1. Hypoglycemia in the Hospital Sara Alexanian, MD Director, Inpatient Diabetes Program Department of Endocrinology, Diabetes and Nutrition

2. Agenda  Glycemic goals  Physiology  Epidemiology and risks of hypoglycemia  Preventing and avoiding hypoglycemia

3. Hyperglycemia in the Hospital: the Facts  Hyperglycemia is noted in 20-40% of hospitalized patients.  Hyperglycemia, irrespective of it’s cause, is unequivocally associated with adverse clinical outcomes.  Intervention studies directed at BG control have resulted in improved outcomes in some, but not all studies.  Insulin therapy, in particular (“intensive glycemic control”) carries a risk of hypoglycemia.

4. What are the recommendations for glucose control in the hospital?

5. AACE/ADA Target Glucose Levels in Non–ICU Patients  Non–ICU setting: –Premeal glucose targets <140 mg/dL –Random BG <180 mg/dL –To avoid hypoglycemia, reassess insulin regimen if BG levels fall below 100 mg/dL –Occasional patients may be maintained with a glucose range below and/or above these cut-points

6. AACE/ADA Target Glucose Level in ICU Patients  ICU setting: –Starting threshold of no higher than 180 mg/dL –Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL –Lower glucose targets (110-140 mg/dL) may be appropriate in selected patients –Lower glucose targets (110-140 mg/dL) may be appropriate in selected patients –Targets 180 mg/dL are not recommended Recommended 140-180 Acceptable 110-140 Not recommended <110 Not recommended >180 Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf.

7. Case #1   60 year-old female with a history of COPD admitted with respiratory failure, intubated, and started on tube feeds in the ICU.   The patient is started on an insulin drip to control glucose. After returning from a CT during which tube feeds were discontinued, her glucose is noted to be 55 mg/dL. The patient is asymptomatic, she is treated with dextrose and tube feeds are restarted. Question: What, if anything, does this low glucose mean for the patients’ prognosis?

8. Hypoglycemia: what and what is happening

9. Background 60-120 mg/dL glucagon Glucose insulin “fed” state “post-absorptive” state G G G G G G G G

10. Defining Hypoglycemia  Symptomatic hypoglycemia: symptoms and BG <70 mg/dL  Severe hypoglycemia: event requiring assistance from another person to administer treatment  Relative hypoglycemia: symptoms and BG >70 mg/dL in patient with chronically poorly controlled DM  Limited utility in studies <80<60<50<40<70

12. normal Counterregulatory hormone release Adrenergic symptoms Neuroglycopenic symptoms lethargy coma seizure 90 70 60 50 40 30 20 Hypoglycemia Symptoms

13. Chronic and Recurrent hypoglycemia

14. Hypoglycemia in Diabetes

15. Proposed mechanism of increased mortality  Prolonged, profound hypoglycemia can cause brain death.  Most deaths are presumed to be due to arrhythmia: –Hypokalemia –Sympathoadrenal activation –Prolonged QT

17. Potential mechanism of iatrogenic hypoglycemia- induced hypoglycemia-associated autonomic failure (HAAF) mediated sudden death in diabetes Cryer. Am J Med 24: 993-996, 2011

18. Inpatient Hypoglycemia: Frequency Hospital LocationFrequency SICU <40 mg/dL 1 5.1% MICU <40 mg/dL 1 18.9% SICU/MICU <40 mg/dL 2 0.34% ICU <40 mg/dL 3 16% ICU <45 mg/dL 4 6.8% ICU <81 mg/dL 5 13.8% Wards ≤50 mg/dL 6 7.7% 1. Van den Berge G et al, Intensive insulin therapy in mixed medical/surgical intensive care units. Diabetes 2006;55(11):3151-9. 2. Krinsley JS et al, The effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic Proc 2004;79(992-1000). 3. Arabi YM et al, Hypoglycemia with intensive insulin therapy in critically ill patients. Crit Care Med 2009;37(9):2536-44. 4. Vriesendorp TM et al, Evaluation of short term consequences of hypoglycemia in an ICU. Crit Care Med 2006;34(11)2714-8. 5. Bagshaw SM et al, the impact of early hypoglycemia and blood glucose variability on outcomes in critical illness. Crit Care Med 2009;13(3):R91. 6. Turchin A et al, Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward. Diabetes Care 2009;32(7):1153-7.

