1. Inpatient Glucose Control
Resident’s conference
Ghana Kang, R2
9/13/2011

2. Hyperglycemia and hospitalization
A recent survey estimated that 22% of all hospital inpatient days were incurred by people with diabetes and that hospital inpatient care accounted for half of the $174 billion total US medical expenditures for this disease
It’s estimated that 12-25% of patients who are in hospital beds have diabetes or some degree of hyperglycemia.
Of patients in the cardiac care unit, one out of two may have diabetes or glucose intolerance.

3. Hyperglycemia and hospitalization
3 possible reasons
Patients who have a previous diagnosis of DM are admitted to the hospital for a reason other than diabetes
Hospitalization is an opportunity to evaluate long-term diabetes control and initiate new therapy
Patients may have undiagnosed diabetes
Hospitalization provides an opportunity to make the diagnosis and initiate long-term care
Patients may have transient hyperglycemia in response to the stress of illness or due to treatments such as high- dose corticosteroids.
Hyperglycemia usually resolves by the time of discharge, but these patients may need long-term f/u because many have some degree of glucose intolerance.

4. Glucose measurement

5. Glucose Measurement Methodologies
The small and colorless glucose molecule is very difficult to measure directly. Therefore, all marketed glucose measurement devices use indirect measurement methods.
All techniques are enzymatic, with measurement of byproducts by optical or electrochemical methods. Byproduct formed is directly proportional to the amount of glucose present.
Hexokinase: used most commonly in central laboratory devices.
Glucose oxidase (GO)
Glucose-1-dehydrogenase (GDH)
A second GDH-based measurement system with steadily increasing market share, Glucose-1-dehydrogenase pyrroloquinolinequinone (GDH-PQQ) is more nonspecific for glucose.
May yield falsely high glucose readings in the presence of maltose, xylose, or galactose

6. Andrew D. Pitkin, et al., Challenges to Glycemic Measurement in the Perioperative and Critically Ill Patient: A Review, J Diabetes Sci Technol 2009;3(6):

7. Factors affecting accuracy of glucose measurement 1. Terminology
A potential error in current practice arises from the use of blood and plasma glucose as interchangeable terms, with the consequent risk of misinterpretation.
The glucose concentration in plasma is approximately 11% higher than that in whole blood because plasma is denser than whole blood
(55%)
(45%)
(<1%)
A mutiplier of 1.11
for the conversion of glucose
in blood to plasma
has been recommended.

8. Factors affecting accuracy of glucose measurement 1. Terminology
The physiologic activity of glucose corresponds more closely with plasma concentration than whole blood glucose concentration, which varies considerably with hematocrit.
Most of the POC devices measure glucose in whole blood and self correct internally, reporting results as plasma glucose.

9. Factors affecting accuracy of glucose measurement 2. Sampling site
ADA and WHO recommend the use of venous plasma glucose for measuring and reporting.
The widespread use of capillary blood sampling despite evidence that this may lead to measurement error (fingertip blood samples ≈ capillary blood samples)
The difference between capillary and venous glucose is typically small in non-hypotensive fasting subjects, but can be up to 8% higher in capillary blood after meals or glucose challenge.
Compared to capillary blood, arterial sampling is generally accepted to be a more accurate measurement.

10. Factors affecting accuracy of glucose measurement 3
Factors affecting accuracy of glucose measurement 3. Patient and Environmental Factors
Hematocrit
hematocrit  glucose
High oxygen tension (ie, pO2 >100 mm Hg) can falsely decrease glucose readings on some glucose oxidase-based blood glucose meters, especially when patients are receiving oxygen therapy.
The enzyme GDH is less specific for glucose than glucose oxidase and but is not as susceptible to variations in oxygen concentration
Andrew D. Pitkin, et al., Challenges to Glycemic Measurement in the Perioperative and Critically Ill Patient: A Review, J Diabetes Sci Technol 2009;3(6):

11. FDA Public Health Notification: potentially fatal errors with GDH-PQQ glucose monitoring technology. August 13, Available at Accessed August 30, 2009.

