Publications

2019
Peter JM Weijs, Kris M Mogensen, James D Rawn, and Kenneth B Christopher. 2019. “Protein Intake, Nutritional Status and Outcomes in ICU Survivors: A Single Center Cohort Study.” J Clin Med, 8, 1.Abstract
BACKGROUND: We hypothesized that protein delivery during hospitalization in patients who survived critical care would be associated with outcomes following hospital discharge. METHODS: We studied 801 patients, age ≥ 18 years, who received critical care between 2004 and 2012 and survived hospitalization. All patients underwent a registered dietitian formal assessment within 48 h of ICU admission. The exposure of interest, grams of protein per kilogram body weight delivered per day, was determined from all oral, enteral and parenteral sources for up to 28 days. Adjusted odds ratios for all cause 90-day post-discharge mortality were estimated by mixed- effects logistic regression models. RESULTS: The 90-day post-discharge mortality was 13.9%. The mean nutrition delivery days recorded was 15. In a mixed-effect logistic regression model adjusted for age, gender, race, Deyo-Charlson comorbidity index, acute organ failures, sepsis and percent energy needs met, the 90-day post-discharge mortality rate was 17% (95% CI: 6⁻26) lower for each 1 g/kg increase in daily protein delivery (OR = 0.83 (95% CI 0.74⁻0.94; = 0.002)). CONCLUSIONS: Adult medical ICU patients with improvements in daily protein intake during hospitalization who survive hospitalization have decreased odds of mortality in the 3 months following hospital discharge.
Gennaro Martucci, Dayre McNally, Dhruv Parekh, Paul Zajic, Fabio Tuzzolino, Antonio Arcadipane, Kenneth B Christopher, Harald Dobnig, and Karin Amrein. 2019. “Trying to identify who may benefit most from future vitamin D intervention trials: a post hoc analysis from the VITDAL-ICU study excluding the early deaths.” Crit Care, 23, 1, Pp. 200.Abstract
BACKGROUND: Vitamin D supplementation has shown promise for reducing mortality in the intensive care setting. As a steroid prohormone with pleiotropic effects, there may be a lag between administration and observing clinical benefit. This secondary analysis of the VITdAL-ICU study sought to explore whether the effect size of vitamin D on mortality was different when study participants who died or were discharged early were excluded. METHODS: The VITdAL-ICU study was a randomized, placebo-controlled trial in critically ill adults who received placebo or 540,000 IU cholecalciferol followed by monthly supplementation. The effect of vitamin D on 28-day mortality was evaluated after exclusion of participants who died or were discharged within 7 days from study drug administration, according to vitamin D concentrations on day 3, using a bivariate analysis adjusted for confounders and in a stepwise multiple analysis. RESULTS: Of 475 study participants, 65 died or were discharged within the first 7 days. In the remaining 410 patients, vitamin D supplementation was associated with a reduction in 28-day mortality [OR 0.58 (95% CI 0.35-0.97) p value = 0.035]. The effect on mortality was not significant after adjusting for age, severity scores, female gender, chronic liver and kidney disease, COPD, diagnosis of the tumor, mechanical ventilation, and vasopressors at enrollment (all p > 0.05). In a multiple model, the mortality reduction by vitamin D supplementation did not remain independently significant [OR 0.61 (95% CI 0.35-1.05) p = 0.075]. Vitamin D metabolite response, in the treatment group, demonstrated that survivors at 28 days, had higher levels of 25-hydroxyvitamin D (34.4 vs 25.4 ng/ml, p = 0.010) and 1,25-dihydroxyvitamin D (107.6 vs 70.3 pg/ml, p = 0.049) on day 3. The increase of plasma metabolites after vitamin D oral supplementation, independent of the baseline value, was associated with lower odds of death [OR 0.48 (95% CI 0.27-0.87) p value = 0.016]. CONCLUSIONS: High-dose vitamin D3 supplementation was associated with a reduction of 28-day mortality in a mixed population of critically ill adults with vitamin D deficiency when excluding patients who died or were discharged within 7 days after study inclusion. However, this survival benefit was not independently confirmed when adjusted for other factors strongly associated with mortality.