19. Inpatient Hypoglycemia: Mortality 1. Egi M et al, Hypoglycemia and outcomes in critically ill patients. Mayo Clin Proc 2010;85(3):217-24. 2. Bagshaw SM et al, the impact of early hypoglycemia and blood glucose variability on outcomes in critical illness. Crit Care Med 2009;13(3):R91 3. Van den Berge et al, Intensive insulin therapy in mixed medical/surgical intensive care units. Diabetes 2006;55(11):3151-9. 4. Kosiborod M et al, Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 2009;301(15):1556-64. 5. Turchin A et al, Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward. Diabetes Care 2009;32(7):1153-7. Hospital LocationNo hyposHypos ICU (<81 mg/dL) 1 19.7%36.6% ICU (<81 mg/dL) 2 15.5%25.6% ICU (≤40 mg/dL) 3 23%52% AMI (<60 mg/dl) 4 9.6%12.7% Wards (≤50 mg/dL) 5 0.82%2.96%

20. Bagshaw SM et al, the impact of early hypoglycemia and blood glucose variability on outcomes in critical illness. Crit Care Med 2009;13(3):R91 <36 mg/dL 38-44 45-52 53-62 63-70 71-80 ≥80

21. We hold these truths to be self- evident… is all hypoglycemia equal?

22. “Spontaneous” Hypoglycemia  Hypoglycemia occurring without prior insulin or anti-hyperglycemic therapy.  Increased in critical illness: mechanical ventilation, sepsis, renal insufficiency, higher APACHE II score.  Frequency: –26% of all ICU pts with hypoglycemia 1 –28% of patients admitted with acute MI 2 1. Krinsley JS et al, The effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic Proc 2004;79(992-1000). 2. Kosiborod M et al, Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 2009;301(15):1556-64.

23. Risk of therapy or marker of illness?  Treated with insulin?: AMI –Mortality with spontaneous hypoglycemia: 18.4%( increased from control) –Mortality of insulin-associated hypoglycemia: 10.4% (NO increase from control) Kosiborod M et al, Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 2009;301(15):1556-64.

25. Risk of therapy or marker of illness?  Correct for comorbid illness: –Study #1: case control correcting for age, sex, duration of ICU stay, APACHE II score: no association with incidental hypoglycemia and death (41% vs. 27%, not significant) 1. –Study #2: case control correcting for diagnosis, APACHE II, age diabetes history: Increase mortality associated with hypoglycemia (55.9% vs. 39.5%) 2. 1. Vriesendorp TM et al, Evaluation of short term consequences of hypoglycemia in an ICU. Crit Care Med 2006;34(11)2714-8. 2. Krinsley JS et al, The effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic Proc 2004;79(992-1000).

26. …but  Time from hypoglycemic episode to death: –221 hours (54-530 hours) 1 –152 hours (87-407 hours) 1 –11 days (0-204 days) 2 1. Van den Berghe, Intensive insulin therapy in mixed medical/surgical intensive care units. Diabetes 2006;55(11):3151-9. 2. Vriesendorp TM et al, Evaluation of short term consequences of hypoglycemia in an ICU. Crit Care Med 2006;34(11)2714-8.

27. Case #1   60 year-old female with a history of COPD admitted with respiratory failure, intubated, and started on tube feeds in the ICU.   The patient is started on an insulin drip to control glucose. After returning from a CT during which tube feeds were discontinued, her glucose is noted to be 55 mg/dL. The patient is asymptomatic, she is treated with dextrose and tube feeds are restarted. Question: What, if anything, does this low glucose mean for the patients’ prognosis? ?????

