortality rate for the cohort was 19.1 and 26.6%, respectively. Obesity is a significant predictor of improved 30-day mortality following adjustment for age, gender, race, medical versus surgical patient type, Deyo-Charlson index, acute organ failure, vasopressor use, and sepsis: underweight odds ratio 30-day mortality is 1.09 (95% CI, 0.80–1.48), overweight 30-day mortality odds ratio is 0.93 (95% CI, 0.80–1.09), class I/II obesity 30-day mortality odds ratio is 0.80 (95% CI, 0.67–0.96), and class III obesity 30-day mortality odds ratio is 0.69 (95% CI, 0.49–0.97), all relative to patients with body mass index 18.5–24.9 kg/m2. Importantly, there is confounding of the obesity-mortality association on the basis of malnutrition. Adjustment for only nutrition status attenuates the obesity–30-day mortality association: underweight odds ratio is 0.74 (95% CI, 0.54–1.00), overweight odds ratio is 1.05 (95% CI, 0.90–1.23), class I/II obesity odds ratio is 0.96 (95% CI, 0.81–1.15), and class III obesity odds ratio is 0.81 (95% CI, 0.59–1.12), all relative to patients with body mass index 18.5–24.9 kg/m2. In a subset of patients with body mass index more than or equal to 30.0 kg/m2 (n = 1,799), those with either nonspecific or protein-energy malnutrition have increased mortality relative to well-nourished patients with body mass index more than or equal to 30.0 kg/m2: odds ratio of 90-day mortality is 1.67 (95% CI, 1.29–2.15; p < 0.0001), fully adjusted. In a cohort of propensity score matched patients (n = 3,554), the body mass index–mortality association was not statistically significant, likely from matching on nutrition status. Conclusions:In a large population of critically ill adults, the association between improved mortality and obesity is confounded by malnutrition status. Critically ill obese patients with malnutrition have worse outcomes than obese patients without malnutrition.

Elevation of blood urea nitrogen is predictive of long-term mortality in critically ill patients independent of normal creatinine

Objective:We hypothesized that elevated blood urea nitrogen can be associated with all-cause mortality independent of creatinine in a heterogeneous critically ill population. Design:Multicenter observational study of patients treated in medical and surgical intensive care units. Setting:Twenty intensive care units in two teaching hospitals in Boston, MA. Patients:A total of 26,288 patients, age ≥18 yrs, hospitalized between 1997 and 2007 with creatinine of 0.80–1.30 mg/dL. Interventions:None. Measurements:Blood urea nitrogen at intensive care unit admission was categorized as 10–20, 20–40, and >40 mg/dL. Logistic regression examined death at days 30, 90, and 365 after intensive care unit admission as well as in-hospital mortality. Adjusted odds ratios were estimated by multivariable logistic regression models. Main Results:Blood urea nitrogen at intensive care unit admission was predictive for short- and long-term mortality independent of creatinine. Thirty days following intensive care unit admission, patients with blood urea nitrogen of >40 mg/dL had an odds ratio for mortality of 5.12 (95% confidence interval, 4.30–6.09; p < .0001) relative to patients with blood urea nitrogen of 10–20 mg/dL. Blood urea nitrogen remained a significant predictor of mortality at 30 days after intensive care unit admission following multivariable adjustment for confounders; patients with blood urea nitrogen of >40 mg/dL had an odds ratio for mortality of 2.78 (95% confidence interval, 2.27–3.39; p < .0001) relative to patients with blood urea nitrogen of 10–20 mg/dL. Thirty days following intensive care unit admission, patients with blood urea nitrogen of 20–40 mg/dL had an odds ratio of 2.15 (95% confidence interval, 1.98–2.33; <.0001) and a multivariable odds ratio of 1.53 (95% confidence interval, 1.40–1.68; p < .0001) relative to patients with blood urea nitrogen of 10–20 mg/dL. Results were similar at 90 and 365 days following intensive care unit admission as well as for in-hospital mortality. A subanalysis of patients with blood cultures (n = 7,482) demonstrated that blood urea nitrogen at intensive care unit admission was associated with the risk of blood culture positivity. Conclusion:Among critically ill patients with creatinine of 0.8–1.3 mg/dL, an elevated blood urea nitrogen was associated with increased mortality, independent of serum creatinine.

Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill*

Objective:Given the importance of inflammation in acute kidney injury and the relationship between vitamin D and inflammation, we sought to elucidate the effect of vitamin D on acute kidney injury. We hypothesized that deficiency in 25-hydroxyvitamin D prior to hospital admission would be associated with acute kidney injury in the critically ill. Design:Two-center observational study of patients treated in medical and surgical intensive care units. Setting:Two hundred nine medical and surgical intensive care beds in two teaching hospitals in Boston, Massachusetts. Patients:Two thousand seventy-five patients, aged ≥18 yrs, in whom serum 25-hydroxyvitamin D was measured prior to hospitalization between 1998 and 2009. Interventions:None. Measurements and Main Results:The exposure of interest was preadmission serum 25-hydroxyvitamin D and categorized a priori as deficiency (25-hydroxyvitamin D <15 ng/mL), insufficiency (25-hydroxyvitamin D 15–30 ng/mL), or sufficiency (25-hydroxyvitamin D ≥30 ng/mL). The primary outcome was acute kidney injury defined as meeting Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) Injury or Failure criteria. Logistic regression examined the RIFLE criteria outcome. Adjusted odds ratios were estimated by multivariate logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive of acute kidney injury. Patients with 25-hydroxyvitamin D deficiency have an odds ratio for acute kidney injury of 1.73 (95% confidence interval 1.30–2.30; p < .0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of acute kidney injury following multivariable adjustment (adjusted odds ratio 1.50; 95% confidence interval 1.42–2.24; p < .0001). Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for acute kidney injury of 1.49 (95% confidence interval 1.15–1.94; p = .003) and an adjusted odds ratio of 1.23 (95% confidence interval 1.12–1.72; p = .003) relative to patients with 25-hydroxyvitamin D sufficiency. In addition, preadmission 25-hydroxyvitamin D deficiency is predictive of mortality. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for 30-day mortality of 1.60 (95% confidence interval 1.18–2.17; p = .003) and an adjusted odds ratio of 1.61 (95% confidence interval 1.06–1.57; p = .004) relative to patients with 25-hydroxyvitamin D sufficiency. Conclusion:Deficiency of 25-hydroxyvitamin D prior to hospital admission is a significant predictor of acute kidney injury and mortality in a critically ill patient population.

