Hyperglycemia in the Hospital

1. Hyperglycemia in the Hospital

2. Case Example 68 y/o female admitted with several days of chest pain. PMHx notable for DM, last A1C 9.6, , HTN, hyperlipidemia Meds: Glyburide 1000 bid, Lisinopril 20 mg bid; Metoprolol 25 bid PE Afeb 142/94 P 110 Lungs: basilar rales. Cor: Tachy No murmurs EKG ST elevation II, III AVF, WBC 6.3, Glu 258, Cr 1.4, ECHO; inferior hypokinesis, EF 38% Admitted CICU: Glyburide was held, ASA Lovenox added, B-blocker increased; Cath and stented in RCA for near total occlusion Sliding Scale Regular: 150-200 2units; 201-150 4 units, 251-300 6 units; 301-350 8 units, 351-400 10 units, >400 call House Officer Hospital Course: Stabilized in 48 hours PO intake adequate Glucose day 2: 280 (serum) Glucose day 3: 245 (serum) Unclear fingerstick values, ordered but not commented on in chart Difficult to find amount of insulin given with sliding scale Discharge day 6 on Glyburide to follow-up with Primary Care Physician

3. Inpatient Hyperglycemia Prevalence: 20% or higher higher in teaching hospitals Effects Immune function Small studies, various populations Phagocyte dysfunction Pathway alteration Reduced superoxide formation from aldose reductase, alterations Protein kinase C, and other mediators Phagocyte adherence, chemotaxis, and bacterial killing decreases with increasing glucose In vitro study that suggests this starts with glu > 200 Phagocyte adherence, chemotaxis, and bacterial killing decreases with increasing glucose In vitro study that suggests this starts with glu > 200

4. More effects Heart � Acute Hyperglycemia Impairs ischemic preconditioning, protective mechanism limits infarct size induce myocyte death through apoptosis exaggerates ischemia reperfusion injury cellular injury Thrombosis increased Increased platelet activation Inflammation Increases variety of factors IL-6, TNF-alpha, Nuclear Factor (NF)-kB Linked to detrimental vascular effects Endothelial cell dysfunction inhibits vasodilatation For example, TNF-alpha extends the area of necrosis following LAD coronary artery ligation in animals Inhibits vasodilatation by inhibiting NOFor example, TNF-alpha extends the area of necrosis following LAD coronary artery ligation in animals Inhibits vasodilatation by inhibiting NO

5. Even More Effects Brain enhanced neuronal damage increased tissue acidosis and lactate levels accumulation glutamate predicts neuronal damage Oxidative Stress Direct tissue damage or activation of mediators Enhanced neuronal degeneration through ischemic animal studiesEnhanced neuronal degeneration through ischemic animal studies

6. Is there a threshold? General Surgery Observational 97 pts. with DM undergoing surgery Blood glucose > 220 POD #1 predicted infections Gen Med - Review 2030 admissions Normoglycemia 108 mg/dl New Onset Hyperglycemia (12%) 189 mg/dl Diabetic Patients (26%) 230 mg/dl Results � Mortality Surg:Infections: sepsis, wound, and pneumonia 5.7x; uti excluded Gen Med: Hypergly fasting >126 or random > 200; Mortality: 16% or 18 fold new onset hyperglycemia, 3% DM, and 1.7% normoglycemia � all significant Included all causes of hyperglycemia, undx. diabetes, uncontrolled diabetes, stress induced Both studies were observation and not controlledSurg:Infections: sepsis, wound, and pneumonia 5.7x; uti excluded Gen Med: Hypergly fasting >126 or random > 200; Mortality: 16% or 18 fold new onset hyperglycemia, 3% DM, and 1.7% normoglycemia � all significant Included all causes of hyperglycemia, undx. diabetes, uncontrolled diabetes, stress induced Both studies were observation and not controlled

