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New Approaches to Managing Inpatient Hyperglycemia
ACP Meeting MTP Session, April 24th, 2009
Review of Recent Developments
in Context
Greg Maynard MD, MScClinical Professor of Medicine and Chief,
Division of Hospital Medicine,University of California, San Diego
Greg Maynard MD, MScGreg Maynard MD, MSc
Has no relationships with any entity Has no relationships with any entity producing, marketing, re-selling, or producing, marketing, re-selling, or
distributing health care goods or services distributing health care goods or services consumed by, or used on, patients.consumed by, or used on, patients.
Disclosure of Financial RelationshipsDisclosure of Financial Relationships
Outline
• Glycemic Target Controversies
• Transition from Infusion
• Ward Glycemic Control
• Hypoglycemia
• Larger Context
AACE - Consensus Conference Blood Glucose Targets
• Upper Limit Inpatient Glycemic Targets:
– ICU: 110 mg/dl (6.1 mmol/L)
– Non-critical care (limited data)• Pre-prandial: 110 mg/dl (6.1 mM)• Maximum: 180 mg/dL (10 mM)
AACE- Endocrine Practice 10 (1): 77-82, 2004ADA- Diabetes Care 27: 553-591, 2004
The current ADA guideline for pre-prandial plasma glucose is now < 126
mg/dLDiabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.
Negative Studies of Infusion Insulin
• Recent negative studies – Glucontrol, VISEP, JAMA Meta-Analysis Vol
300 (8):933-944.
• Caveats– Discontinued early– Poor protocols drove results (viewed as
suboptimal)– Delta Glucose less than desirable– Very high hypoglycemia rates seen in these
studies….3 x hypoglycemia rate seen in U.S.
NICE – SUGARMarch 26, 2009 NEJM Vol 360 (13)
• Open Label RCT, Multinational
• 6104 critically ill patients
• Intensive infusion (81-108 mg/dL) vs “Conventional” control (144 – 180 mg/dL)
• 90 day survival – primary end point
Blood Glucose Values, According to Treatment Group
The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297
Probability of Survival
Odds Ratios for Death, According to Treatment Group
The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297
NICE - SUGAR
90 day mortality 27.5% vs 24.9%Severe hypoglycemia 6.8% vs 0.5%Glucose control (median) 107 vs 141 mg/dLInsulin infusion 97% vs 69%
No difference – 30 day mortality, ICU days, hospital days, days of mechanical ventilation, days of renal replacement, organ failures
Summary Data from Randomized Clinical Trials of Intensive Insulin Therapy in Critically Ill Patients
Inzucchi S and Siegel M. N Engl J Med 2009;360:1346-1349
Severe Hypoglycemia (< 40 mg / dL) with Different Infusion Protocols
Leuven I (Surgical) 5.1%Leuven 2 (Medical) 19%Glucontrol (Med / Surg) 8.6%VISEP (Medical) 17%Yale (Surgical) 0%Yale (Medical) 4.3%Glucommander (Surgical) 2.6%NICE – SUGAR (Med / Surg) 6.8%
Van Den Berghe G, et al. N Engl J Med. 2001:345:1359; Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461; Brunkhorst et al, N Engl J Med 358:125-39, 2008Goldberg PA, et al. Diabetes Care. 2004;27:461; Goldberg PA, et al. J Cardiothorac Vasc Anes. 2004;18:690; Davidson PC. Diabetes Care. 2005;28:2418.NICE – SUGAR investigators NEJM 2009 360 (13) 1283-1297
UCSD Insulin Infusion200 Med Surg patients
>16,000 values Upper Limit – 150 mg /dL
Mean BG126 Median BG121 below 90 6.1% 91-150 76.6% above 150 17.3% % below 70 < 2% Only 2 patients with any glucose < 40 mg/dL
NICE-SUGAR vs UCSD
NICE - SUGAR UCSD
Target Range
(mg / dL)
80 – 110 90 – 150
Median Glucose 118 121
Severe Hypoglycemia
6.8% < 2%
AACE - Consensus Conference Blood Glucose Targets
• Upper Limit Inpatient Glycemic Targets:
– ICU: 110 mg/dl (6.1 mmol/L)
– Non-critical care (limited data)• Pre-prandial: 110 mg/dl (6.1 mM)• Maximum: 180 mg/dL (10 mM)
AACE- Endocrine Practice 10 (1): 77-82, 2004ADA- Diabetes Care 27: 553-591, 2004
The current ADA guideline for pre-prandial plasma glucose is now < 126
mg/dLDiabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.
