Biomarker Evidence of the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) in Chronic Critical Illness (CCI) After Surgical Sepsis.

OBJECTIVE: To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. BACKGROUND: Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. METHODS: PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. RESULTS: CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). CONCLUSIONS: Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.

Audiovisual Modules to Enhance Informed Consent in the ICU: A Pilot Study.

Obtaining informed consent for commonly performed ICU procedures is often compromised by variability in communication styles and inadequate verbal descriptions of anatomic concepts. The objective of this study was to evaluate the efficacy of an audiovisual module in improving the baseline knowledge of ICU procedures among patients and their caregivers. DESIGN: Prospective, observational study. SETTING: Forty-eight-bed adult surgical ICU at a tertiary care center. SUBJECTS: Critically ill surgical patients and their legally authorized representatives. INTERVENTIONS: An audiovisual module describing eight commonly performed ICU procedures. MEASUREMENTS AND MAIN RESULTS: Fifty-nine subjects were enrolled and completed an 11-question pre- and postvideo test of knowledge regarding commonly performed ICU procedures and a brief satisfaction survey. Twenty-nine percent had a healthcare background. High school was the highest level of education for 37% percent of all subjects. Out of 11 questions on the ICU procedure knowledge test, subjects scored an average 8.0 ± 1.9 correct on the pretest and 8.4 ± 2.0 correct on the posttest (p = 0.055). On univariate logistic regression, having a healthcare background was a negative predictor of improved knowledge (odds ratio, 0.185; 95% CI, 0.045-0.765), indicating that those with a health background had a lower probability of improving their score on the posttest. Among subjects who did not have a healthcare background, scores increased from 7.7 ± 1.9 to 8.3 ± 2.1 (p = 0.019). Seventy-five percent of all subjects indicated that the video was easy to understand, and 70% believed that the video improved their understanding of ICU procedures. CONCLUSIONS: Audiovisual modules may improve knowledge and comprehension of commonly performed ICU procedures among critically ill patients and caregivers who have no healthcare background.

Abdominal sepsis patients have a high incidence of chronic critical illness with dismal long-term outcomes.

BACKGROUND: As hospital sepsis mortality has decreased, more surgical ICU survivors are progressing into chronic critical illness (CCI). This study documents the incidence of CCI and long-term outcomes of patients with abdominal sepsis. We hypothesized that patients developing CCI would have biomarker evidence of immune and metabolic derangement, with a high incidence of poor 1-year outcomes. METHODS: Review of abdominal sepsis patients entered in a prospective longitudinal study of surgical ICU sepsis. RESULTS: Of the 144 study patients, only 6% died early, 37% developed CCI (defined as ICU days ≥14 with organ dysfunction) and 57% were classified rapid recovery (RAP). Compared to RAP, CCI patients a) were older (66 vs 58), males who were sicker at baseline (Charlson Comorbidity Index 4 vs 2), b) had persistently elevated biomarkers of dysregulated immunity/metabolism (IL-6, IL-8, sPDL-1, GLP1), c) experienced more secondary infections (4.9 vs 2.3) and organ failure (Denver MOF frequency 40 vs 1%), d) were much more likely to have poor dispositions (85 vs 22%) with severe persistent disabilities by Zubrod Score and e) had a notably higher 1-year mortality of 42% (all p < 0.05). CONCLUSION: Over 1/3rd surgical ICU patients treated for abdominal sepsis progress into CCI and experience dismal long-term outcomes.

Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients.