12. Insulin Analogues

13. History 1922 Banting and Best use bovine insulin extract on human
1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin
1946 Nordisk formulates Isophane porcine insulin (Neutral Protamine Hagedorn or NPH insulin) by adding Neutral Protamine to regular insulin
1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer-lasting insulin
1981 Novo Nordisk chemically and enzymatically converts porcine insulin to 'human' insulin
1983 Lilly produces synthetic, recombinant 'human' insulin, branded Humulin
1996 Lilly Humalog "lispro" insulin analogue approved by the U.S. Food and Drug Administration
2003 Aventis Lantus "glargine" insulin analogue approved in USA
2004 Sanofi Aventis Apidra insulin "glulisine" analogue approved for clinical use in the USA.
2006 Novo Nordisk's Levemir "insulin detemir" analogue approved in USA

14. History 1922 Banting and Best use bovine insulin extract on human
Porcine insulin has only a single amino acid variation from the human insulin, and bovine insulin varies by three amino acids. Both are active on the human receptor with approximately the same strength.
The first commercial insulin preparations contained numerous impurities and varied in potency from lot to lot by as much as 25 percent
1936
Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin

15. Nordisk formulates Isophane porcine insulin (Neutral Protamine Hagedorn or NPH insulin) by adding Neutral Protamine to regular insulin
1946
Protamine
NPH
1953
Novo formulates Lente porcine and bovine insulins by adding zinc for longer-lasting insulin
Zinc
Lente

16. Novo Nordisk chemically and enzymatically converts porcine insulin to 'human' insulin
1981
1983
Lilly produces synthetic, recombinant 'human' insulin, branded Humulin
By the early 1980s, the development of purified pork insulin and then recombinant human insulin virtually eliminated insulin allergy and immune-mediated lipoatrophy.
These achievements marked a slowdown in the innovation of insulin products until the 1990s, when the reports of the Diabetes Control and Complications Trial4 and the United Kingdom Prospective Diabetes Study5 confirmed the value of glycemic control in the delay or prevention of complications of diabetes.

17. Lilly Humalog "lispro" insulin analogue approved by the U.S. FDA 1996
2000
”Aspart” Insulin analogue
2004
”Glulisine” Insulin analogue
The limiting pharmacokinetic and pharmacodynamic features of standard insulins, which frequently lead to hypoglycemia as Hg A1c values approach the normal range, renewed interest in producing safer insulin formulations that more closely duplicate the basal and meal- time components of endogenous insulin secretion.
Insulin lispro is the first rapidly acting analogue that was developed.
It differs from regular insulin by virtue of its capacity to dissociate rapidly into monomers in subcutaneous tissue.
It was formulated on the premise that insulin-like growth factor 1 (IGF-1), which is structurally similar to insulin, does not tend to self-associate, probably because of differences between the C-terminal portion of the B chain of IGF-1 and that of insulin.
Insulin lispro was formulated by Inversion of the lysine of B29 and the proline of B28 of human insulin, which confers a conformational change that results in a shift in the normal binding of the C-terminal portion of the B chain, which in turn reduces the formation of dimers and hexamers.
The second rapidly acting analogue that was introduced was insulin aspart10 (Fig. 1). With its pro- line having been replaced by the negatively charged aspartic acid, insulin aspart is absorbed twice as fast as human insulin.

18. ”Glargine” Insulin analogue
2003
”Glargine” Insulin analogue
2006
”Detemir” Insulin analogue
Insulin glargine is the first long-acting insulin analogue having aa modifications in both chains. In the A chain, the asparagine at position 21 is substituted by glycine and the B chaini is elongated at the C termiinus by addition of two arginine residues. Glargine is a molecule with a changed isoelectric point towards neutral, bearing decreased solubility at physiological PH. This causes precipitation after injection in subcutaneous tissue, stabilization of insulin hexamers, delay of their dissociation and steady absorption into the circulation.
Levemir
Is characterized by acylation of myristic acid to the lysine residue at position 29 in the B chain and deletion of the last threonine (position 30) in the B chain.
Its protracted action is achieved through delayed resorption caused by the increased self-association and reversible albumin binding at the injection site because albumin binding causes buffering of insulin concentration. When compared to NPH and glargine, it offers better weight gain control and results in comparable overall risk of hypoglycemia.

19. AHRQ Pub. No. 08(09)-EHC017-3 March 2009

20. AHRQ Pub. No. 08(09)-EHC017-3 March 2009

21. ???Risk of cancer in patients receiving insulin analogues
In spite of the clinical superiority, the potential mitogenic effect of some analogues remains to be clarified and constitutes a fundamental safety issue.
Insulin and IGF-1 receptors display >50% of amino acid sequence homology and even >84% in the tyrosine kinase domain, while both ligands bind to both receptors.
So far, no reliable date on this has been published.
In 2000, adenocarcinoma with the use of insulin AspB10 in laboratory animals.
In 2009, glargine  ???cancer
The FDA, ADA, AACE, and EASD have formally stated that patients should continue to use insulin analogues until more information is available.