2018
Alexandra Briggs, Joaquim M Havens, Ali Salim, and Kenneth B Christopher. 2018. “Acute kidney injury predicts mortality in emergency general surgery patients.” Am J Surg, 216, 3, Pp. 420-426.Abstract
BACKGROUND: Patients undergoing Emergency General Surgery (EGS) have increased risk of complications and death. The risk of AKI in patients undergoing EGS, along with associated outcomes, is unknown. METHODS: This two-institution observational study included adults admitted to intensive care units between 1997 and 2012. EGS was defined by 7 procedures occurring within 48 hours of ICU admission. The main outcome studied was AKI within 5 days, along with 90-day mortality. RESULTS: In our cohort of 59,604 patients, 1758 (2.9%) underwent EGS. Risk of AKI in EGD patients was significantly increased relative to non-EGS patients, with adjusted odds of 1.7 (95%CI 1.40-1.94; P < 0.001). Risk of renal replacement for EGS patients was also increased, with odds of 1.8 (95%CI 1.37-2.46; P < 0.001). EGS patients were at significantly higher risk of 90-day mortality, with adjusted odds of 3.1 (95%CI 2.16-4.33,p < 0.001) for AKI and 4.5 (95%CI 2.58-7.96,p < 0.001) for AKI requiring renal replacement, relative to the absence of AKI. CONCLUSIONS: EGS is a robust risk factor for AKI in critically ill patients, the development of which is strongly predictive of increased 90-day mortality.
Takuhiro Moromizato, Vanessa Garcia-Larsen, Djøra Soeteman, Paige G Wickner, Joaquim M Havens, Rachel Lund, Rieko Eriguchi, Yasuharu Tokuda, Kenji Murata, Kunitoshi Iseki, Ajay K Singh, and Kenneth B Christopher. 2018. “Addressing the gap in clinical research education: Implementation of the Introduction to Clinical Research Training-Japan program.” J Gen Fam Med, 19, 6, Pp. 188-190.
Hanjo Ko, Julius I Ejiofor, Jessica E Rydingsward, James D Rawn, Jochen D Muehlschlegel, and Kenneth B Christopher. 2018. “Decreased preoperative functional status is associated with increased mortality following coronary artery bypass graft surgery.” PLoS One, 13, 12, Pp. e0207883.Abstract
OBJECTIVES: Functional status prior to coronary artery bypass graft surgery may be a risk factor for post-operative adverse events. We sought to examine the association between functional status in the 3 months prior to coronary artery bypass graft surgery and subsequent 180 day mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a single center retrospective cohort study in 718 adults who received coronary artery bypass graft surgery from 2002 to 2014. EXPOSURES: The exposure of interest was functional status determined within the 3 months preceding coronary artery bypass graft surgery. Functional status was measured and rated by a licensed physical therapist based on qualitative categories adapted from the Functional Independence Measure. MAIN OUTCOMES AND MEASURES: The main outcome was 180-day all-cause mortality. A categorical risk prediction score was derived based on a logistic regression model of the function grades for each assessment. RESULTS: In a logistic regression model adjusted for age, gender, New York Heart Association Class III/IV, chronic lung disease, hypertension, diabetes, cerebrovascular disease, and the Society of Thoracic Surgeons score, the lowest quartile of functional status was associated with an increased odds of 180-day mortality compared to patients with highest quartile of functional status [OR = 4.45 (95%CI 1.35, 14.69; P = 0.014)]. CONCLUSIONS: Lower functional status prior to coronary artery bypass graft surgery is associated with increased 180-day all-cause mortality.
Jean-Louis Vincent, Kenneth B Christopher, and Anthony McLean. 2018. “Do I have a conflict of interest? No.” Intensive Care Med, 44, 10, Pp. 1744-1745.
