Hyperglycemia at admission to the intensive care unit is associated with elevated serum concentrations of interleukin-6 and reduced ex vivo secretion of tumor necrosis factor-&agr;*

Objectives:The aim of the study was to investigate the association between admission blood glucose concentrations and immune function variables and its correlation to mortality rate in patients of a medical intensive care unit. Design:Prospective, observational study. Setting:Medical intensive care unit of a university hospital. Patients:Patients were 189 consecutive critically ill patients in the medical intensive care unit. Interventions:At admission to the intensive care unit, serum concentrations of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-&agr; were measured with immunometric assays. Additionally, ex vivo secretion of tumor necrosis factor-&agr; after stimulation with lipopolysaccharide in a whole blood assay and cytometric human leukocyte antigen-DR expression on monocytes were determined in all study subjects. Simplified Acute Physiology Score II and Therapeutic Intervention Scoring System-28 were calculated for the first day in the intensive care unit. Measurements and Main Results:The relationships between blood glucose concentrations and immunologic variables were analyzed using univariate and multivariate statistical methods. Overall, 75 patients (39.7%) presented with hyperglycemia. An elevated blood glucose concentration at admission was related to an increased risk of mortality in the intensive care unit (odds ratio, 2.6; p = .009). At univariate and multivariate analysis, hyperglycemia was associated with increased serum concentrations of interleukin-6 (p < .05), a reduced ex vivo production of tumor necrosis factor-&agr; (p < .01), and a history of diabetes mellitus (p < .05), whereas other clinical (including Simplified Acute Physiology Score II and Therapeutic Intervention Scoring System-28) and immunologic variables were not statistically related to blood glucose. Conclusions:Our main findings show that admission hyperglycemia is statistically related to distinct changes of humoral and cellular immune functions. Furthermore, elevated glucose concentrations at admission are associated with increased intensive care unit mortality rate in a medical intensive care unit. Although these data do not explain cause and effect, our results provide a strong rationale for studying the immunologic effects of strict glycemic control in the intensive care unit during the course of critical illness.

[1]  T. Evans,et al.  Glucose control and mortality in critically ill patients. , 2004, JAMA.

[2]  G. Van den Berghe,et al.  Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. , 2003, The Journal of clinical endocrinology and metabolism.

[3]  M. Cakir,et al.  Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. , 2003, The Journal of clinical endocrinology and metabolism.

[4]  Miet Schetz,et al.  Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control* , 2003, Critical care medicine.

[5]  R. Marfella,et al.  Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress , 2002, Circulation.

[6]  K. Huber,et al.  Multiple organ failure in patients with cardiogenic shock is associated with high plasma levels of interleukin-6 , 2002, Critical care medicine.

[7]  R. Einspanier,et al.  Insulin Attenuates the Systemic Inflammatory Response to Thermal Trauma , 2002, Molecular medicine.

[8]  J. Cavaillon,et al.  Successful Cardiopulmonary Resuscitation After Cardiac Arrest as a “Sepsis-Like” Syndrome , 2002, Circulation.

[9]  J. Rotich,et al.  Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke , 2002, Neurology.

[10]  J. Pugin Biomarkers of sepsis: is procalcitonin ready for prime time? , 2002, Intensive Care Medicine.

[11]  M. Sampson,et al.  Monocyte and Neutrophil Adhesion Molecule Expression During Acute Hyperglycemia and After Antioxidant Treatment in Type 2 Diabetes and Control Patients , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[12]  R. Cooper,et al.  Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans. , 2002, American journal of physiology. Endocrinology and metabolism.

[13]  N. Heussen,et al.  Can the interleukin-6 response to endotoxin be predicted? Studies of the influence of a promoter polymorphism of the interleukin-6 gene, gender, the density of the endotoxin receptor CD14, and inflammatory cytokines. , 2002, Critical care medicine.

