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

Supplemental Digital Content is available in the text 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.

[1]  B. Brumback,et al.  Older adults demonstrate biomarker evidence of the persistent inflammation, immunosuppression and catabolism syndrome (PICS) after sepsis. , 2021, The journals of gerontology. Series A, Biological sciences and medical sciences.

[2]  L. Moldawer,et al.  Immunological Endotyping of Chronic Critical Illness After Severe Sepsis , 2021, Frontiers in Medicine.

[3]  B. Brumback,et al.  DISTINCT IMMUNOLOGIC ENDOTYPES ARE ASSOCIATED WITH CLINICAL TRAJECTORY AFTER SEVERE BLUNT TRAUMA AND HEMORRHAGIC SHOCK. , 2020, The journal of trauma and acute care surgery.

[4]  G. O’Keefe,et al.  Persistent metabolomic alterations characterize chronic critical illness after severe trauma , 2020, The journal of trauma and acute care surgery.

[5]  B. Brumback,et al.  Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study , 2020, Critical Care.

[6]  B. Brumback,et al.  Older Sepsis Survivors Suffer Persistent Disability Burden and Poor Long-Term Survival , 2020, Journal of the American Geriatrics Society.

[7]  S. Anton,et al.  Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-Year Outcomes. , 2019, Annals of surgery.

[8]  Octavia M Peck Palmer,et al.  Long-term Host Immune Response Trajectories Among Hospitalized Patients With Sepsis , 2019, JAMA network open.

[9]  C. Coopersmith,et al.  Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559)* , 2019, Critical care medicine.

[10]  B. Brumback,et al.  The Development of Chronic Critical Illness Determines Physical Function, Quality of Life, and Long-Term Survival Among Early Survivors of Sepsis in Surgical ICUs* , 2019, Critical care medicine.

[11]  D. Herndon,et al.  Burn Injury May Have Age-Dependent Effects on Strength and Aerobic Exercise Capacity in Males. , 2018, Journal of burn care & research : official publication of the American Burn Association.

[12]  H. Ueno,et al.  Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy , 2018, Front. Immunol..

[13]  R. Hotchkiss,et al.  Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. , 2018, JCI insight.

[14]  A. Mebazaa,et al.  Protracted immune disorders at one year after ICU discharge in patients with septic shock , 2018, Critical Care.

[15]  Derek C. Angus,et al.  Enhancing Recovery From Sepsis: A Review , 2018, JAMA.

[16]  B. Brumback,et al.  Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients , 2017, The journal of trauma and acute care surgery.

[17]  B. Brumback,et al.  The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level–One Trauma Centers* , 2017, Critical care medicine.

[18]  Susan Gruber,et al.  Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014 , 2017, JAMA.

[19]  B. Brumback,et al.  Evidence for Persistent Immune Suppression in Patients Who Develop Chronic Critical Illness After Sepsis , 2017, Shock.

[20]  Y. Vodovotz,et al.  The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure. , 2017, The journal of trauma and acute care surgery.

[21]  B. Brumback,et al.  Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients , 2017, BMJ Open.

[22]  B. Brumback,et al.  Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock , 2017, Annals of surgery.

[23]  R. Martindale,et al.  Nutrition Support for Persistent Inflammation, Immunosuppression, and Catabolism Syndrome. , 2017, Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition.

[24]  L. Moldawer,et al.  Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome , 2017, Critical care medicine.

[25]  M. D. Hashem,et al.  Early Mobilization and Rehabilitation in the ICU: Moving Back to the Future , 2016, Respiratory Care.

[26]  R. Bellomo,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[27]  N. Anstey,et al.  Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients , 2014, Critical Care.

[28]  S. Reis,et al.  Risk of cardiovascular events in survivors of severe sepsis. , 2014, American journal of respiratory and critical care medicine.

[29]  J. Marshall Why have clinical trials in sepsis failed? , 2014, Trends in molecular medicine.

[30]  P. Pronovost,et al.  Physical Complications in Acute Lung Injury Survivors: A Two-Year Longitudinal Prospective Study , 2014, Critical care medicine.

[31]  D. Herndon,et al.  Survivors Versus Nonsurvivors Postburn: Differences in Inflammatory and Hypermetabolic Trajectories , 2014, Annals of surgery.

[32]  A. Gabrielli,et al.  Computer versus paper system for recognition and management of sepsis in surgical intensive care , 2014, The journal of trauma and acute care surgery.

[33]  W. Saris,et al.  Protein supplementation augments the adaptive response of skeletal muscle to resistance-type exercise training: a meta-analysis. , 2012, The American journal of clinical nutrition.

[34]  L. Moldawer,et al.  Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care , 2012, The journal of trauma and acute care surgery.

[35]  R. Tompkins,et al.  The Glue Grant experience: characterizing the post injury genomic response , 2011, European Journal of Trauma and Emergency Surgery.

[36]  B. McKinley,et al.  Computer protocol facilitates evidence-based care of sepsis in the surgical intensive care unit. , 2011, The Journal of trauma.

[37]  L. Kao,et al.  The epidemiology of sepsis in general surgery patients. , 2011, The Journal of trauma.

[38]  D. Heyland,et al.  Perioperative use of arginine-supplemented diets: a systematic review of the evidence. , 2011, Journal of the American College of Surgeons.

[39]  P. Pronovost,et al.  Long-term mortality and quality of life in sepsis: A systematic review* , 2010, Critical care medicine.

[40]  Peter Bauer,et al.  Sepsis mortality prediction based on predisposition, infection and response , 2008, Intensive Care Medicine.

[41]  M. Braga,et al.  Hospital resources consumed for surgical morbidity: effects of preoperative arginine and omega-3 fatty acid supplementation on costs. , 2005, Nutrition.

[42]  Mitchell M. Levy,et al.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference , 2003, Intensive Care Medicine.

[43]  C. Moorehead All rights reserved , 1997 .

[44]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.

[45]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[46]  S. Brakenridge,et al.  Chronic Critical Illness: Application of What We Know. , 2018, Nutrition in clinical practice.