Joaquim M Havens, Alexandra B Columbus, Anupamaa J Seshadri, Olubode A Olufajo, Kris M Mogensen, James D Rawn, Ali Salim, and Kenneth B Christopher. 2018. “Malnutrition at Intensive Care Unit Admission Predicts Mortality in Emergency General Surgery Patients.” JPEN J Parenter Enteral Nutr, 42, 1, Pp. 156-163.Abstract
BACKGROUND: Emergency general surgery (EGS) patients are at an increased risk for morbidity and mortality compared with non-EGS patients. Limited information exists regarding the contribution of malnutrition to the outcome of critically ill patients who undergo EGS. We hypothesized that malnutrition would be associated with increased risk of 90-day all-cause mortality following intensive care unit (ICU) admission in EGS patients. MATERIALS AND METHODS: We performed an observational study of patients treated in medical and surgical ICUs at a single institution in Boston. We included patients who underwent an EGS procedure and received critical care between 2005 and 2011. The exposure of interest, malnutrition, was determined by a registered dietitian's formal assessment within 48 hours of ICU admission. The primary outcome was all-cause 90-day mortality. Adjusted odds ratios were estimated by multivariable logistic regression models. RESULTS: The cohort consisted of 1361 patients. Sixty percent had nonspecific malnutrition, 8% had protein-energy malnutrition, and 32% were without malnutrition. The 30-day readmission rate was 18.9%. Mortality in-hospital and at 90 days was 10.1% and 17.9%, respectively. Patients with nonspecific malnutrition had a 1.5-fold increased odds of 90-day mortality (adjusted odds ratio [OR], 1.51; 95% confidence interval [CI], 1.09-5.04; P = .009) and patients with protein-energy malnutrition had a 3.1-fold increased odds of 90-day mortality (adjusted OR, 3.06; 95% CI, 1.89-4.92; P < .001) compared with patients without malnutrition. CONCLUSION: In critically ill patients who undergo EGS, malnutrition at ICU admission is predictive of adverse outcomes. In survivors of hospitalization, malnutrition at ICU admission is associated with increases in readmission and mortality.
Kenneth B Christopher. 2018. “Nutritional metabolomics in critical illness.” Curr Opin Clin Nutr Metab Care, 21, 2, Pp. 121-125.Abstract
PURPOSE OF REVIEW: Disruption of metabolic homeostasis is universal in the critically ill. Macronutrients and micronutrients are major environmental regulators of metabolite production through their gene regulation effects. The study of large numbers of circulating metabolites is beginning to emerge through the comprehensive profiling of the critically ill. In the critically ill, metabolomic studies consistently show that changes in fatty acids, lipids and tryptophan metabolite pathways are common and are associated with disease state and outcomes. RECENT FINDINGS: Metabolomics is now being applied in research studies to determine the critical illness response to nutrient deficiency and delivery. Nutritional metabolomics approaches in nutrient deficiency, malnutrition and nutrient delivery have included single time point studies and dynamic studies of critically ill patients over time. Integration of metabolomics and clinical outcome data may create a more complete understanding of the control of metabolism in critical illness. SUMMARY: The integration of metabolomic profiling with transcription and genomic data may allow for a unique window into the mechanism of how nutrient deficiency and delivery alters cellular homeostasis during critical illness and modulates the regain of cellular homeostasis during recovery. The progress and the challenges of the study of nutritional metabolomics are reviewed here.
Pär I Johansson, Kiichi Nakahira, Angela J Rogers, Michael J McGeachie, Rebecca M Baron, Laura E Fredenburgh, John Harrington, Augustine MK Choi, and Kenneth B Christopher. 2018. “Plasma mitochondrial DNA and metabolomic alterations in severe critical illness.” Crit Care, 22, 1, Pp. 360.Abstract
BACKGROUND: Cell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. A substantial alteration in metabolic homeostasis is commonly observed in severe critical illness. We hypothesized that metabolic profiles significantly differ between critically ill patients relative to their level of plasma mtDNA. METHODS: We performed a metabolomic study with biorepository plasma samples collected from 73 adults with systemic inflammatory response syndrome or sepsis at a single academic medical center. Patients were treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to plasma NADH dehydrogenase 1 (ND1) mtDNA levels in critical illness, we first generated metabolomic data using gas and liquid chromatography-mass spectroscopy. We performed fold change analysis and volcano plot visualization based on false discovery rate-adjusted p values to evaluate the distribution of individual metabolite concentrations relative to ND1 mtDNA levels. We followed this by performing orthogonal partial least squares discriminant analysis to identify individual metabolites that discriminated ND1 mtDNA groups. We then interrogated the entire metabolomic profile using pathway overrepresentation analysis to identify groups of metabolite pathways that were different relative to ND1 mtDNA levels. RESULTS: Metabolomic profiles significantly differed in critically ill patients with ND1 mtDNA levels ≥ 3200 copies/μl plasma relative to those with an ND1 mtDNA level < 3200 copies/μl plasma. Several analytical strategies showed that patients with ND1 mtDNA levels ≥ 3200 copies/μl plasma had significant decreases in glycerophosphocholines and increases in short-chain acylcarnitines. CONCLUSIONS: Differential metabolic profiles during critical illness are associated with cell-free plasma ND1 mtDNA levels that are indicative of cell damage. Elevated plasma ND1 mtDNA levels are associated with decreases in glycerophosphocholines and increases in short-chain acylcarnitines that reflect phospholipid metabolism dysregulation and decreased mitochondrial function, respectively.