7. Cardiac Studies Meta-analysis of 15 studies of AMI patients (Capes, et al) and admission glucose values threshold 110 for patients w/out DM; Rel Risk is 3.9 in-hospital mortality threshold 180 for patients with DM; Rel Risk is 1.7 in-hospital mortality Consecutive admissions of all patients with AMI (Bolk, et al) 1 year mortality was about 20% for glucose < 100 and rose to 44% for glucose > 200 Diabetes and Insulin-Glucose Infusion in Acute MI: [DIGAMI, Malberg, et al, 1995]: prospective : 620 DM with AMI, Randomized Intervention: Maintain Glucose 126-196, followed intensive outpt SQ Insulin results: baseline glucose 270's, decreased to 170 within 1st 24 hrs vs 210 control Hospital mortality (12% vs. 5%;) Rel. reduction 58% p<0.05 One year mortality was 26% vs. 19%. p<0.05 AMI: 110 mg/dl RR is 3.9 in-hospital mortality 180 risk of death increased 1.7 Consecutive admissions -- all comers -- for AMI with follow-up 14 months, 1 year mortality was about 20% for glucose < 100 and rose to 44% for glucose > 200; observational study DIGAMI: prospective trial of insulin glucose infusion followed by SC insulin in DM pts. with AMI. Basline glu 270's, decreased to 170 within 1st 24 hrs vs 210 One year mortality was 19% vs. 26%.AMI: 110 mg/dl RR is 3.9 in-hospital mortality 180 risk of death increased 1.7 Consecutive admissions -- all comers -- for AMI with follow-up 14 months, 1 year mortality was about 20% for glucose < 100 and rose to 44% for glucose > 200; observational study DIGAMI: prospective trial of insulin glucose infusion followed by SC insulin in DM pts. with AMI. Basline glu 270's, decreased to 170 within 1st 24 hrs vs 210 One year mortality was 19% vs. 26%.

8. Two more studies (DIGAMI 2, CREATE-ECLA, 2005) used an insulin-glucose infusion showed that blood glucose levels were positively correlated with mortality although this was not reduced. Malberg et al. DIGAMI 2, Eur Heart J 26:650-661,2005 Mehta et al, CREATE-ECLA JAMA 293:437-446,2005 More Cardiac Studies

9. Cardiac Surgery Observational study 1987-1991: SC Insulin 1991-1998: IV Insulin: Target 150-200 1999-2000: IV Insulin: Target 125-175 2001-2003: IV Insulin:Target 100-150 Trends for decreased wound infection and hospital mortality Showed the various historical treatments for DM undergoing cardiac surgery 1987-1991 � no target glucose Showed the various historical treatments for DM undergoing cardiac surgery 1987-1991 � no target glucose

10. Critical Care Randomized Controlled Trial 1548 SICU patients on Mechanical Ventilation Intensive Insulin Tx. Target 80-110 Conventional Target 180-200 Results: Reduction in-hospital mortality 34%, linear association, both DM and non-DM 60% admission were cardiac surgery conventional group: tx only if >215 60% admission were cardiac surgery conventional group: tx only if >215

11. Critical Care MICU study, similar to SICU protocol studied one group with intensive insulin tx (mean glucose 110) vs. conventional tx (mean 160) Reduced morbidity and reduced mortality for patients treated > 3days but unable to identify prospectively [van der Berge G. intensive insulin tx in the MICU, NEJM 354:449-461, 2006]

12. Neurology Observational Studies In general, hyperglycemia assoc. with worsened outcomes in stroke and head injury Glucose Insulin Stroke Trial GIST Assess safety of lowered glucose in acute stroke target 72-126 mg/dl appeared acceptable No data suggests control improves clinical outcomes The American Heart Association/American Stroke Association guidelines recommend treatment with insulin in patients glucose concentrations >140 to 185 mg/dL European Stroke Initiative guidelines recommend treatment for glucose >180 mg/dL European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis 2003;16(4):311-37. Is there a threshold for stroke patients? acceptable: no increased risk of hypoglycemia or mortality; however still considered experimentalIs there a threshold for stroke patients? acceptable: no increased risk of hypoglycemia or mortality; however still considered experimental

13. Common Errors in Management Admission Orders Usually continued from outpatient regimen: Failure to modify High Glycemic Targets ADA for hospitalized patients: Preprandial: less than 110 Postprandial: less than 180

14. Common Errors in Management Lack of Therapeutic Adjustment Day of discharge, team realizes patient has been on regular insulin during entire hospital stay Overutilization of Sliding Scales Underutilization of Insulin Infusions Sliding scales when defined as regular insulin alone have actually been shown to increase mortality in some studies.Sliding scales when defined as regular insulin alone have actually been shown to increase mortality in some studies.

15. What�s our practice at Wade Park? DM inpatient nurse managers Monitor all patients who have a glucose less than 70 Nurse run inpatient programs are the trend Improved patient satisfaction Reduced length of stay Sampson, et al. Trends in bed occupancy for inpatients with diabetes before and after the introduction of a diabetes inpatient specialist nurse service. Diabetic Medicine: 23, 1008-1015 (2006)

16. Summary: ADA Major recommendations for hospital management of hyperglycemia Target plasma Glucose: <110 preprandial and <180 postprandial, flexible Scheduled insulin improve blood glucose control compared to sliding scale alone Intensive IV insulin tx, goal of glucose 80-100, may reduce morbidity and mortality among critically ill patients but risk of hypoglycemia IV insulin infusion is safe and effective (not available on Wards yet) Team based approach with std. hospital protocols reduces hyper and hypo-glycemics events Essential components are education, nutrition tx and proper discharge planning