BACKGROUND: A growing number of patients survive sepsis but remain chronically critically ill. We sought to define clinical outcomes and incidence of chronic critical illness (CCI) after sepsis and to determine whether selected biomarkers of inflammation, immunosuppression, and catabolism differ between these patients and those that rapidly recover (RAP). METHODS: This 3-year prospective observational cohort study (NCT02276417) evaluated 145 surgical intensive care unit patients with sepsis for the development of CCI (≥14 days of intensive care unit resource utilization with persistent organ dysfunction). Patient clinical demographics, outcomes, and serial serum/urine samples were collected for plasma protein and urinary metabolite analyses. RESULTS: Of 145 sepsis patients enrolled, 19 (13%) died during their hospitalization and 71 (49%) developed CCI. The CCI patients were significantly older (mean, 63 ± 15 vs. 58 ± 13 years, p = 0.006) and more likely to be discharged to long-term acute care facilities (32% vs. 3%, p < 0.0001), whereas those with RAP were more often discharged to home or a rehabilitation facility. Six-month mortality was significantly higher in CCI as compared with RAP cohort (37% vs. 2%; p < 0.01). Multivariate logistic regression modeling revealed delayed onset sepsis (>48 hours after admission; odds ratio [OR], 10.93; 95% confidence interval [CI], 4.15-28.82]), interfacility transfer (OR, 3.58; 95% CI, 1.43-8.96), vasopressor-dependent septic shock (OR, 3.75; 95% CI, 1.47-9.54), and Sequential Organ Failure Assessment score of 5 or greater at 72 hours (OR, 5.03; 95% CI, 2.00-12.62) as independent risk factors for the development of CCI. The CCI patients also demonstrated greater elevations in inflammatory cytokines (IL-6, IL-8, IL-10), and biomarker profiles are consistent with persistent immunosuppression (absolute lymphocyte count and soluble programmed death ligand 1) and catabolism (plasma insulin-like growth factor binding protein 3 and urinary 3-methylhistidine excretion). CONCLUSION: The development of CCI has become the predominant clinical trajectory in critically ill surgical patients with sepsis. These patients exhibit biomarker profiles consistent with an immunocatabolic phenotype of persistent inflammation, immunosuppression, and catabolism. LEVEL OF EVIDENCE: Prognostic, level II.

Adolescent fiber intake and mammographic breast density in premenopausal women.

BACKGROUND: To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent fiber intake with mammographic density in premenopausal women. METHODS: This study included 743 cancer-free premenopausal women (mean age, 44.9 years) within the Nurses' Health Study II cohort. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique. Adolescent and adult diet were assessed with a food frequency questionnaire; energy-adjusted nutrient intakes were estimated for each food item. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusted for potential confounders. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber (fruits, vegetables, and nuts). RESULTS: In multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of fiber from fruits, vegetables, legumes, or cereal nor specific sources of fiber intake (fruits, vegetables, or nuts) during adolescence were associated with any of the mammographic density phenotypes. CONCLUSIONS: Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic breast density.

Associations of individual characteristics and lifestyle factors with metabolism of di-2-ethylhexyl phthalate in NHANES 2001-2012.

BACKGROUND: Previous studies suggest that a higher ratio of primary to secondary metabolites of di-2-ethylhexyl phthalate (DEHP), reflective of a slower DEHP conversion rate, is associated with a greater physiologic effect. We examined associations of several individual characteristics and lifestyle factors with the ratio of mono-2-ethylhexyl phthalate to mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHP:MEHHP) and %MEHP (the ratio of MEHP to the sum of the secondary metabolites). METHODS: We used the data from the National Health and Nutrition Examination Survey, 2001-2012. The study included adults with BMI<30 and no diabetes. Pregnant women were excluded. We examined associations of age, race, gender, Body Mass Index, smoking, alcohol and caffeine consumption, medication use, cancer history, and menopausal status and postmenopausal hormone use (in women) with MEHP:MEHHP and %MEHP using multivariable linear regression. The values for %MEHP were log-transformed in the analysis. RESULTS: In multivariable analysis, non-Caucasian individuals had higher %MEHP (non-Hispanic Blacks: ß=0.114, 95% Confidence interval [CI]: 0.050, 0.177; Hispanic: ß=0.089, 95% CI: 0.024, 0.154; other race: ß=0.126, 95% CI: 0.033, 0.219). Age was inversely associated with MEHP:MEHHP (ß=-0.001, 95% CI: -0.002, -0.001) and %MEHP (ß=-0.006, 95% CI: -0.008, -0.004). Overweight individuals had lower MEHP: MEHHP and lower %MEHP (ß=-0.035, 95% CI: 0.062, -0.008 and ß=-0.104, 95% CI: -0.162, -0.046, respectively). Alcohol consumption was inversely associated with %MEHP among men (p-trend=0.03). CONCLUSIONS: Individual and lifestyle characteristics are associated with differences in DEHP metabolism. Understanding underlying biological mechanisms could help to identify individuals at a greater risk of adverse effects from DEHP exposure.