Gerdine CI von Meijenfeldt, Maarten J van der Laan, Clark JAM Zeebregts, and Kenneth B Christopher. 2018. “Red cell distribution width at hospital discharge and out-of hospital outcomes in critically ill non-cardiac vascular surgery patients.” PLoS One, 13, 9, Pp. e0199654.Abstract
OBJECTIVE: Red cell distribution width (RDW) is associated with mortality and bloodstream infection risk in the critically ill. In vascular surgery patients surviving critical care it is not known if RDW can predict subsequent risk of all-cause mortality following hospital discharge. We hypothesized that an increase in RDW at hospital discharge in vascular surgery patients who received critical care would be associated with increased mortality following hospital discharge. DESIGN, SETTING, AND PARTICIPANTS: We performed a two-center observational cohort study of critically ill non-cardiac vascular surgery patients surviving admission 18 years or older treated between November, 1997, and December 2012 in Boston, Massachusetts. EXPOSURES: RDW measured within 24 hours of hospital discharge and categorized a priori as ≤13.3%, 13.3-14.0%, 14.0-14.7%, 14.7-15.8%, >15.8%. MAIN OUTCOMES AND MEASURES: The primary outcome was all cause mortality in the 90 days following hospital discharge. RESULTS: The cohort included 4,715 patients (male 58%; white 83%; mean age 62.9 years). 90 and 365-day post discharge mortality was 7.5% and 14.4% respectively. In the cohort, 47.3% were discharged to a care facility and 14.8% of patients were readmitted within 30 days. After adjustment for age, gender, race, Deyo-Charlson comorbidity Index, patient type, acute organ failures, prior vascular surgery and vascular surgery category, patients with a discharge RDW 14.7-15.8% or >15.8% have an adjusted OR of 90-day post discharge mortality of 2.52 (95%CI, 1.29-4.90; P = 0.007) or 5.13 (95%CI, 2.70-9.75; P <0.001) relative to patients with a discharge RDW ≤13.3%. The adjusted odds of 30-day readmission in the RDW >15.8% group was 1.52 (95%CI, 1.12-2.07; P = 0.007) relative to patients with a discharge RDW ≤13.3%. Similar adjusted discharge RDW-outcome associations are present at 365 days following hospital discharge and for discharge to a care facility. CONCLUSIONS: In critically ill vascular surgery patients who survive hospitalization, an elevated RDW at hospital discharge is a strong predictor of subsequent mortality, hospital readmission and placement in a care facility. Patients with elevated RDW are at high risk for adverse out of hospital outcomes and may benefit from closer post discharge follow-up and higher intensity rehabilitation.