Evidence for a U-shaped relationship between prehospital vitamin D status and mortality: a cohort study.

OBJECTIVE The objective of the study was to examine the association between prehospital serum 25-hydroxyvitamin D [25(OH)D]and the risk of mortality after hospital admission. DESIGN We performed a retrospective cohort study of adults hospitalized for acute care between 1993 and 2011. SETTING The study was conducted at two Boston teaching hospitals. PATIENTS A total of 24,094 adult inpatients participated in the study. INTERVENTION There was no intervention. MEASUREMENTS All patients had serum 25(OH)D measured before hospitalization. The exposure of interest was 25(OH)D categorized as less than 10 ng/mL, 10-19.9 ng/mL, 20-29.9 ng/mL, 30-49.9 ng/mL, 50-59.9 ng/mL, 60-69.9 ng/mL, and 70 ng/mL or greater. The main outcome measure was 90-day mortality. Adjusted odds ratios (ORs) were estimated by multivariable logistic regression with inclusion of potential confounders. RESULTS After adjustment for age, gender, race (white vs nonwhite), patient type (surgical vs medical), season of 25(OH)D draw, and the Deyo-Charlson index, patients with 25(OH)D levels less than 30 ng/mL or 60 ng/mL or greater had higher odds of 90-day mortality compared with patients with levels of 30-49.9 ng/mL [adjusted OR (95% confidence interval) for 25(OH)D <10 ng/mL, 10-19.9 ng/mL, 20-29.9 ng/mL, 50-59.9 ng/mL, 60-69.9 ng/mL, and ≥70 ng/mL was 2.01 (1.68-2.40), 1.89 (1.64-2.18), 1.34 (1.16-1.56), 0.94 (0.69-1.26), 1.52 (1.03-2.25), and 1.69 (1.09-2.61), respectively, compared with patients with 25(OH)D levels 30-49.9 ng/mL]. LIMITATIONS A causal relationship between either low or high 25(OH)D levels and increased mortality can not necessarily be inferred from this observational study. CONCLUSIONS Analysis of 24 094 adult patients showed that 25(OH)D levels less than 20 ng/mL and 60 ng/mL or greater before hospitalization were associated with an increased odds of 90-day mortality. Although previous reports have suggested an association between low vitamin D status and mortality, these data raise the issue of potential harm from high serum 25(OH)D levels, provide a rationale for an upper limit to supplementation, and emphasize the need for caution in the use of extremely high doses of vitamin D among patients.

Analysis of the Innate and Adaptive Phases of Allograft Rejection by Cluster Analysis of Transcriptional Profiles

Both clinical and experimental observations suggest that allograft rejection is a complex process with multiple components that are, at least partially, functionally redundant. Studies using graft recipients deficient in various genes including chemokines, cytokines, and other immune-associated genes frequently produce a phenotype of delayed, but not indefinitely prevented, rejection. Only a small subset of genetic deletions (for example, TCRα or β, MHC I and II, B7-1 and B7-2, and recombinase-activating gene) permit permanent graft acceptance suggesting that rejection is orchestrated by a complex network of interrelated inflammatory and immune responses. To investigate this complex process, we have used oligonucleotide microarrays to generate quantitative mRNA expression profiles following transplantation. Patterns of gene expression were confirmed with real-time PCR data. Hierarchical clustering algorithms clearly differentiated the early and late phases of rejection. Self-organizing maps identified clusters of coordinately regulated genes. Genes up-regulated during the early phase included genes with prior biological functions associated with ischemia, injury, and Ag-independent innate immunity, whereas genes up-regulated in the late phase were enriched for genes associated with adaptive immunity.

Graft produced interleukin-6 functions as a danger signal and promotes rejection after transplantation

Background. Interleukin (IL)-6 is a pleiotropic cytokine that functions in both the innate and adaptive immune responses. However, the role of IL-6 in allograft rejection remains poorly understood. Methods. In this study, we demonstrate a critical role for graft-produced IL-6 in allograft rejection in a murine model of cardiac allograft transplantation. Results. The results show that IL-6-deficient grafts transplanted into allogeneic wild-type recipients have significantly prolonged survival, approximately three times the survival time of wild-type controls. In contrast, allogeneic cardiac transplants into IL-6-deficient recipients do not have prolonged graft survival, indicating that donor graft cells are the relevant source of IL-6. Our investigation of potential mechanisms shows that graft-produced IL-6 promotes the activation of peripheral CD4 and CD8 T cells. Furthermore, we show that IL-6 deficiency prolongs graft survival only in the presence of CD25+ T cells that have a phenotype consistent with regulatory T cells. Interestingly, IL-6 production by the graft is triggered by antigen-independent innate immune mechanisms. Conclusions. Thus, our results suggest the paradigm that graft rejection versus tolerance is determined by a balance between the activation of effector T cells versus immune suppression by regulatory T cells, and that after transplantation, IL-6 functions as a systemic danger signal that overcomes constitutive immune suppression mediated by regulatory T cells and promotes the activation of effector T cells.