Effective Glycemic Control Outside of the Critical Care Unit

1
Effective Glycemic Control Outside of the
Critical Care Unit

• Christopher A. Newton, MD, FACE
• canewto_at_emory.edu
• Division of Endocrinology
• Grady Memorial Hospital
• Emory University
• November 3, 2012

2
Objectives

• Describe acute care populations that are at high
  risk for hyperglycemia
• Identify essential components to achieving
  glycemic control in the acute care setting

3
Definitions
4
Accepted Glycemic Ranges
5
Glycemic Thresholds

• In-hospital hyperglycemia is defined as an
  admission or in-hospital blood glucose gt140 mg/dL
• Hypoglycemia is defined as any blood glucose lt70
  mg/dL
• A patient with an HbA1c gt6.5 can be identified
  as having diabetes

6

• Comparison of sensitivity and specificity
  achieved for the diagnosis of diabetes based on
  fasting plasma glucose at various levels of HbA1c
  from data in NHANES III and 1999-2004 NHANES

J Clin Endocrinol Metab, July 2008,
93(7)24472453
7
Incidence of Hyperglycemia
8
Distribution of Patient-Day-Weighted Mean POC BG
Values
DATA from 49 million POC-BG testing (12 M ICU
37 M non-ICU) from 3.5 million patients (653,359
ICU 2,831,436 non-ICU). The mean POC-BG was 167
mg/dL for ICU patients and 166 mg/dL for non-ICU
patients.
ICU
Non-ICU
Swanson et al. Endocrine Practice, October 2011
9
Distribution of Patient-Day-Weighted Mean POC BG
Values

• Data from 37 million BG readings from 2,831,436
  non-ICU patients - mean POC-BG 166 mg/dL

Swanson et al. Endocrine Practice, October 2011
10
Hyperglycemia Is Common
Patients,
Mean BG, mg/dL
Kosiborod M, et al. J Am Coll Cardiol.
200749(9)1018-183283A-284A.
11
IGT and Undiagnosed T2DM Are Common in Acute MI
and Stroke
2-hour OGTT
Norhammar A, et al. Lancet 20023592140-4.Matz
K, et al. Diabetes Care 2006792-7.
12
Clinical Outcomes Associated With Hyperglycemia
13
Hyperglycemia Independent Marker of In-Hospital
Mortality

P lt 0.01
Umpierrez GE et al, J Clin Endocrinol Metabol
87978, 2002
14
Hyperglycemia and Pneumonia Outcomes


Plt0.05 vs BGlt198 mg/dL N2471 patients with
community acquired pneumonia


McAllister et al, Diabetes Crae 28810-815, 2005
15
30 Day Mortality and In-hospital Complications
among Non-cardiac Surgery Patients







p 0.1 p 0.001 p 0.017
A Frisch et al. Diabetes Care, May 2010
16
Insulin Protocol Development
17
Key Elements BG Targets

• Glucose Target in non-ICU setting
• Premeal glucose targets lt140 mg/dL
• Random glucose lt180 mg/dL
• To avoid hypoglycemia, reassess insulin regimen
  if glucose levels fall below 100 mg/dL
• Occasional patients may be maintained with a
  glucose range below and/or above these cut-points

Moghissi ES, et al AACE/ADA Inpatient Glycemic
Control Consensus Panel. Endocr Pract.
200915(4). http//www.aace.com/pub/pdf/guidelines
/InpatientGlycemicControlConsensusStatement.pdf
18
Key Elements - Monitoring

• Glucose monitoring is an obvious, but crucial,
  element of success
• Monitoring glucoses
• Provides assessment of current glucose
• Are interpreted for adjusting medications based
  upon the trends in the glucoses
• Frequency depends upon treatment regimen utilized
• Quicker interventions need more frequent
  assessments

19
Key Elements - Personnel

• Physician / Physician Assistant / Nurse
  Practitioner
• Nurses
• Pharmacy Staff
• Laboratory Staff
• Administration
• Many other people
• Patients?