[14]  I. Hirsch In-patient hyperglycemia--are we ready to treat it yet? , 2002, The Journal of clinical endocrinology and metabolism.

[15]  P. Póvoa,et al.  C-reactive protein: a valuable marker of sepsis , 2002, Intensive Care Medicine.

[16]  W. Evans,et al.  Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia. , 2001, American journal of physiology. Endocrinology and metabolism.

[17]  N. Barzilai,et al.  Hyperglycemia-induced Production of Acute Phase Reactants in Adipose Tissue* , 2001, The Journal of Biological Chemistry.

[18]  D. Pittet,et al.  Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. , 2001, American journal of respiratory and critical care medicine.

[19]  H. Gerstein,et al.  Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview , 2000, The Lancet.

[20]  L. Rydén,et al.  Admission plasma glucose. Independent risk factor for long-term prognosis after myocardial infarction even in nondiabetic patients. , 1999, Diabetes care.

[21]  K. Alberti,et al.  Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke Trial (GIST). , 1999, Stroke.

[22]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[23]  M. Netea,et al.  High glucose concentrations increase the tumor necrosis factor-alpha production capacity by human peripheral blood mononuclear cells. , 1998, Romanian journal of physiology : physiological sciences.

[24]  D. Papanicolaou,et al.  The Pathophysiologic Roles of Interleukin-6 in Human Disease , 1998, Annals of Internal Medicine.

[25]  K. Malmberg Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus , 1997, BMJ.

[26]  F. Numano,et al.  Glucose-Dependent Interleukin 6 and Tumor Necrosis Factor Production by Human Peripheral Blood Monocytes In Vitro , 1996, Diabetes.

[27]  D. Hoyt,et al.  Immunosuppression after endotoxin shock: the result of multiple anti-inflammatory factors. , 1996, The Journal of trauma.

[28]  J. Ross,et al.  Serum concentrations of inflammatory mediators related to organ failure in patients with acute pancreatitis , 1996, The British journal of surgery.

[29]  F. Schildberg,et al.  Downregulation of proinflammatory cytokine release in whole blood from septic patients. , 1995, Blood.

[30]  R. Bone,et al.  Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome , 1993, Annals of Internal Medicine.

[31]  R. Bone Guidelines for the Use of Innovative Therapies in Sepsis , 1993 .

[32]  J. Cavaillon,et al.  Influence of surgery on in-vitro cytokine production by human monocytes. , 1992, Cytokine.

[33]  A. Heyman,et al.  The Influence of Hyperglycemia on Outcome of Cerebral Infarction , 1992, Annals of Internal Medicine.

[34]  J. Cavaillon,et al.  Dysregulation of in vitro cytokine production by monocytes during sepsis. , 1991, The Journal of clinical investigation.

[35]  J. French,et al.  The Prognostic Value of Stress Hyperglycaemia and Previously Unrecognized Diabetes in Acute Stroke , 1987, Diabetic medicine : a journal of the British Diabetic Association.

[36]  J. Yudkin,et al.  Determinants and importance of stress hyperglycaemia in non-diabetic patients with myocardial infarction. , 1986, British medical journal.

[37]  B. Bistrian,et al.  Intensive insulin therapy in critically ill patients. , 2002, The New England journal of medicine.

[38]  A. Malhotra,et al.  Stress-induced hyperglycemia. , 2001, Critical care clinics.

[39]  H Wedel,et al.  Infarction : Long-Term Results From the Diabetes and Insulin-Glucose Infusion Conventionally Treated Patients With Diabetes Mellitus and Acute Myocardial Glycometabolic State at Admission : Important Risk Marker of Mortality in , 1999 .

[40]  W. Schaufeli,et al.  Simplified Therapeutic Intervention Scoring System: the TISS-28 items--results from a multicenter study. , 1996 .

[41]  S. Lemeshow,et al.  A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. , 1993, JAMA.

[42]  D. Ritchie Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools. , 1990, The American journal of physiology.