Insulin : In-patient use

1. Insulin : In-patient use Novo Nordisk India, Bangalore

2. Insulin : In-patient use • Section 1: Background • Section 2: Advantages, indications, components • Section 3: Insulin IV infusion protocols • Section 4: Practical considerations • Section 5: Conclusion

3. Insulin : In-patient use Section 1: Background

4. Insulin : in-patient use – current status • Adults with diabetes • 6 times more likely to be hospitalized than those without diabetes • Hospitalized diabetic patients • often have poor glycemic control • increased susceptibility to complications • lengthening their hospital stays. • We all accept • importance of tight glucose control in outpatient settings • We do not appreciate • its importance in hospitalized patients

5. Reasons and consequence • Reason for admission • not diabetes • Infection, fever, surgery, intensive care • Consequence • Diabetes treatment becomes secondary • The above reasons impair insulin action • Steroid therapy commonly used in ICU and wards also impair insulin action

6. Clinicians’ perceptions about hyperglycemia in in-patients • Hyperglycemia is beneficial • brain & injured tissues require glucose • they don’t require insulin for glucose uptake • Treat hyperglycemia only if BG>215 mg/dl • BG<200 mg/dl is acceptable • We do not want hypoglycemia as a complication

7. Insulin: in-patient use - Summary • Hospital diabetes is suboptimally managed • There is a case for • promoting a more aggressive approach • developing a framework for attaining glycemic control in diabetic inpatients

8. Insulin : In-patient use Section 2: Advantages, indications and components

9. Why insulin and not OADs in hospitalized diabetics? (1) • OADs disadvantages in hospital • Sulfonylureas • Long-acting , hypoglycemia • Metformin • Renal impairment common in ICU/ward patients • Acarbose • Effective only with food • Glitazones • Not preferred in hospitalized cardiac patients

10. Why insulin and not OADs in hospitalized diabetics? (2) • Insulin - advantages in hospital • Short-acting • Easy switch-on & off • Substantial benefits irrespective of reason for admission • Inexpensive therapy • Reduces in-hospital stay • Reduces ICU complications • need for mechanical ventilation, blood transfusion • Acute renal failure, polyneuropathy (muscle wasting)

11. Indications for insulin in hospital • Diabetic ketoacidosis / HONK • Others • Poorly controlled diabetes despite regular treatment with/without insulin (BG>350 mg/dl) • Type 1 diabetes patients who are fasting or perioperative • Hyperglycemic postoperative ICU patients • Diabetic patients with myocardial infarction

12. Components of insulin therapy in hospital • Rehydration • Patients are given IV fluids (e.g. saline infusion) • Intravenous infusion of insulin (Actrapid®) • Each unit will have a protocol • Electrolyte correction • Irrespective of Serum K levels, DKA patients require K • All IV insulin therapy promotes K uptake along with glucose by body cells. • Any K-loss makes heart susceptible to arrhythmias • Most IV insulin thearpy will have added K • GIK (Glucose-Insulin-Potassium) infusion • Attention to cardiac and renal function

13. Insulin : In-patient use Section 3: Insulin IV infusion protocols

14. History • Sliding scales and earlier practices • Recommendations

15. History

16. History of acute dosing • Fixed dosing regimens • Subcutaneous injections • Subcutaneous infusions • Intravenous infusions • ‘Sliding scale’ regimens • Subcutaneous injections • Intravenous infusions • Intravenous infusion ‘algorithms’ • Eg. Post CABG, post-MI, critically-ill

17. Sliding scales and earlier practices

18. Sliding Scale Insulin (1) Subcutaneous ‘conventional’ example • Monitor [BG] q 4-6 h [BG] (mg/dL) Regular SC insulin < 70 1 amp D50W, specialist consultn 70 – 200 No insulin 201 – 250 2 U 251 – 300 4 U 301 – 350 6 U 351 – 400 8 U > 400 10 U, specialist consultn Arch Intern Med 1997;157:545-552

19. Sliding Scale Insulin (2) • Shortcomings • Queale et al, 1997, prospective cohort study • Inpatients receiving ‘sliding scale’ subcutaneous regimens • 23 % experienced hypoglycemia (≤ 60 mg/dL) • 40 % experienced hyperglycemia (≥ 300 mg/dL) • Patients receiving ‘sliding scale’ alone had 3x higher risk of hyperglycemia than those on standing regimen Arch Intern Med 1997;157:545-552.