20
Key Elements - Medication
Antihyperglycemic Therapy
SC Insulin Recommended for most medical-surgical
patients
OADs Not Generally Recommended
ACE/ADA Task Force on Inpatient Diabetes.
Diabetes Care. 2006 2009 Diabetes Care.
200931(suppl 1)S1-S110..
21
Key Elements - Medication

• AACE/ADA Consensus Statement Non-insulin
  therapies in the hospital?
• Sulfonylureas are a major cause of hypoglycemia
• Metformin contraindicated in setting of decreased
  renal blood flow and with use of iodinated
  contrast dye
• Tyiazolidinediones associated with edema and CHF
• Alpha-glucosidase inhibitors are weak glucose
  lowering agents
• GLP1-directed therapies can cause nausea and have
  a greater effect on postprandial glucose

Moghissi ES, et al AACE/ADA Inpatient Glycemic
Control Consensus Panel. Endocr Pract. 2009
22
Key Elements - Insulin

• Sliding scale short-acting insulin (SubQ)
• Subcutaneous basal/bolus therapy
• NPH and Regular
• Long-acting and Rapid-acting analogs
• Subcutaneous continuous infusion
• Intravenous insulin

23
Key Elements - Insulin

• Study Type Prospective, multicenter RCT
• Population 130 subjects insulin naïve T2DM
• Basal-Bolus Protocol
• Starting total daily dose (TDD)
• 0.4 unit/kg/day for BG between 140-200 mg/dL
• 0.5 unit/kg/day for BG between 201-400 mg/dL
• ½ TDD as insulin glargine and ½ as glulisine
• Glargine once daily at same time each day
• Glulisine three equally divided doses with meals

Umpierrez et al, Diabetes Care 3021812186, 2007
24
Sliding Scale Insulin

• Before meal Supplemental Sliding Scale Insulin
  ( of units)
• Bedtime Give ½ of Supplemental Sliding Scale
  Insulin

Blood Glucose (mg/dL) Insulin Sensitive Usual Insulin Resistant
gt141-180 2 4 6
181-220 4 6 8
221-260 6 8 10
261-300 8 10 12
301-350 10 12 14
351-400 12 14 16
gt400 14 16 18
Umpierrez GE et al. Diabetes Care.
2007302181-2186.
25
Rabbit 2 Trial Changes in Glucose Levels With
Basal-Bolus vs. Sliding Scale Insulin
240
220
a
a
200
a
b
b
b
180
b
BG, mg/dL
Sliding-scale
160
140
Basal-bolus
120
100
3
4
5
6
7
8
9
10
Admit
1
2
aPlt.05.
Days of Therapy
bPlt.05.

• Sliding scale regular insulin (SSRI) was given 4
  times daily
• Basal-bolus regimen glargine was given once
  daily glulisine was given before meals.
• 0.4 U/kg/d x BG between 140-200 mg/dL
• 0.5 U/kg/d x BG between 201-400 mg/dL

Umpierrez GE, et al. Diabetes Care.
200730(9)2181-2186.
26
Hypoglycemia rate
Rabbit 2 Trial Treatment Success With
Basal-Bolus vs. Sliding Scale Insulin
Sliding-scale
Basal-bolus
300
280
260
240

• Basal Bolus Group
• BG lt 60 mg/dL 3
• BG lt 40 mg/dL none
• Sliding Scale Group
• BG lt 60 mg/dL 3
• BG lt 40 mg/dL none

220
BG, mg/dL
200
180
160
140
120
100
1
3
3
4
5
6
7
2
4
2
1
Admit
Days of Therapy

• Persistent hyperglycemia (BGgt240 mg/dl) is common
  (15) during SSI therapy

Umpierrez GE, et al. Diabetes Care.
200730(9)2181-2186.
27
Basal-Bolus vs Sliding Scale Insulin in
Hospitalized Patients with T2DM

• The mean insulin daily dose was significantly
  higher in the basal-bolus group than in the
  sliding scale group

Insulin Type Mean Insulin Dose, units / day Mean Insulin Dose, units / day
Insulin Type Basal-Bolus Group SSI Group
Basal insulin 22 2 -
Rapid-acting insulin 20 1 -
Regular insulin - 12.5 2
Umpierrez GE, et al. Diabetes Care.
200730(9)2181-2186.
28

• Study Type Prospective, multicenter, randomized,
  open-label trial in general surgery (non-ICU)
• Population 211 subjects with T2DM on diet and/or
  oral hypoglycemic agents or low dose insulin
  (lt0.4 units/kg/day)
• Primary Outcomes Differences between groups in
  mean daily blood glucose and composite of
  hospital complications (wound infection,
  pneumonia, respiratory failure, acute renal
  failure, bacteremia