28. So…hypoglycemia is bad. However there is confounding from illness, and spontaneous hypoglycema. However, we should avoid it. So what can I do?

29. Know the Risk Factors  Advanced age  Slender and or longstanding diabetes  Malnutrition  Active cancer  Renal disease  Liver disease  Congestive heart failure  History of heavy alcohol intake  Chronic pancreatitis  Critical illness

30. Know who is at most risk to suffer adverse consequences  Inability to recognize or communicate hypoglycemic symptoms  Stroke patients  Dementia  Altered Mental Status: sedation, intubated, previous hypoglycemia

31. Treating your patients’ hyperglycemia  Always use weight-based insulin  Do not simply order a patients’ outpatient regimen if it does not appear safe. Beware of programs > 1 unit/kg/day.  Review your patients glucose levels at least twice per day  Consider a change if a glucose is <100.  Ask yourself, why is my patient low? Why is my patient high?

32. Case #2  76 yo M with DM2 on admitted from NH when found confused, BG 58 mg/dL.  Patient with prior CVA, CKD, HTN.  Labs on admit: BG 121, Cr 2.72 mg/dL, normal LFTs.  Weight: 98 kg.

33. Case #2  Outpatient program: glargine 45 units at HS, novolog 35 units prebreakfast and presupper.  Per NH, FS run 90-180  Most recent A1c 1 month ago 5.1%.

34. Case #2  What are the red flags here? –High outpatient dose –Low A1c –Dementia –CKD –Advanced age

35. What insulin program do YOU recommend? Average insulin need: 0.5 u/kg/day Advance age: -0.1 u/kg/day Renal insufficiency: -.0 1 u/kg/day Initial TDD : 0.3 u/kg/day 50% basal 15 units of glargine 50% nutritional 5 units lispro TID Correction CF 1:50, start at 200 HS 98 kg x 0.3 = apx 30 u/day

36. How did he do?  Fasting Bg on chemistry: 99 mg/dL  2 POC: 127 mg/dL, 157 mg/dL

37. Case #3  23 yo M with type 1 diabetes.  Weight: 58 kg  Inpatient insulin program: 16 units of glargine at HS, lispro 5 TID with meals, lispro SS. TDD: 30 units.

38. Case #3 C7 287 lunch 313 supper 330 Bedtime 257 MN >600 5:40 AM 30 Meal insulin and SS Lispro 9 SS Lispro 10 X 1 2:45 AM 405 Lispro 10 X 1 TDD 30 units/day

39. Truth and Consequences  Hyperglycemia is a common problem that requires treatment.  Insulin treatment carries a risk of hypoglycemia (even just “sliding scale”).  Both hyper- and hypoglycemia are associated with an increase in hospital mortality, hospital cost, and increase LOS.  Frequency of hypoglycemia can be mitigated by following current guidelines for BG targets, tailoring insulin programs, and being active in assessing your insulin program.

40. What can you do?  Critically evaluate your patients insulin program, on admission and daily.  Tailor your program to your patient  Be aware of insulin “stacking” and appropriate correction insulin doses  Always re-evaluate a program if the BG is low, and reconsider if <100.  Take the time to figure out what is happening.  Consult the GLUC or NP service if you need help.

41. Thanks!

42. What do i do for an insulin program?

44. Remaining Questions  What cutoffs should define hypoglycemia in studies?  How do we sort out the risk of iatrogenic hypoglycemia from hypoglycemia as a marker of disease?  How does hypoglycemia increase mortality?

45. Hypoglycemia in Patients with Diabetes: contributing factors  Medication/iatrogenic: insulin, sulfonylureas, meglitinides  Abnormal hormonal counter- regulation  Hypoglycemic unawareness  autonomic dysregulation  exercise

46. Hypoglycemia in patients with Diabetes: contributing factors  Medications/iatrogenic: insulin, sulfonylureas, meglitinides  Abnormal hormonal counter-regulation  Hypoglycemic unawareness  Renal and hepatic dysfunction  Autonomic dysregulation  Age  Exercise  Alcohol