Joaquim Michael Havens, Anupamaa J Seshadri, Ali Salim, and Kenneth B Christopher. 2018. “Red cell distribution width predicts out of hospital outcomes in critically ill emergency general surgery patients.” Trauma Surg Acute Care Open, 3, 1, Pp. e000147.Abstract
Introduction: Red cell distribution width (RDW) is associated with mortality and bloodstream infection risk in critically ill patients. We hypothesized that an increase in RDW at hospital discharge in critically ill patients who received emergency general surgery (EGS) would be associated with increased mortality after hospital discharge. Methods: We performed a two-center observational study of patients treated in medical and surgical intensive care units. We studied 1567 patients, who received critical care between 1998 and 2012 who underwent EGS and survived hospitalization. The exposure of interest was RDW within 24 hours of hospital discharge and categorized a priori in quintiles as ≤13.3%, 13.3% to 14.0%, 14.0% to 14.7%, 14.7% to 15.8%, 15.8% to 17.0% and >17.0%. The primary outcome was 90-day all-cause mortality. Adjusted ORs were estimated by multivariable logistic regression models with inclusion of covariate terms for age, race, gender, Deyo-Charlson Index, sepsis and number of organs with acute failure. Results: The cohort patients were 51.4% male and 23.2% non-white. 23.9% had sepsis and the mean age was 58 years. 90-day postdischarge mortality was 6.8%. Patients with a discharge RDW 15.8% to 17.0% or RDW >17.0% have an adjusted OR of 90-day postdischarge mortality of 3.64 (95% CI 1.04 to 12.68; p=0.043) or 4.58 (95% CI 1.32 to 15.93; p=0.02), respectively, relative to patients with a discharge RDW ≤13.3%. Further, patients with a discharge RDW ≥15.8 have an adjusted OR of 30-day hospital readmission of 2.12 (95% CI 1.17 to 3.83; p=0.013) relative to patients with a discharge RDW ≤13.3%. Conclusions: In EGS patients requiring critical care who survive hospitalization, an elevated RDW at the time of discharge is a robust predictor of all-cause patient mortality and hospital readmission after discharge. Level of evidence: Level II, prognostic retrospective study.
2017
V Schwetz, C Schnedl, T Urbanic-Purkart, C Trummer, HP Dimai, A Fahrleitner-Pammer, C Putz-Bankuti, KB Christopher, B Obermayer-Pietsch, TR Pieber, H Dobnig, and K Amrein. 2017. “Effect of vitamin D3 on bone turnover markers in critical illness: post hoc analysis from the VITdAL-ICU study.” Osteoporos Int, 28, 12, Pp. 3347-3354.Abstract
In this post hoc analysis of the VITdAL-ICU study, an RCT in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml, vitamin D3 did not have a significant effect on β-Crosslaps and osteocalcin. INTRODUCTION: Observational studies have shown accelerated bone loss in ICU survivors. A reversible contributor is vitamin D deficiency. In a post hoc analysis of the VITdAL-ICU study, we evaluated the effect of high-dose vitamin D3 on the bone turnover markers (BTM) β-Crosslaps (CTX) and osteocalcin (OC). METHODS: The VITdAL-ICU study was a randomized, double-blind, placebo-controlled trial in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml who received placebo or high-dose vitamin D3 (a loading dose of 540,000 IU and starting 1 month after the loading dose five monthly maintenance doses of 90,000 IU). In this analysis on 289 survivors (209 telephone, 80 personal follow-up visits), BTM were analyzed on days 0, 3, 7, 28, and 180; self-reported falls and fractures were assessed. Bone mineral density (BMD) was measured after 6 months. RESULTS: At baseline, CTX was elevated; OC was low in both groups-after 6 months, both had returned to normal. There were no differences between groups concerning BTM, BMD, falls, or fractures. In linear mixed effects models, CTX and OC showed a significant change over time (p < 0.001, respectively), but there was no difference between the vitamin D and placebo group (p = 0.688 and p = 0.972, respectively). CONCLUSIONS: Vitamin D supplementation did not have a significant effect on BTM. Further studies should assess the effectiveness of vitamin D on musculoskeletal outcomes in ICU survivors.
Jean Reignier, Kenneth B Christopher, and Yaseen Arabi. 2017. “Focus on nutrition and glucose control in the intensive care unit: recent advances and debates.” Intensive Care Med, 43, 12, Pp. 1904-1906.