Umpierrez et al, Diabetes Care 34 (2)16, 2011
29
RABBIT 2 Surgery
Treatment on Admission All SSI GlarGlu P-value
Diet alone, n 17 11 6 NS
Oral antidiabetic agents, n 153 80 73 NS
Insulin oral antidiabetic agents, n 20 11 9 NS
Type of surgery All SSI GlarGlu P-value
Cancer 76 40 36 NS
GI-GU benign 59 28 31 NS
Vascular 31 15 16 NS
Trauma 38 20 18 NS
Others 7 5 2 NS
Umpierrez et al, Diabetes Care 34 (2)16, 2011
30
RABBIT 2 SurgeryBasal-Bolus Regimen

• D/C oral anti-diabetic drugs on admission
• Starting total daily dose (TDD) 0.5 unit/kg/day
• TDD reduced to 0.3 unit/kg/day in patients gt70
  years old or with creatinine gt2 mg/dL
• ½ TDD as glargine and ½ TDD as glulisine
• Glargine once daily at same time of day
• Glulisine three equally divided doses with
  meals
• Goal glucoses 100-140 mg/dL

Umpierrez et al, Diabetes Care 34 (2)16, 2011
31
Basal-Bolus Dose Adjustment
Blood glucose levels Change in Daily Insulin Dose
Fasting and pre-meal BG between 100-140 mg/dl in the absence of hypoglycemia no change
Fasting and pre-meal BG between 141-180 mg/dl in the absence of hypoglycemia Increase by 10
Fasting and pre-meal BG between gt181 mg/dl in the absence of hypoglycemia Increase by 20
Fasting and pre-meal BG between 70-99 mg/dl in the absence of hypoglycemia Decrease by 10
Fasting and pre-meal BG between lt70 mg/dl Decrease by 20

• Daily insulin adjustment was primarily focused
  on glargine dose.
• The treating physicians were allowed to adjust
  prandial (glulisine) insulin dose, and to use the
  total supplemental dose, patients nutritional
  intake, and results of BG testing to adjust
  insulin regimen.

Umpierrez et al, Diabetes Care 34 (2)16, 2011
32
RABBIT 2 SurgeryGlucoses During Therapy






plt0.001 p0.01 p0.02
R Randomization
Umpierrez et al, Diabetes Care 34 (2)16, 2011
33
RABBIT 2 SurgeryMean Glucose During Day




plt0.001
Umpierrez et al, Diabetes Care 34 (2)16, 2011
34
RABBIT 2 SurgeryPostoperative Complications
P0.003
P0.05
P0.10
P0.24
PNS
Composite of hospital complications wound
infection, pneumonia, respiratory failure, acute
renal failure, and bacteremia.
Umpierrez et al, Diabetes Care 34 (2)16, 2011
35
RABBIT 2 SurgeryImpact on Need for ICU

• Post-surgical ICU Admission

• ICU Length of Stay

P0.003
P0.16
Umpierrez et al, Diabetes Care 34 (2)16, 2011
36
RABBIT 2 SurgeryHypoglycemia
plt0.001
There were no differences in hypoglycemia between
patients treated with insulin prior to admission
compared to insulin-naïve patients.
plt0.001
p0.057
Umpierrez et al, Diabetes Care 34 (2)16, 2011
37
RABBIT 2 SurgeryInsulin Doses
Insulin Type Mean Insulin Dose, units / day Mean Insulin Dose, units / day
Insulin Type Basal-Bolus Group SSI Group
Total daily dose 33.4 12.3
Basal insulin 21.8 8.6 -
Rapid-acting insulin 14.8 7.6 -
Regular insulin - 12.3 6.5

• SSI range of daily regular insulin 9.7 to 14.4
  units after 24hr treatment
• 88.5 of patients received lt20 units and 39.4
  lt10 units per day.

Umpierrez et al, Diabetes Care 34 (2)16, 2011
38

• Study Type Prospective, randomized, open-label
  trial
• Population 130 subjects with T2DM on oral
  hypoglycemic agents or insulin therapy
• Study Sites
• Grady Memorial Hospital, Atlanta, GA
• Rush University Medical Center, Chicago, IL

Umpierrez et al, J Clin Endocrinol Metab 94
564569, 2009
39
DEAN Trial Changes in Mean Daily Blood Glucose
Concentration
240
Detemir aspart
NPH regular
220
200
PNS
180
BG, mg/dL
160
140
120
100
Pre-Rx
0
1
2
3
4
5
6-10
BG
Duration of Therapy, d
Data are means ?SEM.
Basal-bolus regimen detemir was given once
daily aspart was given before meals. NPH/regular
regimen NPH and regular insulin were given twice
daily, 2/3 in AM, 1/3 in PM.
Umpierrez GE, et al. J Clin Endocrinol Metab.
200994(2)564-569.
40
DEAN Trial
Detemir Novolog
NPH Regular
Blood glucose (mg/dL)
Umpierrez GE, et al. J Clin Endocrinol Metab.
200994(2)564-569.
41
DEAN Trial Insulin Doses