20. Sliding Scale Insulin (3) • Shortcomings (contd.) • Non-physiologic strategy with a retrospective reaction to BG • Arbitrary thresholds of goal BG require hyperglycemia before any intervention • Fails to incorporate basal requirements and cannot predict dosage requirements • Promotes glucose ‘roller coaster’ • Failure to re-evaluate promotes poor titration and reinforces ‘ignorance is bliss’ • Patients rate control as only ‘fair’

21. Sliding Scale Insulin (3) • Shortcomings (contd.) • Does anyone here know how to make insulin work backwards?” • “…invented by a ‘take it easy’ mind.” • “…sliding scale orders do not serve any • purpose other than sugar-coating the physician’s clinical deficiencies.” • “Action without benefit.” Arch Intern Med 1997;157:489 Practical Diabetol 1990;9:1-4 Arch Intern Med 1998;158:1472

22. Sliding Scale Insulin (3) • Call to action against the lip service paid to inpatient diabetes care • Call for the banning of the insulin sliding scale use as the sole diabetes order J Gen Intern Med. 2004 May;19(5 Pt 1):466-71.

23. Sliding Scale Insulin (4) IV infusion example • Start infusion at 1.0 U/hr • Monitor [BG] q 2 h • [BG] (mg/dL) Regular IV insulin • < 70 D/C infusion, give glucose • 71 – 110 ↓ rate by 0.6 U/hr • 111 – 150 ↓ rate by 0.3 U/hr • 151 – 200 No change • 201 – 250 ↑ rate by 0.3 U/hr • 251 – 300 ↑ rate by 0.6 U/hr • > 300 Bolus 8 units IV, ↑ by 1.0 U/hr

24. Sliding Scale Insulin (4) Early IV infusion algorithms - impact • Hyperglycemic Crises • IV infusion algorithm reduced the risk of hypoglycemia vs. conventional therapy 5 % vs. 23 % (p < 0.01) • Post-surgical patients • IV infusion algorithm reduced BG to between 120 - 180 mg/dL within 8 hours Arch Intern Med 1997;157:669-75; Diabetes Care 1987;10:722-8

25. Recommendations

26. Recommended infusion algorithms • For diabetics undergoing surgery • European Diabetes Policy Group, 1991 • Clinical Outcome Studies • Post-CABG • ‘Portland’ Protocol (150 – 200 mg/dL) • Post-MI • ‘DIGAMI’ Protocol (126 – 196 mg/dL) • Critically-ill • ‘Leuven’ Protocol (80 – 110 mg/dL)

27. Diabetics undergoing surgery - EDPG, 1991 recommendation (1) General instructions • Surgeries and procedures should be scheduled for the early morning, • when they will have the least effect on the patient’s treatment program. • Blood glucose levels should be monitored q1h/q2h • before, during, and after surgery or procedure. • Sliding scale • discouraged • greater likelihood of wider fluctuations in blood glucose levels, especially in type 1 diabetic patients

28. Diabetics undergoing surgery - EDPG, 1991 recommendation (2) • Type 1 diabetes • Place on an insulin drip (maintenance rate, 1 to 2 U/h) with a 5% dextrose solution at 75 to 125 cc/h, adjusted to maintain blood glucose levels between 100 and 150 mg/dL. • Alternatively, give 1/2 to 2/3rd of the usual dose of long-/intermediate-acting insulin on the morning of procedure. • Type 2 diabetes, taking an oral hypoglycemic agent • Hold the medication on the day of procedure and resume when tolerating a normal diet. • Metformin must be held for safety concerns (i.e., possible perioperative alteration in renal function) - resumed 48 h postoperatively after normal renal function is secured • Alpha-glucosidase inhibitors - because these drugs are effective only when taken with meals • If pills are allowed, thiazolidinediones can be continued, although, due to their prolonged action, missing a dose or two should not affect glycemic control. • Type 2 diabetes, treated with insulin • Give one half of long-/intermediate-acting insulin on the morning of procedure.

