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Insulin : In-patient use

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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 I’ll be presenting the topic under these 5 sections

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 This slide discusses the current status of mangement of hospitalized diabetic 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 Here we discuss the reasons and consequence of the current status discussed in the previous slide

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 More than the reasons recounted in the previous slide, these perceptions are probably responsible for the current status

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 These summarize the current status and build our case for the current topic

8 Insulin : In-patient use
Section 2: Advantages, indications and components Let us begin by looking at the advantages, indications and components of insulin therapy for in-patients

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 This slide recounts the obvious reasons for not considering oral antidiabetic drugs for hospitalized diabetics

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) These are the advantages of insulin for hospitalized diabetics

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 These are the standard indications for insulin use in hospital

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 This in a nutshell are the components of insulin therapy in hospital.

13 Insulin : In-patient use
Section 3: Insulin IV infusion protocols In this section, we will explore the various Insulin IV infusion protocols

14 Sliding scales and earlier practices Recommendations
History Sliding scales and earlier practices Recommendations Since Insulin IV infusion are yet a evolving subject, the last word is still to be written, I’ll discuss the topic under these heads.

15 History The history.

16 History of acute dosing
Fixed dosing regimens Subcutaneous injections Subcutaneous infusions Intravenous infusions ‘Sliding scale’ regimens Intravenous infusion ‘algorithms’ Eg. Post CABG, post-MI, critically-ill This is how IV insulin infusion has evolved. from fixed dosage regimens to sliding scales to the various protocols published as clinical trial reports in standard literature.

17 Sliding scales and earlier practices
We’ll now look at sliding scales, earlier practices based on sliding scales and their shortcomings

18 Sliding Scale Insulin (1)
Subcutaneous ‘conventional’ example Monitor [BG] q 4-6 h [BG] (mg/dL) Regular SC insulin < amp D50W, specialist consultn 70 – No insulin 201 – U 251 – U 301 – U 351 – U > U, specialist consultn Arch Intern Med 1997;157: This is the classical sliding scale we all know and may have practised or still practising

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: Literature comes down quite heavily on sliding scales as presented here and the next two slides

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’ see previous slide

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 see previous slide

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 May;19(5 Pt 1):

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 – No change 201 – ↑ rate by 0.3 U/hr 251 – ↑ rate by 0.6 U/hr > Bolus 8 units IV, ↑ by 1.0 U/hr How about a sliding scale infusion

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 mg/dL within 8 hours Arch Intern Med 1997;157:669-75; Diabetes Care 1987;10:722-8 The impact of these early infusion algorithms indeed was better

25 Sliding Scale Insulin (4)
IV infusion vs. Subcutaneous dosing Hyperglycemic Crises IV infusion had faster decline in BG and ketones within first 2 hours Lower incidence of hypoglycemia and hypokalemia Simpler and more convenient Post-surgical patients IV infusion had better control of BG during surgery and post-op days 1-3 Proportion of patients with target BG twice as high N Engl J Med 1977;297:238-41 J Pediatr 1977;91:701-5 Anaesthesia 1988;43:533-7. And the betterment came about in these ways

26 Recommendations Having looked at the history and sliding scales, let us now look at some standard IV infusion protocols which could be the “recommendations” going by the current level of evidence-based approach to the topic

27 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) These are the ones which could be recommended. Let us look at each one individually.

28 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 This and the next 2 slides contain recommendation on IV insulin infusion for diabetics posted for surgey. These are generally applicable.

29 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. And these are specific to type 1 and type 2 diabetics prior to surgery.

30 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 min after first meal Use higher strength glucose solutions if water volume a problem Check for dilutional hyponatraemia daily This is Prof Alberti’s protocol followed by most and recommended by the European diabetes policy group

31 Post-CABG - ‘Portland’ Protocol (1)
Initiation ‘Goal’ 150 – 200 mg/dL BG (mg/dL) Insulin (units/hr) < 150 – 201 – > Monitoring Q 1 h until BG 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: This is the famous Portland protocol for post-CABG patients. This is how IV insulin was initiated.

32 Post-CABG - ‘Portland’ Protocol (2)
Titration These were the titration steps

33 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 Now we come to the famous DIGAMI protocol from the Swedish group of Malmberg et al. But first, let us look at reasons why cardiologists have still not taken up GIK infusions

34 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 However DIGAMI changed all that. What was DIGAMI?

35 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 These were the study questions and the answer

36 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 > Increase infusion rate by 6 ml/h > Maintain current rate > Decrease infusion rate by 6 ml/h < 4 Stop infusion until glucose > 7 mmol/l Give ml glucose iv if symptomatic hypoglycemia Restart infusion with rate decreased by 6 ml/h What was the protocol itself? These were the titration steps J Am Coll Cardiol 1995;26:57-65

37 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. These were the maintenance and follow-up recommendations J Am Coll Cardiol 1995;26:57-65

38 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% Finally, we look at the Leuven protocol. This is a famous paper Published in New England Journal of Medicine Nov 2001, the study challenged all doctors’ perceptions about hyperglycemia as myths. Leuven is a place in Belgium and some of you might have heard the main author Greet van den Berghe, a lady doctor and a intensive care specialist who has visited India and spoken about her study at a past NNDU. Leuven study was sponsored by Novo Nordisk.

39 Critically ill - Leuven protocol (2)
Initiation ‘Goal’ 80 – 110 mg/dL BG (mg/dL) Insulin (units/hr) > > Initial titration [BG] (mg/dL) Insulin (units/hr) No change 110 – ↑ by 1 unit/hr > ↑ 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 This is the protocol.

40 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 The protocol appeared exclusively as a special supplement as there was a great demand from the readers of the main study paper in the journal. N Engl J Med 2002;346:1586-8, Supplementary Appendix 1

41 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

42 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

43 Insulin : In-patient use
Section 4: Practical considerations Let us look at some practical aspects of implementing these protocols in our hospitals

44 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 All institutions must develop these IV insulin infusion protocols that are desirable in all our hospitals

45 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 We need to overcome a few of these and then improve implementation

46 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 These are a few tips to monitoring hyperglycemia

47 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 And these to monitor hypoglycemia

48 Insulin : In-patient use
Section 5: Conclusion

49 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 Let me conclude with these statements

50 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

51 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. And a quoteworthy quote

52 And a quoteworthy quote
Thank You

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