Stephanie Nitzschke, Anaeze C Offodile, Ryan P Cauley, Jason E Frankel, Andrew Beam, Kevin M Elias, Fiona K Gibbons, Ali Salim, and Kenneth B Christopher. 2017. “Long term mortality in critically ill burn survivors.” Burns, 43, 6, Pp. 1155-1162.Abstract
INTRODUCTION: Little is known about long term survival risk factors in critically ill burn patients who survive hospitalization. We hypothesized that patients with major burns who survive hospitalization would have favorable long term outcomes. METHODS: We performed a two center observational cohort study in 365 critically ill adult burn patients who survived to hospital discharge. The exposure of interest was major burn defined a priori as >20% total body surface area burned [TBSA]. The modified Baux score was determined by age + %TBSA+ 17(inhalational injury). The primary outcome was all-cause 5year mortality based on the US Social Security Administration Death Master File. Adjusted associations were estimated through fitting of multivariable logistic regression models. Our final model included adjustment for inhalational injury, presence of 3rd degree burn, gender and the acute organ failure score, a validated ICU risk-prediction score derived from age, ethnicity, surgery vs. medical patient type, comorbidity, sepsis and acute organ failure covariates. Time-to-event analysis was performed using Cox proportional hazard regression. RESULTS: Of the cohort patients studied, 76% were male, 29% were non white, 14% were over 65, 32% had TBSA >20%, and 45% had inhalational injury. The mean age was 45, 92% had 2nd degree burns, 60% had 3rd degree burns, 21% received vasopressors, and 26% had sepsis. The mean TBSA was 20.1%. The mean modified Baux score was 72.8. Post hospital discharge 5year mortality rate was 9.0%. The 30day hospital readmission rate was 4%. Patients with major burns were significantly younger (41 vs. 47 years) had a significantly higher modified Baux score (89 vs. 62), and had significantly higher comorbidity, acute organ failure, inhalational injury and sepsis (all P<0.05). There were no differences in gender and the acute organ failure score between major and non-major burns. In the multivariable logistic regression model, major burn was associated with a 3 fold decreased odds of 5year post-discharge mortality compared to patients with TBSA<20% [OR=0.29 (95%CI 0.11-0.78; P=0.014)]. The adjusted model showed good discrimination [AUC 0.81 (95%CI 0.74-0.89)] and calibration (Hosmer-Lemeshow χ P=0.67). Cox proportional hazard multivariable regression modeling, adjusting for inhalational injury, presence of 3rd degree burn, gender and the acute organ failure score, showed that major burn was predictive of lower mortality following hospital admission [HR=0.34 (95% CI 0.15-0.76; P=0.009)]. The modified Baux score was not predictive for mortality following hospital discharge [OR 5year post-discharge mortality=1.00 (95%CI 0.99-1.02; P=0.74); HR for post-discharge mortality=1.00 (95% CI 0.99-1.02; P=0.55)]. CONCLUSIONS: Critically ill patients with major burns who survive to hospital discharge have decreased 5year mortality compared to those with less severe burns. ICU Burn unit patients who survive to hospital discharge are younger with less comorbidities. The observed relationship is likely due to the relatively higher physiological reserve present in those who survive a Burn ICU course which may provide for a survival advantage during recovery after major burn.
Kris M Mogensen, Clare M Horkan, Steven W Purtle, Takuhiro Moromizato, James D Rawn, Malcolm K Robinson, and Kenneth B Christopher. 2017. “Malnutrition, Critical Illness Survivors, and Postdischarge Outcomes: A Cohort Study.” JPEN J Parenter Enteral Nutr, Pp. 148607117709766.Abstract
BACKGROUND: We hypothesized that preexisting malnutrition in patients who survived critical care would be associated with adverse outcomes following hospital discharge. METHODS: We performed an observational cohort study in 1 academic medical center in Boston. We studied 23,575 patients, aged ≥18 years, who received critical care between 2004 and 2011 and survived hospitalization. RESULTS: The exposure of interest was malnutrition determined at intensive care unit (ICU) admission by a registered dietitian using clinical judgment and on data related to unintentional weight loss, inadequate nutrient intake, and wasting of muscle mass and/or subcutaneous fat. The primary outcome was 90-day postdischarge mortality. Secondary outcome was unplanned 30-day hospital readmission. Adjusted odds ratios were estimated by logistic regression models adjusted for age, race, sex, Deyo-Charlson Index, surgical ICU, sepsis, and acute organ failure. In the cohort, the absolute risk of 90-day postdischarge mortality was 5.9%, 11.7%, 15.8%, and 21.9% in patients without malnutrition, those at risk of malnutrition, nonspecific malnutrition, and protein-energy malnutrition, respectively. The odds of 90-day postdischarge mortality in patients at risk of malnutrition, nonspecific malnutrition, and protein-energy malnutrition fully adjusted were 1.77 (95% confidence interval [CI], 1.23-2.54), 2.51 (95% CI, 1.36-4.62), and 3.72 (95% CI, 2.16-6.39), respectively, relative to patients without malnutrition. Furthermore, the presence of malnutrition is a significant predictor of the odds of unplanned 30-day hospital readmission. CONCLUSIONS: In patients treated with critical care who survive hospitalization, preexisting malnutrition is a robust predictor of subsequent mortality and unplanned hospital readmission.