29. Diabetics undergoing surgery - EDPG, 1991 recommendation (3) • Use 500 ml 10 % ( 100 g/l ) glucose ( dextrose ) containing : • Human Actrapid 16 U • potassium chloride 10 mmol • Infuse at 80 ml/h • Consider higher dose ( 20 U ) if obese, or initial blood glucose high • Consider lower dose ( 12 U ) if very thin, or usual insulin dose low • Decrease dose by 4 U if glucose falling and normal or low • Increase dose by 4 U if glucose rising or high • Continue the GIK infusion until 30-60 min after first meal • Use higher strength glucose solutions if water volume a problem • Check for dilutional hyponatraemia daily

30. Post-CABG - ‘Portland’ Protocol (1) • Initiation ‘Goal’ 150 – 200 mg/dL BG (mg/dL) Insulin (units/hr) < 150 0 150 – 200 1 201 – 250 2 > 251 3 • Monitoring • Q 1 h until BG 125-175 mg/dL with < 15 mg/dL change • and infusion rate unchanged x 4 hours, then q 2 h • Q 30 min when weaning vasopressors (epi) • May stop q 2 h testing on post op day 3 Ann Thorac Surg 1999;67:352-362

31. Post-CABG - ‘Portland’ Protocol (2) Titration

32. Post-MI - DIGAMI protocol (1) • Reasons why cardiologists have not taken up glucose -insulin infusion • Supply of Glucose means ATP is required for its cellular uptake. This means ATP required for myocardium may be diverted elsewhere • Increased glucose means increased lactic acid accumulation in myocardial cells • Prior trials • Large number, small sample size, low doses of GIK, conflicting reports and inconclusive • No pharmaceutical sponsors for GIK

33. Post-MI - DIGAMI protocol (2) • “Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction” study • Swedish study of 1990s • Participants • acute MI and diabetes (FPG > 198 mg/dl) • randomly assigned to either to IV insulin and glucose for at least 24h • followed by • daily insulin injections 4 times-a-day for the next 3 months or • conventional therapy

34. Post-MI - DIGAMI protocol (3) • Study question: whether mortality was decreased by tight control both initially and if continued over time. • The results showed that insulin-glucose infusion followed by intensive subcutaneous insulin in patients with acute MI and diabetes improves long-term survival. • The mortality reduction was 30% in the treatment group vs controls • This reduced mortality was maintained at a mean follow-up of 3.4 years

35. Post-MI - DIGAMI protocol (3) • Prepare infusion mixture as follows: • Add 80 iu soluble insulin to 500 ml 5 % glucose • Infuse initially at 30 ml per hour • Measure blood glucose every 1-2 h • Titration steps > 15 mmol/L Give 8 iu soluble insulin as iv bolus increase infusion rate by 6 ml/h > 11 -14.9 Increase infusion rate by 6 ml/h > 7 - 10.9 Maintain current rate > 4 - 6.9 Decrease infusion rate by 6 ml/h < 4 Stop infusion until glucose > 7 mmol/l Give 20 - 30 ml glucose iv if symptomatic hypoglycemia Restart infusion with rate decreased by 6 ml/h J Am Coll Cardiol 1995;26:57-65

36. Post-MI - DIGAMI protocol (3) Maintenance and follow-up • Continue the insulin infusion till stable normoglycemia and maintained for > 24 hour • Later, start subcutaneous insulin administration • Regimen • Human Actrapid three times a day before meals • Human Insulatard (NPH) in the evening (to provide overnight basal insulin requirement) • Adjust dose by periodic blood glucose estimations. J Am Coll Cardiol 1995;26:57-65

37. Critically ill - Leuven protocol (1) • Study challenged all existing perceptions about hyperglycemia as myths • Hypothesis: All ICU cases require insulin • Aggressively lower BG < 110 mg/dl • Benefits of intensive insulin so good that study was stopped midway and all patients given intensive insulin • Mortality reduction 40%

38. Critically ill - Leuven protocol (2) • Initiation ‘Goal’ 80 – 110 mg/dL BG (mg/dL) Insulin (units/hr) • > 110 2 • > 220 4 • Initial titration [BG] (mg/dL) Insulin (units/hr) • 80 - 110 No change • 110 – 140 ↑ by 1 unit/hr • > 140 ↑ by 2 unit/hr • Monitor [BG] q 1-2 h initially, q 4 h once patient stable N Engl J Med 2002;346:1586-8, Supplementary Appendix 1