• The mean total daily insulin dose was not
  significantly different between treatment groups

Insulin Type Mean Insulin Dose, units / day Mean Insulin Dose, units / day
Insulin Type Detemir-Novolog NPH-Regular
Total Units/day 56 45 45 32
Basal insulin/day Detemir 30 28 NPH 27 20
Rapid-acting insulin Novolog 27 20 Regular 18 14
P lt 0.05
Umpierrez GE, et al. J Clin Endocrinol Metab.
200994(2)564-569.
42
DEAN Trial Hypogylcemia

• NPH/Regular
• BG lt40 mg/dL 1.6
• BG lt60 mg/dL 25.4
• Detemir/Aspart
• BG lt40 mg/dL 4.5
• BG lt60 mg/dL 32.8

Umpierrez GE, et al. J Clin Endocrinol Metab.
200994(2)564-569.
43
Interim Summary

• Treatment with basal bolus improved glycemic
  control and reduced hospital complications
  compared to SSI in medicine and surgery patients
  with T2DM
• Basal-bolus insulin regimen is preferred insulin
  regimen over Sliding Scale Insulin in the
  hospital management of non-ICU patients with T2DM

44
Hypoglycemia Risk Factors
p-value p-value
Variable (univariate) BG lt60 mg/dL BG lt70 mg/dL
Age 0.036 0.001
Weight 0.027 0.001
HbA1c 0.521 0.658
Creatinine 0.011 0.002
Enrollment BG 0.166 0.319
Previous treatment 0.005 lt0.001
Previous insulin treatment lt0.001 lt0.001
Treatment group lt0.001 lt0.001
p-values are from Wilcoxon Two-Sample Test
Umpierrez et al, ADA Scientific Meeting, Poster
516, 2009
45
Can Hypoglycemia from Insulin Be Avoided?
46
HypoglycemiaTriggering Events

• Transportation off ward, causing meal delay
• Failure to measure blood glucose before insulin
  doses
• New NPO status
• Interruption of
• IV dextrose therapy
• TPN
• Enteral feedings
• Continuous venovenous hemodialysis

Especially in setting of continued/unchanged
insulin dosing
47
SubQ Basal Insulin Action
sc insulin
n20 T1DM Mean SEM
4.0 3.0 2.0 1.0 0
24 20 16 12 8 4 0
mg/Kg/min
Glargine
0 4 8 12 16
20 24
Time (hours)
Adapted from Lepore M. et al., Diabetes
492142-8, 2000
48
Intravenous Insulin

• By-passes the delay associated with subcutaneous
  insulin administration
• Insulin from an IV infusion or IV bolus will
  disappear from bloodstream in 7 minutes
• With sufficiently frequent monitoring, can
  decrease the insulin dose prior to onset of
  hypoglycemia
• Majority of medical centers limit this option to
  intensive/critical care settings

49
IV versus SubQ Insulin

• Long-acting subcutaneous insulin
• Slow steady release of insulin into blood stream
• Can be mimicked by continuous infusion
• Rapid-acting subcutaneous insulin
• Faster absorption of insulin from subcutaneous
  space (doesnt last)
• Similar to a temporary increased infusion rate
  (not the same as IV bolus)

50
Successful Insulin Infusion Protocols

• Reaches and maintains BG successfully within a
  prespecified target range
• Includes a clear algorithm for making temporary
  corrective changes in the IV insulin rate as
  patient requirements change
• Incorporates the rate of change in BG, not just
  the absolute values
• Incorporates the current IV insulin rate
• Minimizes hypoglycemia provides specific
  directions for its treatment when it occurs
• Provides specific guidelines for timing and
  selection of doses for the transition to SC
  insulin

51
IV Insulin in Non-ICU

• Retrospective review in 200 patients
• 90 General Medicine /110 General Surgery
• Mean glucose 322 mg/dL
• Targeted glucose lt150 mg/dL for 85
• 67 achieved glucose lt150 by day 2
• Mean glucose during infusion 170 mg/dL

Smiley D, et al. J Hosp Med. 20105212-217.
52
Hypoglycemia on IV Insulin
Smiley D, et al. J Hosp Med. 20105212-217.
53
Transition from IV Continuous Insulin Infusion to
SC Insulin Therapy

• We recommend that all patients with type 1 and
  type 2 diabetes be transitioned to scheduled sc
  insulin therapy at least 12 h before
  discontinuation of CII.
• We recommend that sc insulin be administered
  before discontinuation of CII for patients
  without a history of diabetes who have
  hyperglycemia requiring more than 2 unit/h.
• We recommend POC testing with daily adjustment of
  the insulin regimen after discontinuation of CII.