Kris M Mogensen, Jessica Lasky-Su, Angela J Rogers, Rebecca M Baron, Laura E Fredenburgh, James Rawn, Malcolm K Robinson, Anthony Massarro, Augustine MK Choi, and Kenneth B Christopher. 2017. “Metabolites Associated With Malnutrition in the Intensive Care Unit Are Also Associated With 28-Day Mortality.” JPEN J Parenter Enteral Nutr, 41, 2, Pp. 188-197.Abstract
BACKGROUND: We hypothesized that metabolic profiles would differ in critically ill patients with malnutrition relative to those without. MATERIALS AND METHODS: We performed a prospective cohort study on 85 adult patients with systemic inflammatory response syndrome or sepsis admitted to a 20-bed medical intensive care unit (ICU) in Boston. We generated metabolomic profiles using gas and liquid chromatography and mass spectroscopy. We followed this by logistic regression and partial least squares discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis and network model construction of chemical-protein target interactions to identify groups of metabolites and pathways that were differentiates in patients with and without malnutrition. RESULTS: Of the cohort, 38% were malnourished at admission to the ICU. Metabolomic profiles differed in critically ill patients with malnutrition relative to those without. Ten metabolites were significantly associated with malnutrition ( P < .05). A parsimonious model of 5 metabolites effectively differentiated patients with malnutrition (AUC = 0.76), including pyroglutamine and hypoxanthine. Using pathway enrichment analysis, we identified a critical role of glutathione and purine metabolism in predicting nutrition. Nutrition status was associated with 28-day mortality, even after adjustment for known phenotypic variables associated with ICU mortality. Importantly, 7 metabolites associated with nutrition status were also associated with 28-day mortality. CONCLUSION: Malnutrition is associated with differential metabolic profiles early in critical illness. Common to all of our metabolome analyses, glutathione and purine metabolism, which play principal roles in cellular redox regulation and accelerated tissue adenosine triphosphate degradation, respectively, were significantly altered with malnutrition.
Jessica Lasky-Su, Amber Dahlin, Augusto A Litonjua, Angela J Rogers, Michael J McGeachie, Rebecca M Baron, Lee Gazourian, Diana Barragan-Bradford, Laura E Fredenburgh, Augustine MK Choi, Kris M Mogensen, Sadeq A Quraishi, Karin Amrein, and Kenneth B Christopher. 2017. “Metabolome alterations in severe critical illness and vitamin D status.” Crit Care, 21, 1, Pp. 193.Abstract
BACKGROUND: Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status. METHODS: We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to vitamin D status in critical illness, we first generated metabolomic data using gas and liquid chromatography mass spectroscopy. We followed this by partial least squares-discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis to identify groups of metabolites and pathways that were differentiates of vitamin D status. Finally we performed logistic regression to construct a network model of chemical-protein target interactions important in vitamin D status. RESULTS: Metabolomic profiles significantly differed in critically ill patients with 25(OH)D ≤ 15 ng/ml relative to those with levels >15 ng/ml. In particular, increased 1,5-anhydroglucitol, tryptophan betaine, and 3-hydroxyoctanoate as well as decreased 2-arachidonoyl-glycerophosphocholine and N-6-trimethyllysine were strong predictors of 25(OH)D >15 ng/ml. The combination of these five metabolites led to an area under the curve for discrimination for 25(OH)D > 15 ng/ml of 0.82 (95% CI 0.71-0.93). The metabolite pathways related to glutathione metabolism and glutamate metabolism are significantly enriched with regard to vitamin D status. CONCLUSION: Vitamin D status is associated with differential metabolic profiles during critical illness. Glutathione and glutamate pathway metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly altered with vitamin D status.