22. QUESTION 1: Does improving glycemic control improve clinical outcomes for inpatients with hyperglycemia?
Yes No

23. Era of unawareness
A decade ago, there was a general lack of recognition of the need to identify and treat hyperglycemia among hospitalized patients.
Acute hyperglycemia was often considered to be benign and even a physiological reaction to acute illness.
There were no published guidelines or glycemic targets for the inpatient setting, so hyperglycemia in the hospital setting was essentially ignored.

24. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes
Diabetes contributes to longer hospital length of stay regardless of the reason for admission.

25. Completed Intensive Insulin Interventions Studies showing benefit
Study
Patient Populations
Methodology
Intervention
Outcome
Malmberg 1995
(DIGAMI I)
AMI in diabetes
Prospective, case control study
IV insulin therapy followed by multiple insulin injections ( mg/dl)
1-year mortality 29%
Van Den Berghe 2001
Surgical ICU
Prospective, randomized controlled
Glucose level mg/dl vs. conventional tx.
Mortality 34%
Furnary 2003
Diabetes-CABG surgery
Case/control study
IV insulin maintains a glucose<200 compared with SQ insulin
Mortality 50% with IV insulin
Krinsley 2004
Mixed medical/surgical ICU
(historical control group)
Compared preprotocol with postprotocol to maintain glucose<140
Mortality 29.3%
These are important studies from late 1990s to early 2000s showing benefit of intensive insulin interventions.
DIGAMI1 stands for diabetes and insulin-glucose infusion in Acute MI. This study showed that in patients with AMI and DM, iv insulin therapy with target glucose levels of 126 to 196 lowered a 1 year mortality by 29%.
Other studies also showed reduction in mortaliby by 30 to 50%.
But the varying
In 2001, Van den Berghe published a landmark study of intensive insulin therapy in the setting of a surgical ICU.
DIGAMI: Diabetes and Insulin-Glucose Infusion in Acute MI
Glucose target mg/dl
DIGAMI-2: target mg/dl
The varying glucose target levels of these studies make it difficult to compare their results
The varying glucose target levels of these studies make it difficult to compare their results

26. Prospectively evaluated 1500 patients in the surgical ICU.
Van den Berghe G, et. al. Intensive insulin therapy in critically ill patients.
N Engl J Med. 2001; 345:
Prospectively evaluated 1500 patients in the surgical ICU.
For the first time, patients’ BG was controlled to a very low target (80-110mg/dL)
Intensive insulin therapy reduced overall in-hospital mortality by 34%,
bloodstream infections by 46%, acute renal failure requiring dialysis by 41 %.

27. In response……
Because of the dramatic reduction in mortality with normalization of glucose levels in the single center, the Van den Berghe study led to widespread adoption of this practice in ICUs worldwide.
On the basis of initial studies, the American Association of Clinical Endocrinologists (AACE) convened a consensus conference and published the first inpatient glycemic targets in 2004.
Tight glycemic control for the critically ill patient
In 2005, for the first time, the American Diabetes Association (ADA) published recommendations for inpatient glycemic care in its yearly standards of care.
Very quickly it was recognized that implementing inpatient glycemic control was not a simple task and that there were many barriers to overcome.
In 2006, conference was held to address some of the barriers and make recommendations on how to overcome them.
Call for creation of inpatient multidisciplinary steering committees