54
Transition From Intravenous to Subcutaneous
Insulin

• Known Diabetics
• Calculate total daily insulin requirement
• based on insulin rate during the last 4-hours of
  infusion, (e.g., 2 units/hour 48 U/day)
• Start SC insulin as follow
• ½ dose as basal (Glargine, Detemir)
• ½ dose as prandial (Lispro, Aspart, Glulisine)
• If patient not able to eat give basal but hold
  prandial insulin

Smiley et al. Ann. N.Y. Acad. Sci 12121-11, 2010
55
Transition From Intravenous to Subcutaneous
Insulin

• No History of Diabetes (stress hyperglycemia)
• If HbA1c gt7, treat as diabetes
• If HbA1c lt6.4
• If insulin requirements during CII is lt2 U/hr,
  stop infusion and use correction doses for BG
  gt140 mg/dl
• If requirements gt2 U/hr during CII, start SC
  insulin
• ½ dose as basal (Glargine, Detemir)
• ½ dose as prandial (Lispro, Aspart, Glulisine)

Smiley et al. Ann. N.Y. Acad. Sci 12121-11, 2010
56
Continuous Subcutaneous Insulin Infusion
57
Keys to CSII Use in the Hospital

• AACE/ADA Inpatient Hyperglycemia
• Candidates for inpatient CSII use are those using
  CSII as outpatients
• Must have mental and physical capacity to do so
• Nursing personnel must document basal rates and
  bolus doses on regular basis
• Hospital personnel with expertise in CSII therapy
  is essential

58
Potential Issues with CSII Use

• Many nurses (and physicians) are unfamiliar with
  the technology and thus uncomfortable with
  allowing its continued use
• Knowledge scores 67 for those with prior
  experience with CSII user vs 17 (plt0.01)
• Agreed CSII effective strategy for managing
  diabetes in the hospital
• Only 27 thought they could safely care for a
  patient using CSII

Noschese et al. Diabetes. 200655846-P.
59
Policy for Continued CSII Use

• List of suggested contraindications
• Altered state of consciousness
• Critically ill
• Risk of suicide
• other reason deemed appropriate by MD
• Set of rules to guide medical staff
• Requirement of signed informed consent detailing
  conditions for CSII use

Bailon et al. Endocr Pract. 20091524-29.
60
Procedures for Patients Admitted to Hospital on
CSII

• Presence of insulin pump, brand of pump and
  insulin type are identified
• Blood or capillary glucose level is determined
• Contraindications for continued use of insulin
  pump are assessed
• Physician order for alternate insulin therapy is
  obtained if CSII must be discontinued
• Patients consent for CSII is obtained
• Admitting physician writes initial order for
  insulin pump therapy using the preprinted order
  form
• Endocrinology, diabetes education, and nutrition
  consultations are ordered by admitting physician
• Insulin pump basal-bolus blood glucose record
  flow sheet is placed at the patients bedside

Bailon et al. Endocr Pract. 20091524-29.
61
Insulin Pump TherapyOne Institutions Experience

• Frequency of hypoglycemic and hyperglycemic
  events among hospitalized patients receiving
  continuous subcutaneous insulin infusion (insulin
  pump) therapy

Leonhardi BJ, et al. J Diabetes Sci Technol.
20082(6)948-962
62
Pump On vs Pump Off
BG gt 200 mg/dL
BG lt 70 mg/dL
Bailon et al. Endocr Pract. 20091524-29.
63
Hypo and Hyperglycemia With and Without CSII
Bailon et al. Endocr Pract. 20091524-29.
64
Pitfalls to Continued CSII Use

• Limited experience
• Published reports suggest 1-2 patients/mo
• Supplies
• Tubing needs to be changed at most Q3days
• Different pumps need different reservoirs
• Determining who is in charge and tracking the
  insulin dosing
• Pumps and MRIs dont mix
• Note, this is continued not initiating

65
Conclusions
66
Summary

• Hyperglycemia is common in hospitals
• Evidence on the management of hyperglycemia in
  non-ICU settings is increasing
• Vast majority of studies utilize subQ insulin
• Intravenous insulin can be implemented in
  non-ICUs
• Has been most often studied in ICUs
• SubQ insulin infusion can be continued