Steven W Purtle, Clare M Horkan, Takuhiro Moromizato, Fiona K Gibbons, and Kenneth B Christopher. 2017. “Nucleated red blood cells, critical illness survivors and postdischarge outcomes: a cohort study.” Crit Care, 21, 1, Pp. 154.Abstract
BACKGROUND: Little is known about risk factors associated with out-of-hospital outcomes in survivors of critical illness. We hypothesized that the presence of nucleated red blood cells in patients who survived critical care would be associated with adverse outcomes following hospital discharge. METHODS: We performed a two-center observational cohort study of patients treated in medical and surgical intensive care units in Boston, Massachusetts. All data were obtained from the Research Patient Data Registry at Partners HealthCare. We studied 2878 patients, age ≥ 18 years, who received critical care between 2011 and 2015 and survived hospitalization. The exposure of interest was nucleated red blood cells occurring from 2 days prior to 7 days after critical care initiation. The primary outcome was mortality in the 90 days following hospital discharge. Secondary outcome was unplanned 30-day hospital readmission. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both nucleated red blood cells and outcome. Adjustment included age, race (white versus nonwhite), gender, Deyo-Charlson Index, patient type (medical versus surgical), sepsis and acute organ failure. RESULTS: In patients who received critical care and survived hospitalization, the absolute risk of 90-day postdischarge mortality was 5.9%, 11.7%, 15.8% and 21.9% in patients with 0/μl, 1-100/μl, 101-200/μl and more than 200/μl nucleated red blood cells respectively. Nucleated red blood cells were a robust predictor of postdischarge mortality and remained so following multivariable adjustment. The fully adjusted odds of 90-day postdischarge mortality in patients with 1-100/μl, 101-200/μl and more than 200/μl nucleated red blood cells were 1.77 (95% CI, 1.23-2.54), 2.51 (95% CI, 1.36-4.62) and 3.72 (95% CI, 2.16-6.39) respectively, relative to patients without nucleated red blood cells. Further, the presence of nucleated red blood cells is a significant predictor of the odds of unplanned 30-day hospital readmission. CONCLUSION: In critically ill patients who survive hospitalization, the presence of nucleated red blood cells is a robust predictor of postdischarge mortality and unplanned hospital readmission.
Kenneth B Christopher. 2017. “Response to Letter to the Editor 'Long term mortality in critically ill burn survivors: Methodological issues'.” Burns, 43, 8, Pp. 1820.
TMN Otero, DJ Monlezun, KB Christopher, CA Camargo, and SA Quraishi. 2017. “Vitamin D Status and Elevated Red Cell Distribution Width in Community-Dwelling Adults: Results from the National Health and Nutrition Examination Survey 2001-2006.” J Nutr Health Aging, 21, 10, Pp. 1176-1182.Abstract
OBJECTIVES: Elevated red cell distribution width (RDW) is associated with morbidity and mortality in community-dwelling individuals. Although RDW is traditionally used to diagnose anemia, it may also be a marker of systemic inflammation. Since vitamin D is a potent modulator of inflammatory cytokines our goal was to investigate whether 25-hydroxyvitamin D levels (25OHD) are associated with RDW in non-hospitalized adults. DESIGN: To investigate this association, we conducted a cross-sectional study. Stepwise multivariable linear and logistic regression models were used to assess the independent association of 25OHD with RDW. Elevated RDW was defined as >14.5%. SETTING: Nationwide sample of non-hospitalized adults within the United States. PARTICIPANTS: Individuals from the National Health and Nutrition Examination Survey from 2001-2006. RESULTS: 15,162 individuals comprised the analytic cohort. Mean 25OHD was 24.9 ng/mL (SE 0.4) and the prevalence of elevated RDW was 6.3%. Linear regression analysis, controlling for age, sex, race, mean corpuscular volume, albumin, and neutropenia, demonstrated that 25OHD was inversely associated with RDW (β=-0.01; 95%CI -0.01 to -0.01). Logistic regression analysis, controlling for the same covariates, also demonstrated an inverse association of 25OHD with elevated RDW (OR 0.96; 95%CI 0.94-0.99). Individuals with 25OHD <30 ng/mL were more likely to have elevated RDW (OR 1.65; 95%CI 1.13-2.40) compared to those individuals with levels ≥30ng/mL. CONCLUSIONS: In a nationwide sample of non-hospitalized adults within the United States, low 25OHD was associated with increased likelihood of elevated RDW. Further studies are needed to determine whether optimizing vitamin D status can reduce the prevalence of elevated RDW, and thereby reduce morbidity and mortality in the general population.

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