28. Completed Intensive Insulin Interventions Studies showing no benefit
Most recent studies have not shown a major benefit from controlling BG to a target of mg/dL.
Study
Patient Populations
Methodology
Intervention
Outcome
Malmberg 2005
(DIGAMI 2)
AMI in diabetes
Prospective, randomized, multicenter trial
3 distinct insulin strategies including IV insulin
No difference in mortality
Van Den Berghe 2006
Medical ICU
Prospective, randomized, controlled study
Glucose level mg/dl vs conventional treatment
No significant decrease in mortality
NICE-SUGAR 2009
Mixed medical/surgical ICU
Prospective, randomized, controlled, multi-center trial
Glucose of ml/dl vs conventional glucose<180mg/dl
Mortality 2.6% in the intensive-control group
Sebsequent to the initial Van den Berghe study, other multicenter trials have been fraught with an increased frequency of hypoglycemia and have failed to consistently demonstrate improved outcomes with intensive insulin therapy.
Several studies have attempted to reproduce the favorable outcomes observed with early implementation of insulin therapy reported in the first Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial (33). DIGAMI 2, a multicenter RCT of 1,253 patients with AMI and diabetes, failed to show a decrease in mortality with such intervention
However, implementation of the identical protocol in 1,200 medical ICU patients by the same investigators in the same institution diminished morbidity but failed to reduce mortality. A 6- fold increase in severe hypoglycemic events (BG <40 mg/ dL [2.2 mmol/L]) was observed in the intensively treated group (18.7% versus 3.1%), and hypoglycemia was identified as an independent risk factor for mortality

29. Intensive versus Conventional Glucose Control in Critically Ill Patients The NICE-SUGAR Study Investigators N Engl J Med Volume 360(13):
target: mg/dL
Target<180mg/dL
The largest study to date, Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation (NICE-SUGAR), a multicenter, multinational RCT, tested the effect of tight glycemic control on out- comes among 6,104 critically ill participants, the majority of whom (>95%) required mechanical ventilation (14)
Study participants were randomly assigned to glucose control with one of two target ranges: the intensive (i.e., tight) control target of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), based on that used in previous studies or a conventional-control target of 180 mg or less per deciliter (10.0 mmol or less per liter), based on practice surveys in Australia, New Zealand, and Canada.
NICE-SUGAR: Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation

30. Data on Blood Glucose Level, According to Treatment Group
Conventional control group
Target<180mg/dL
Intensive control group
target: mg/dL
achievement of a glucose level
modestly above the target range
in a substantial proportion of patients
in the intensive-control group.
This is data on actual blood glucose level that they achieved.
Figure 2. Data on Blood Glucose Level, According to Treatment Group. Panel A shows mean blood glucose levels. Baseline data are the averages of the last blood glucose measurement obtained before randomization; day 1 data are the average levels from the time of randomization to the end of the day of randomization. The bars indicate the 95% confidence intervals. The dashed line indicates 108 mg per deciliter, the upper limit of the target range for intensive glucose control. Panel B shows the density plot for the mean time-weighted blood glucose levels for individual patients. The dashed lines indicate the modes (most frequent values) in the intensive-control group (blue) and the conventional-control group (red), as well as the upper threshold for severe hypoglycemia (black). To convert the values for blood glucose to millimoles per liter, multiply by
achievement of a glucose level modestly above the target range in a substantial proportion of patients in the intensive-control group.
The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:

31. Probability of Survival and Odds Ratios for Death, According to Treatment Group
hazard ratio, 1.11; 95% CI, 1.01 to 1.23; P=0.03
Figure 3. Probability of Survival and Odds Ratios for Death, According to Treatment Group. Panel A shows Kaplan-Meier estimates for the probability of survival, which at 90 days was greater in the conventional-control group than in the intensive-control group (hazard ratio, 1.11; 95% confidence interval, 1.01 to 1.23; P=0.03). Panel B shows the odds ratios (and 95% confidence intervals) for death from any cause in the intensive-control group as compared with the conventional-control group, among all patients and in six predefined pairs of subgroups. The size of the symbols indicates the relative numbers of deaths. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score can range from 0 to 71, with higher scores indicating more severe organ dysfunction.
The 90-day mortality was significantly higher in the inten- sively treated versus the conventionally treated group (78 more deaths; 27.5% versus 24.9%; P = .02) in both sur- gical and medical patients. Mortality from cardiovascular causes was more common in the intensively treated group (76 more deaths; 41.6% versus 35.8%; P = .02). Severe hypoglycemia was also more common in the intensively treated group (6.8% versus 0.5%; P<.001).
-The 90-day mortality was significantly higher in the intensively treated versus the conventionally treated group (78 more deaths; 27.5% versus 24.9%; P = .02) in both surgical and medical patients.
-Mortality from cardiovascular causes was more common in the intensively treated group (76 more deaths; 41.6% versus 35.8%; P = .02).
-Severe hypoglycemia was also more common in the intensively treated group (6.8% versus 0.5%; P<.001).
The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:

