Paul E Wischmeyer1, Rachael A Mintz-Cole2, Christine H Baird3, Kirk A Easley4, Addison K May5, Harry C Sax6, Kenneth A Kudsk7, Li Hao8, Phong H Tran9, Dean P Jones10, Henry M Blumberg11, Thomas R Ziegler12. 1. Duke University Hospital, Department of Anesthesiology and Duke Clinical Research Institute, 2301 Erwin Rd, Durham, NC 27710, USA. Electronic address: Paul.wischmeyer@duke.edu. 2. Duke University Hospital, Department of Anesthesiology and Duke Clinical Research Institute, 2301 Erwin Rd, Durham, NC 27710, USA. Electronic address: rachael.mintzcole@gmail.com. 3. University of Colorado Denver Anschutz Medical Campus, Anesthesiology, 12700 E. 19th Avenue Box 8602, Aurora, CO 80045, USA. Electronic address: Christine.baird@ucdenver.edu. 4. Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA. Electronic address: keasle2@emory.edu. 5. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37240, USA. Electronic address: Addison.may@vanderbilt.edu. 6. Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: SaxH@cshs.org. 7. Department of Surgery, University of Wisconsin, Schools of Medicine and Public Health, Madison, Madison, WI 53792, USA. Electronic address: kudsk@surgery.wisc.edu. 8. Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: lhao2@emory.edu. 9. Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: phong.tran@emory.edu. 10. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: Dpjones@emory.edu. 11. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA. Electronic address: hblumbe@emory.edu. 12. Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, GA 30322, USA; Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA. Electronic address: tzieg01@emory.edu.
Abstract
BACKGROUND: Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited. OBJECTIVE: Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations. METHODS: Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLN dipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up. RESULTS: eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN. CONCLUSION: Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70.
BACKGROUND: Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited. OBJECTIVE: Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations. METHODS: Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLNdipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up. RESULTS: eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN. CONCLUSION: Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70.
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