ESPEN Congress Madrid 2018

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1 ESPEN Congress Madrid 2018 Dysglycaemia In Acute Patients With Nutritional Therapy Mechanisms And Consequences Of Dysglycaemia In Patients Receiving Nutritional Therapy M. León- Sanz (ES)

2 Mechanisms and consequences of dysglycaemia in patients receiving nutritional therapy MIGUEL L EON-SANZ, MD, PhD HOSPITAL DOCE DE OCTUBRE, ENDOCRINOLOGY & NUTRITION COMPLUTENSE UNIVERSITY MADRID-SPAIN

3 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences Effects of macronutrients Unsolved issues

4 Dysglycaemia in hospitalized patients Prevalence

5 Dysglycaemia in hospitalized patients

6 Association between intensive care unit acquired dysglycemia and in-hospital mortality 344 ICUs, 194,772 patients, ICU LOS > 48 hrs Hyperglycemia (%) Hypoglycemia (%) Both (%) Dysgycemia 1 st day Euglycemia 1 st day Development of dysglycemia in ICU LOS DM before admission Dysglcyemia was defined as the presence of at least one of the following during the first 24 hrs of the ICU stay: 1. a single glucose value >180 mg/dl (10.0 mmol/l), 2. a time-weighted average daily glucose (ADG) >150 mg/dl (8.3 mmol/l), or 3. a single glucose value <60 mg/dl (3.3 mmol/l). Crit Care Med 2012; 40:

7 Association between intensive care unit acquired dysglycemia and in-hospital mortality 344 ICUs, 194,772 patients, ICU LOS > 48 hrs Crit Care Med 2012; 40:

8 Adjusted RR 1. age 2. sex 3. race 4. admission diagnosis 5. history of diabetes 6. APACHE score 7. admission glucose 8. admission temp 9. n glucose values/d 10. highest temperature 11. WBC count 12. serum sodium 13. serum creatinine 14. duration of MV 15. year ICU admission 16. ICU-acquired AKI, 17. respiratory failure 18. sepsis Crit Care Med 2012; 40:

highest average daily glucose (x-axis) 25-50 % Adjusted odds ratios (ORs) for hospital mortality by categories of ICU-acquired

9 highest average daily glucose (x-axis) % Adjusted odds ratios (ORs) for hospital mortality by categories of ICU-acquired hyperglycemia, hypoglycemia, and variability quartile of variability lowest single glucose value (y-axis) % Crit Care Med 2012; 40:

10 Liberal Glucose Control in ICU Patients With Diabetes: A Before-and-After Study Variable Liberal control (n=350; glycemia = mg/dl) Diabetes Type % 94.9 % Insulin treatment at home 33.5 % 31.0 % Insulin treatment at ICU 38 % 54 % Peak insulin infusion rate in treated patients, median (IQR) 5 (2 7) U/hr 4 (2 6) U/hr Episodes of Hypoglycemia 46/7,611 (0.6 %) 45/6,439 (0.7 %) In-hospital mortality 57 (16.3 %) 49 (14.0 %) ICU-free days through day 30, median (IQR) Conventional control (n=350; glycemia = mg/dl) 26.9 ( ) d 27.5 ( ) d Mechanical ventilation 19 (9 70) h 16 (9 46) h Crit Care Med 2018; 46:

11 Dysglycaemia in hospitalized patients Prevalence Mechanisms

12 The Relationship between Acute Illness and Hyperglycemia N Engl J Med 2006;355:

13 Glucose Administration Anesthesiology , Vol.114,

14 Lancet 2009; 373:

15 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences

16 Damages to mitochondrial proteins Shift from glycolysis to accessory metabolic pathways Formation of reactive oxygen species Toxicity associated with High Glucose Concentrations Protein glycosylation Inflammatory pathways Complement activity Endothelial & hepatic mitochondrial function Anesthesiology , Vol.114,

17 macrophage/neutrophil function coagulation and fibrinolysis superoxide production Benefits from Insulin Therapy levels of circulating adhesion molecules inducible nitric oxide synthase gene expression in post-mortem liver and skeletal muscle circulating nitric oxide levels protection of endothelial function Lipid control more than glucose control Diabetologia 2006; 49:

18 Diabetologia 2008; 51:

19 Diabetologia 2006; 49:

20 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences

21 1. Absolute or relative insulin excess 2. Inadequate or interrupted provision of exogenous carbohydrate 3. Critical illness that limit endogenous glucose production and accelerate glucose utilisation Exogenous insulin administration is necessarily imperfect and circulating insulin levels are largely unregulated by ambient glucose levels Normal minute-to-minute glucose-regulated endogenous insulin secretion Therapy Insulin is infused intravenously in doses based on blood glucose measurements at intervals of 1 4 h 1. responses of glucagon and epinephrine to falling glucose levels 2. Glucocorticoid deficiency 3. Lack of access to ingestion of food based on the perception of symptoms of hypoglycaemia 2. Sepsis 3. Hepatic, renal or cardiac failure 4. Drugs other than insulin 5. Human treatment error 1. Hypoglycaemia was identified statistically as an independent risk factor for death in the medical ICU 2. Iatrogenic hypoglycaemia may be the limiting factor in the glycaemic management of the critically ill, just as it is in the short- and long-term glycaemic management of diabetes Diabetologia 2006; 49:

22 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences Effects of macronutrients

23 25 patients admitted to a medicosurgical ICU Indirect Calorimetry Glucose metabolism and hepatic de Novo Lipogenesis were measured in the fasting state or after 3 d of continuous isoenergetic enteral feeding providing 28%, 53%, or 75% carbohydrate continuous (2 μg kg1 min1) IV infusion of [ 2 H 7 ]glucose continuous (0.1 mmol/min) intravenous infusion of NaH 13 CO 3 Infusion of [6,6-2 H]glucose via NGT Infusion of [1-13C]acetate 0.5 g/h Am J Clin Nutr 2000;72:940 5

24 Glucose appearance, endogenous glucose production, and gluconeogenesis in patients who received isoenergetic, isonitrogenous continuous enteral nutrition providing 28% (EN-28%), 53% (EN-53), or 75% (EN-75%) of energy as carbohydrate. Am J Clin Nutr 2000;72:940 5

25 Fractional hepatic de novo lipogenesis (DNL) in critically ill patients who had fasted for an average of 28 h (n = 5) or in patients who received isoenergetic, isonitrogenous continuous enteral nutrition providing 28% (EN-28%), 53% (EN-53), or 75% (EN-75%) of energy as carbohydrate Am J Clin Nutr 2000;72:940 5

26 Intermediary metabolism in patients receiving nutritional therapy The amount of lipid newly synthesized from glucose concomitant oxidation of fat DNL changes with high carbohydrate feeding irrespective of the of the route of substrate administration: EN or PN Inflammation mediators are unable to stimulate DNL in the absence of nutritional factors: DNL was virtually absent in fasted, critically ill patients Is there defective inhibition by insulin and glucose of gluconeogenic enzymes, but a normal insulin-induced activation of lipogenic enzymes critical illness? release of extrahepatic gluconeogenic precursors may be primarily involved in both the maintenance of a high rate of endogenous glucose production and stimulation of lipogenesis by carbohydrate in critically ill patients. Am J Clin Nutr 2000;72:940 5

27 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences Effects of macronutrients

28 Theoretical Biology and Medical Modelling (2016) 13:3

29 Theoretical Biology and Medical Modelling (2016) 13:3

Subcutaneous Lispro insulin mean glucose concentrations glucose variability in a nonlinear fashion In patients with high insulin resistance and nutrition at goal, rebound hyperglycemia

insulin mean glucose concentrations and glucose variability in a linear fashion No hypoglycemic episodes were noted It is better suited for a sliding-scale protocol The longer duration

30 Subcutaneous Lispro insulin mean glucose concentrations glucose variability in a nonlinear fashion In patients with high insulin resistance and nutrition at goal, rebound hyperglycemia was noted after the insulin analog was rapidly metabolized When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses Subcutaneous regular insulin mean glucose concentrations and glucose variability in a linear fashion No hypoglycemic episodes were noted It is better suited for a sliding-scale protocol The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial Theoretical Biology and Medical Modelling (2016) 13:3

31 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences Effects of macronutrients Unsolved issues

32 Unsolved issues in Stress hyperglycemia 1. Optimal BG target? 2. Are there categories of patients who could benefit most from IIT? 3. What is the optimal carbohydrate intake according to the type, severity of pathology, and delay from onset of disease? 4. What are the logistical requirements for safe and reliable glucose control? 5. Can we rely on continuous intravascular glucose monitoring and computerized automated algorithms for insulin infusión?

33 Dysglycaemia in hospitalized patients Prevalence Mechanisms Consequences Effects of macronutrients I wish this introduction has been useful for your practice Unsolved issues Thank you for your attention!

ESPEN Congress Lisbon Water and electrolytes. Hyperglycemia management. G Van Den Berghe

ESPEN Congress Lisbon Water and electrolytes. Hyperglycemia management. G Van Den Berghe ESPEN Congress Lisbon 2004 Water and electrolytes Hyperglycemia management G Van Den Berghe Intensive Insulin Therapy in ICU G. Van den Berghe M.D., Ph.D. Department of Intensive Care Medicine University