32. Severe hypoglycemia in NICE-SUGAR study
Glucose levels were measured using either Point-of- care (POC) devices or Central laboratory devices (CLD) with samples obtained from either arterial catheters or capillary sites.
The recorded number of episodes of severe hypoglycemia (defined as a blood glucose level ≤40mg/dL) was 272 in the intensive control group, as compared with 16 in the conventional-control group; 173 of all 288 episodes (60.1%) were confirmed by a laboratory measurement.
Safe and rational glycemic management relies on the accuracy of BG measurements performed with use of POC glucose meters, which have several important limitations. Although the US Food and Drug Administration allows a ±20% error for glucose meters, questions have been raised about the appropriateness of this criterion
Significant discrepancies among capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations, hypoperfusion, or the presence of interfering substances (139,140). Analytical variability has been described with several POC glucose meters (141). Any glucose result that does not correlate with the patient’s clinical status should be confirmed through conventional laboratory sampling of plasma glucose.

33. Hyperglycemia in Hospitalized Medical and Surgical Patients in Non-ICU Settings
No RCTs have examined the effect of intensive glycemic control on outcomes in hospitalized patients outside ICU settings.
Several observational studies, however, point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after discharge from the hospital, and death

34. The reasons for this inconsistency are not entirely clear.
QUESTION 1: Does improving glycemic control improve clinical outcomes for inpatients with hyperglycemia?
Overall, although a very tight glucose target (80 to 110 mg/dL) was beneficial in a predominantly surgical ICU population, this target has been difficult to achieve in subsequent studies, including NICE-SUGAR study, without increasing the risk for severe hypoglycemia.
There has been no consistent reduction in mortality with intensive control of glycemia, and increased mortality was observed in the largest published study to date.
The reasons for this inconsistency are not entirely clear.

35. Fasting <140 Random 140-180 None of the above A and B
QUESTION 2: What glycemic targets can be recommended in hospitalized patients?
Fasting <140
Random
None of the above
A and B

36. Recommendation of Glycemic targets in different patient populations in the hospital setting -Review of guidelines

37. AACE-ADA guideline (2009)
Moghissi,et.al., Consensus: Inpatient Hyperglycemia, Endocr Pract. 2009;15(No. 4)

38. Avoiding targets less than 140 should be a priority because harms are likely to increase at lower blood glucose targets.
While the evidence is not sufficient to give a precise range for blood glucose levels, target values of 140 to 200mg/dL is a reasonable option in patients in the ICU, because insulin therapy targeted at blood glucose levels of is a/w similar mortality outcomes as IIT(intensive insulin therapy) targeted at blood glucose levels of and is a/w a lower risk for hypoglycemia.
Amir Qaseem, et.al., Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: A clinical practice guideline from the American College of Physicians, Ann Intern Med. 2011; 154:

41. ACC/AHA Guidelines (2007)
“The usefulness of strict control of blood glucose concentration during the perioperative period is uncertain in patients with diabetes mellitus or acute hyperglycemia who are undergoing noncardiac surgical procedures without planned ICU admission.”
“It is reasonable that blood glucose concentration be controlled during the perioperative period in patients with diabetes mellitus or acute hyperglycemia who are at high risk for myocardial ischemia or who are undergoing vascular and major noncardiac surgical procedures with planned ICU admission.”
J Am Coll Cardiol 2007:50:e242

42. Question 2. What glycemic targets can be recommended in different patient populations in the hospital setting?
All experts now seem to agree that a target of near- normalization of blood glucose levels in hospitalized patients is inappropriate but also that hyperglycemia can have adverse consequences and should be treated in a substantial fraction of hospitalized patients.
AACE/ADA guidelines
ICU patients:
non-ICU patients: Fasting<140, random <180
ACP guidelines
ICU patients:
There is difference of opinion revolving around the details of the specific target range for blood glucose in hospitalized patients, a subject that is evolving as the research base increases.