39. Critically ill - Leuven protocol (3) If [BG] ↓ by > 50% after dosage adjustment, ↓ infusion rate, monitor [BG] more frequently Maximal arbitrary dose is 50 units/hr At ICU discharge, d/c protocol, adopt BG goal of 200 mg/dL N Engl J Med 2002;346:1586-8, Supplementary Appendix 1

40. Guidelines (1): ACE American College of Endocrinology • Hyperglycaemia is common • Tight metabolic control is important • Upper limit for glycemic targets in ICU: 110 mg/dl • Insulin- currently the only available agent for effectively controlling glycemia in hospital • Protocols for CII therapy have been shown to be safe & effective in achieving glucose targets • Surgical pts. discharged from ICU to lower –acuity units- glucose levels should be maintained as close as possible to normal either by intensive SQ therapy or preferably by continuation of IV insulin therapy if possible ACE position statement on in patient diabetes & metabolic control, Endocr Pract. 2004;10(1):77-82

41. Guidelines (2): ADA • The only method of insulin delivery specifically developed for use in the hospital is continuous intravenous infusion, using regular crystalline insulin • IV route for insulin administration surpasses s.c. route w.r.t. • rapidity of onset of effect in controlling hyperglycemia • overall ability to achieve glycemic control • most importantly, nonglycemic patient outcomes • During IV insulin infusion used to control hyperglycemic crises, hypoglycemia (if it occurs) is short-lived, whereas in the same clinical settings repeated administration of subcutaneous insulin may result in “stacking” of the insulin’s effect, causing protracted hypoglycemia Clement S et al. Diabetes Care Feb 2004; 27(2):553-91

42. Insulin : In-patient use Section 4: Practical considerations

43. Practical considerations (1) • Desirable IV insulin (Actrapid®) infusion protocols • Diabetic Ketoacidosis • For diabetics undergoing surgery • For diabetics who have a AMI • For all ICU patients

44. Practical considerations (2) • We need to overcome these • Limitations of literature • Not applicable to many populations • Safety concerns over widespread application • Lack of simple, easy to use algorithms • The implementation will improve with these • Consider enrolment in clinical trials • Multidisciplinary approach • Monitoring is paramount

45. Practical considerations (3) Monitoring - Hyperglycemia • Vitals: • Temp, BP, HR, RR • Physical examination: • Fatigue, drowsiness, obtundation, coma • Blurred vision, dry eyes/mouth/mucus membranes • Weak, rapid pulse • Deep, labored breathing, acetone breath • Polyphagia, polydipsia, polyuria • Flushed, dry skin • Labs: • BG, ketones, electrolytes, BUN, Cr, urine electrolytes, osmolarity and urinalysis prn

46. Practical considerations (4) Monitoring – Hypoglycemia • Vitals: • Temp, BP, HR, RR • Physical examination • Irritability, anxiety, tremors, confusion, weakness, • fatigue, dizziness, drowsiness, obtundation, coma • Headache, visual changes, diaphoresis, moist mucusmembranes, tingling lips, slurred speech • Rapid bounding pulse • Hunger or abdominal pain • Pale, moist cool skin • Labs: • BG, electrolytes

47. Insulin : In-patient use Section 5: Conclusion

48. Conclusions (1) • We all accept importance of tight glucose control in outpatient settings • We must appreciate its importance in hospitalized patients • ‘Sliding scale’ subcutaneous insulin is suboptimal • Intravenous dosing with early algorithms • safer and more effective than subcutaneous dosing • Insulin infusion algorithms used in clinical trials • effectively control BG and improve outcomes in acutely-ill patient subgroups

49. Conclusions (2) Let us focus on better practices………… • Routine ward cases • any diabetic admitted in a ward for reasons other than diabetes • Diabetics who undergo surgery • Any surgery • Diabetics who have AMI • along with routine thrombolysis • Intensive care units • All cases (even non-diabetics) because of stress hyperglycemia

50. Conclusions (3) • Irl B. Hirsch “Indeed, inpatient diabetes management has developed into an area of medicine that is less evidence-based and more of an ignorance-based culture with a core component of sliding scale insulin, a relic from generations past with no proven efficacy” J Clin Endocrinol Metab 2002;87:976.