17. How to achieve target levels ? Oral hypoglycemics do not allow rapid dose changes may be contraindicated Metformin, TZD�s Insulin: Sliding Scale without other intermediate or long acting insulins Ineffective vs. Dangerous Not modified during admission Treats after the fact Reason that no regular insulin is given at bedtime Metformin: CHF, Renal Failure, states of hypoxia and hypoperfusion; Thiazolidinediones: CHFMetformin: CHF, Renal Failure, states of hypoxia and hypoperfusion; Thiazolidinediones: CHF

18. Conceptualizing Insulin Basal Infusion, NPH, Glargine Prandial/Nutritional Regular, Lispro and Aspart Carb Counting Correction - �functional� sliding scale Basal: Amount of Insulin required when food is not being absorbed Prandial: Amount of insulin in relation to normal meals Correction dose: Supplemental; amount of insulin given to hyperglyemia associated with meals � given in addition to prandial doseBasal: Amount of Insulin required when food is not being absorbed Prandial: Amount of insulin in relation to normal meals Correction dose: Supplemental; amount of insulin given to hyperglyemia associated with meals � given in addition to prandial dose

19. Pharmacokinetics NPH Onset: 2-4 hours Peak 4-10 hours Duration 12-18 hours Glargine Onset: 2-4 hours Peak None Duration 20-24 hours

20. Pharmacokinetics Regular Onset: 30-60 minutes Peak: 2-3 hours Duration 8-10 hours Lispro Onset: 5-15 minutes Peak: 30-90 minutes Duration: 4-6 hours

21. Insulin Infusion Insulin infusion started at 1 unit/hr � assumption that 50% of the ambulatory daily insulin dose is the basal requirement may also be used to estimate initial hourly requirements --- Alternatively, 0.02 units/kg per hr Use lower rate for patients with renal or hepatic failure Check glucose q. hour until stable about 6-8 hours; then every 2-3 hours Transition to SQ insulin No priming bolus necessary Transition � Give short acting insulin 1-2 hours SC prior to d/c Give long acting 2-3 hours No priming bolus necessary Transition � Give short acting insulin 1-2 hours SC prior to d/c Give long acting 2-3 hours

22. Example of standardized Insulin ordersExample of standardized Insulin orders

24. Calculating Insulin Dose 1. Start with 70% (60% if EGFR<60) of Total home Daily Dose. 2. If not on insulin at home, then estimate the total daily dose based on 0.4 units/Kg. 3. In general, half can be given as long acting and half can be given pre- meals. 4. In case of NPH (which is � the total daily insulin), split the dose by 2 and give q AM & q HS. 5. In case of Glargine (which is � the total daily insulin) give the full dose at bedtime. 6. Short acting insulin (which is � the total daily insulin) can be divided by three and given prior to meals. 7. Supplemental Sliding scale is added to the prandial dosages. 8. If patient is NPO, then only � the long-acting insulin should be used. 9. Continuous Tube Feeding Reg Insulin q. 6 hours, Bolus tube feeding bolus Reg insulin or consult Endocrinology

25. Case Example Revisited 68 y/o female admitted with several days of chest pain. PMHx notable for DM, last A1C 9.6, , HTN, hyperlipidemia Meds: Glyburide 10 bid, Lisinopril 20 mg bid; Metoprolol 50 bid PE Afeb 142/94 P 110 Lungs: basilar rales. Cor: Tachy No murmurs EKG ST elevation II, III AVF, WBC 6.3, Glu 258, Cr 1.4, ECHO; inferior hypokinesis, EF 38% Admitted CICU: Glyburide was held, ASA Lovenox added, B-blocker increased; Cath and stented in RCA for near total occlusion Sliding Scale Regular: 150-200 2units; 201-150 4 units, 251-300 6 units; 301-350 8 units, 351-400 10 units, >400 call House Officer

26. More Cases 78 y/o woman with DM type 2, A1c 7.6, takes Metformin 1g bid and 10mg glyburide, admitted with USA. Cath to occur in AM, npo after midnite. Admission Glucose 132. How should she be treated?

27. More cases (cont) If pt. npo, hold oral agents D/C Metformin until 48 hours after procedure* Patient should be monitored off meds and given her hx. of controlled DM should not require insulin *not evidenced based medicine, more consensus based*not evidenced based medicine, more consensus based

28. More cases (cont) 61 y/o male with 12 yr. Hx DM type II, hospitalized with LLE cellulitis. Outpt. Meds are Glyburide 10 BID and Metformin 1 g bid. Admission Glucose is 248 and HbA1c 11.4 How to treat this patient?

29. More cases (cont) Hospitalization offers opportunity to change regimen Value of adding TZD? Consult Nutritionist Bedtime NPH Insulin