43. Tailoring insulin use to the clinical scenario

44. Sliding Scale Insulin
To date, since the discovery of insulin in 1921, no study has shown a benefit of SSI in improving glycemic control or clinical outcome.
“cookbook” approach to hyperglycemia
Simple and convenient, avoids telephone calls to the physicians
Retroactive and inefficient therapy that allows wide glycemic fluctuation, putting patients on a roller coaster of fluctuations in blood glucose.
In a prospective RCT(RABBIT 2 Trial)*, it was found that basal- bolus insulin resulted in lower mean fasting and random blood glucose levels in comparison with SSI alone without the use of basal insulin.
*Umpierrez GE , Smiley D, Zisman A, et al., Randomized study of basal-bolus insulin therapy in the
inpatient management of patients with type 2 diabetes (RABBIT2 trial), Diabetes Care. 2007; 30;

45. AACE-ADA guideline (2009)
Moghissi,et.al., Consensus: Inpatient Hyperglycemia, Endocr Pract. 2009;15(No. 4)

46. Physiologic Subcutaneous Insulin Protocols
Basal insulin
glargine, detemir, or NPH
Prevents gluconeogenesis and ketogenesis
Bolus insulin (nutritional or prandial)
Lispro, aspart, or regular
Attempts to control the prandial glucose excursion
Correction insulin (supplemental)
Fine tunes suboptimal glycemic control by offering the flexibility of adding insulin beyond the calculated nutritional dose.
Needs to be distinguished from SSI, which refers to an insulin regimen that is given alone with the sole purpose of “resolving” hyperglycemia and is not scheduled in combination with basal insulin.

47. Correction or Supplemental Insulin Algorithms
Blood glucose (mg/dL)
Low-dose algorithm for pts taking≤0.5U/kg daily
Moderate-dose algorithm for pts taking>0.5U/kg daily
High-dose algorithm for pts taking>1U/kg daily Ac Hs 1 2 3 4 6 9 8 12 5 10 15
>400 18
Ariana R. Pichardo-Lowden, et.al., Management of hyperglycemia in the non-intensive care patient: Featuring subcutaneous insulin protocols, Endocrine practice vol 17 No.2 March/April 2011

48. Total Daily Dose (TDD)
Can be determined by considering preadmission insulin needs, overall glycemic control, body weight, or intravenous insulin requirements.
When a dose is selected on the basis of weight,
0.5U/kg is an adequate starting dose for most patients.
0.4U/kg for patients at risk for hypoglycemia (advanced age, hemodialysis, low body weight) or with type1 diabetes
0.7U/kg or higher for more insulin-resistant patients

49. 1. Patients Eating (an intake of at least 50% of the scheduled meals)
Basal insulin
Nutritional or prandial insulin
Supplemental or correctional insulin
Detemir or Glargine: 50% of TDD as a single injection in the morning or bedtime
NPH: 50% of TDD (70% of basal dose in the morning ac and 30% ac supper or hs)
50% of TDD divided equally between meals.
Most patients
0.5U/kg (TDD)
Low dose ac & hs
Risk of hypoglycemia
0.4U/kg (TDD)
Insulin resistant
0.7U/kg (TDD)
Moderate dose ac & hs

50. Example
A 50 y.o man with diabetes who is 180cm (71in) tall and weighs 90kg(198 lb) is admitted for pneumonia treatment with a random blood glucose level of 300mg/dL and an A1c level of 10.8%. Oral diabetic agents are discontinued, and blood glucose testing is ordered before meals and at bedtime.
Calculate total daily dose of insulin
0.5U/kg X 90kg = 45 units.
50%
50%
Basal insulin
Nutritional or prandial insulin
Supplemental or correctional insulin
23 units of insulin glargine taken once daily (50% of TDD)
7-8 units of insulin aspart (Novolog) taken zero to 15 minutes before meals (50% of TDD, in three divided doses)
Based on glucose readings, give additional aspart (novolog) per standard correctional insulin schedule

51. 2. Patients Fasting Basal insulin Nutritional or prandial insulin
Supplemental or correctional insulin
Detemir or Glargine: 50% of TDD as a single injection in the morning or bedtime
NPH: 50% of TDD (Divide amount in 3 equal doses to be given q 8h if GFR>50ml/min or divide in 2 equal doses to be given q 12h if GFR<50ml/min)
None if entirely fasting.
If glucose>180mg/dL X 2 days and taking clear liquids, start 25% of TDD divided equally between meals.
Most patients
0.5U/kg (TDD)
Low dose q6h
Risk of hypoglycemia
0.4U/kg (TDD)
Insulin resistant
0.7U/kg (TDD)
Moderate dose q6h

52. 3. Transition from IV to SC insulin
Patients who receive IV insulin infusions will usually require transition to subcutaneously administered insulin when they begin eating regular meals or are transferred to lower intensity care.
Typically, a percentage (usually 75% to 80%) of the total daily IV infusion dose is proportionately divided into basal and prandial components
Amount used in last 6 hours X 4.
If insulin drip rate is fluctuating >1U/h within past 6 hours, consider continuing the drip and reassess, or calculate TDD= 80% of 6 stable doses (insulin units/h) within the last 12 hours X 4.
Subcutaneously administered insulin must be given 2 to 3 hours before discontinuation of IV insulin therapy in order to prevent hyperglycemia.

53. Example 1AM 2AM 3AM 4AM 5AM 6AM 7AM 8AM 9AM Noon 7U/h 8U/h 6U/h 5U/h
Insulin requirement in the past 6 hours
= = 22 units
TDD =0.8 X (22 units X 4) = 70 units.
Basal = 50% of TDD = 35 units
Prandial= 50% of TDD in 3 divided doses=35 units/3 =12 units each meal.

54. Specific clinical situations 4. Patients Receiving high dose steroids
Hyperglycemia is a common complication of corticosteroid therapy.
Several approaches have been proposed for treatment of this condition, but no published protocols or studies have investigated the efficacy of these approaches.
A reasonable approach is to institute glucose monitoring for at least 48 hours in all patients receiving high-dose glucocorticoid therapy and to initiate insulin therapy as appropriate.

55. Patients receiving high-dose steroids
Corticosteroids has an effect on the overall insulin requirements several hours after their administration, and they notoriously exaggerate postprandial glucose.
A strategy to address persistent hyperglycemia related to a single dose of a corticosteroid, typically given in the morning, is the initiation of NPH insulin, taking advantage of similar peak and duration effects of NPH and prednisone/prednisolone.
0.1U/kg for every 10mg of prednisone a day up to 0.4U/kg. (Clore and Thurby-Hay)

56. Patients receiving high-dose steroids
The administration of multiple high doses of glucocorticoids throughout the day.
In this situation, NPH alone may fail to achieve and maintain glycemic control, usually because of postprandial hyperglycemia.
Basal insulin
Nutritional or prandial insulin
Supplemental or correctional insulin
30% of the TDD for patients eating
70% of the TDD divided equally between meals.
Moderate dose q ac & hs if eating or q 6h if NPO for taking<0.5U/kg TDD or at risk of hypoglycemia.
High dose for taking>0.5U/kg TDD

57. Patients receiving high-dose steroids
During corticosteroid tapers, insulin dosing should be proactively adjusted to avoid hypoglycemia.
Percentage of insulin decrease or increase should be half the percent steroid decrease or increase. (i.e., if steroid dose is reduced or increased 50%, insulin dose is reduced or increased 25% simultaneously-basal and nutritional)

58. Specific clinical situations 5. Patients Receiving TPN
The high glucose load in standard parenteral nutrition frequently results in hyperglycemia, which is associated with a higher incidence of complications and mortality in critically ill patients in the ICU.
Insulin therapy is highly recommended, with glucose targets as defined previously on the basis of the severity of illness.

59. Patients receiving TPN
Basal insulin
Nutritional or prandial insulin
Supplemental or correctional insulin
Use insulin drip X 24 h.
Calculate TDD as per IV to SQ protocols.
Incorporate 80% of the new TDD as regular insulin in the TPN bag.
When TPN bag containing insulin is started, discontinue insulin infusion.
Daily dose adjustment:
If BG>180, insulin in the TPN by 20% (most patients) or 10% if risk of hypoglycemia.
May use SQ long- or intermediate-acting insulin while waiting for insulin dose adjustment in subsequent TPN bag.
None if entirely fasting
Initiate preprandial insulin if daytime glucose>180mg/dl X 2 days.
If taking clear liquids: give 0.05U/kg ac
If taking food: give 0.1U/kg ac
If at risk for hypoglycemia, give 0.05U/kg ac
Low dose q ac & hs if eating or q 6h if NPO for taking<0.5U/kg TDD or at risk of hypoglycemia.
Moderate dose for taking>0.5U/kg TDD

60. Specific clinical situations 6. Patients Using an Insulin Pump
Patients who use continuous subcutaneous insulin infusion (pump) therapy in the outpatient setting can be candidates for diabetes self-management in the hospital, provided they have the mental and physical capacity to do so.
Of importance, nursing personnel must document basal rates and bolus doses on a regular basis (at least daily).
The availability of hospital personnel with expertise in continuous subcutaneous insulin infusion therapy is essential

61. Daily dose adjustment Basal insulin Nutritional or prandial insulin
Supplemental or correctional insulin
If fasting and morning BG>140mg/dL
If eating and random/postprandial BG>180mg/dL
Patients on≤0.5U/kg or *at risk for hypoglycemia
 By 10%
Patients on >0.5U/kg
 By 20%
If fasting and morning BG<100mg/dL X 2 or B<70mg/dL anytime
If eating and random/postprandial BG<100mg/dL X 2 or B<70mg/dL anytime
For all patients
 By 20%
*at risk for hypoglycemia: insulin naïve, Elderly (>75 years), underweight-BMI<18.5kg/m2,
renal dysfunction (GFR<50ml/min), severe hepatic or cardiac dysfunction,
known gastroparesis (consider using regular insulin instead of lispro or Aspart)

62. Transition to outpatient care
Preparation for transition to the outpatient setting should begin at the time of hospital admission.
Early assessment of a patient’s cognitive abilities, literacy level, visual acuity, dexterity, cultural context, and financial resources for acquiring outpatient diabetic supplies allows sufficient time to prepare the patient and address problem areas.
Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management.

63. THD Practice AS-IS TO-BE??
Universal SSI in EPIC unless physicians create their own SSI.
No consideration of the degree of insulin resistance.
SSI (novolog) +/- Long acting (Lantus)
Does this novolog SSI include prandial and correctional components or is it just correctional without prandial component?
SSI-L, SSI-M, SSI-H in order set.
Prandial component based on individual patient’s TDD should be incorporated
THD Insulin Sliding Scale
Glucose AC HS
NO insulin NO insulin
units NO insulin
units NO insuiln
units units
units units
units units
units units
> units units
TO-BE??

64. CONCLUSIONS
Hyperglycemia in hospitalized patients is extremely common. Hospitalization is an opportunity to evaluate long-term diabetes control and initiate new therapy.
Think about various factors that may affect accuracy of glucose measurement, if there are discrepancies between venous and capillary readings.
A target of near-normalization of blood glucose levels in most hospitalized patients is inappropriate.
Different targets for different patient populations. Always use your clinical judgment.
Stringent targets for patients with high risk of MI, vascular and noncardiac major surgery with planned ICU admission
Do more than SSI. Physiologic Insulin protocol is the preferred method.
Always reassess and adjust accordingly.

65. References
1.Ven den Berghe G, et. al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001; 345: Moghissi ES, Reexamining the evidence for inpatient glucose control: New recommendations for glycemic targets, Am J Health-Syst Pharm, vol 67, Aug 15, 2010 Suppl 8 3. The nice-sugar study investigators, Intensive versus Conventional Glucose Control in Critically Ill Patients, N Engl J Med Volume 360(13): Moghissi,et.al., Consensus: Inpatient Hyperglycemia, Endocr Pract. 2009;15(No. 4) 5. Amir Qaseem, et.al., Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: A clinical practice guideline from the American College of Physicians, Ann Intern Med. 2011; 154: Ariana R.Pichardo-Lowden, et.al., Management of hyperglycemia in the non-intensive care patient: Featuring subcutaneous insulin protocols, Endocr Pract. 2011; 17 (No.2) 7. Visiliki Valla, Review article: Therapeutics of diabetes mellitus: Focus on insulin analogues and insulin pumps, Hindawi Publishing corporation Esperimental diabetes research volume 2010, article ID , 14 pages 8. Leile K.Dawson and et.al., Risk of cancer in patients receiving insulin glargine, Am J Health-Syst Pharm Vol 67 Dec 1, 2010,

66. References
9. I.B. Hirsch, Insulin analogues, N Engl J Med 2005;352:174-83
10. Umpierrez GE , Smiley D, Zisman A, et al., Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT2 trial), Diabetes Care. 2007; 30;
11. Ariana R. Pichardo-Lowden, et.al., Management of hyperglycemia in the non- intensive care patient: Featuring subcutaneous insulin protocols, Endocrine practice vol 17 No.2 March/April 2011
12. Konrad C.Nau, et.al., Glycemic control in hospitalized patients not in intensive care: beyond sliding-scale insulin, Americal Family Physician, volume 81, number 9,
13. Andrew D. Pitkin, et al., Challenges to Glycemic Measurement in the Perioperative and Critically Ill Patient: A Review, J Diabetes Sci Technol 2009;3(6):
14.