AACE - Consensus Conference Blood Glucose Targets
• Upper Limit Inpatient Glycemic Targets:
– ICU: 110 mg/dl (6.1 mmol/L)
– Non-critical care (limited data)• Pre-prandial: 110 mg/dl (6.1 mM)• Maximum: 180 mg/dL (10 mM)
AACE- Endocrine Practice 10 (1): 77-82, 2004ADA- Diabetes Care 27: 553-591, 2004
The current ADA guideline for pre-prandial plasma glucose is now < 126
mg/dLDiabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.
RCTs with demonstrating convincing benefit of TGC on general med – surg wards:
? New AACE / ADA Guidelines ?
BAD BADGOOD
Hypoglycemia HyperglycemiaSomewhere in the Middle
<40 70 110 140 170 >200
Transitions
Transition from Infusion InsulinRamos, Childers, Maynard – SHM Abstract
N = 41
UCSD new Transition Protocol
• Need SC insulin when infusion stops?YES-
DM1 DM 2 or A1c ≥ 6 and infusion rate ≥ 1 unit / hourOn high dose steroids and rate ≥ 1 unit / hour
NO-Type 2 DM with infusion rate < 1 unit / hourStress hyperglycemia with HbA1c < 6
Even if high infusion rates
Step by Step
• Stable enough for transition?• Need SC insulin with transition?• Calculate TDD
– If taking in nutrition on infusion:IR x 20 = TDD– If not taking nutrition on infusion, infusion only
serving basal needsIR x 40 = TDD
• Give 40-50% of TDD as basal glargine BEFORE you stop the insulin infusion
Run Chart: Outcome MeasuresGlycemic control 48 hrs post transition with and without
protocol.Glucose averages before and after transition from infusion insulin
75
100
125
150
175
200
225
250
6HR 5HR 4HR 3HR 2HR 1HR 1-6HR
7-12HR
13-18HR
19-24 HR
25-30 HR
31-36 HR
37-42 HR
43-48HR
Avera
ge g
lucose m
g/
dL
Protocol NotUsed
Insulin PerProtocol
No Insulin PerProtocol
Insulin Infusion Day 1 Day 2
Transition Time
Outcome Measures
Severe Hypoglycemia (<40 mg/dL)3 of 114 transitions or 2.6%.
Protocol followed1 of 66 patients or 1.5%
Protocol not followed2 of 48 patients or 4.2%
Methods for Managing Methods for Managing Hospitalized Non-ICU Patients Hospitalized Non-ICU Patients
With DiabetesWith Diabetes
• Basal/bolus therapy (MDI)Basal/bolus therapy (MDI)
– Long-acting and rapid-acting insulinLong-acting and rapid-acting insulin
– NPH and Regular insulinNPH and Regular insulin
• Sliding Scale Short-Acting Insulin Sliding Scale Short-Acting Insulin
Treatment Groups:
Insulin glargine once daily + supplemental insulin glulisine (n=65) N= 130
Sliding scale regular insulin four-times daily (n=65)
Study Type: Prospective, randomized, open-label trial
Patient Population: 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy
Study Sites: Grady Memorial Hospital, AtlantaJackson Memorial Hospital, Miami
Randomized Basal Bolus versus Sliding Scale Regular Insulin Therapy in patients with type 2 Diabetes (RABBIT-2 Trial)
• D/C oral antidiabetic drugs on admission
• Starting total daily dose (TDD): – 0.4 U/kg/d x BG between 140-200 mg/dL– 0.5 U/kg/d x BG between 201-400 mg/dL
• Half of TDD as insulin glargine and half as rapid-acting insulin (lispro, aspart, glulisine)– Insulin glargine - once daily, at the same time/day. – Rapid-acting insulin- three equally divided doses (AC)
Smiley & Umpierrez, Southern Med J, June 2006
(RABBIT-2 Trial) Basal / Bolus arm
Blood Glucose Levels During Isulin Treatment
Days of Therapy
Blo
od
glu
cose
(m
g/d
L)
100
120
140
160
180
200
220
240
Admit 1 2 3 4 5 6 7 8 9 10
SSRI
Lantus + glulisine
Mean Blood Glucose Levels During Insulin Therapy
* p<0.01¶ p<0.05
¶* * *
¶ ¶ ¶
Day 3: P=0.06
Umpierrez, Diabetes Care 30: 2007
Basal–Bolus Insulin Regimen in Basal–Bolus Insulin Regimen in Noncritically Ill Patients Noncritically Ill Patients
Days of Therapy
0 1 2 3 4 5 6 7 8 9 10 11 12
Blo
od G
luco
se (
mg/
dL)
100
120
140
160
180
200
220
240
260
280
300
SSRILantus plus Glulisine
Admit 1 2 3 4 1 2 3 4 5 6 7
Blood Glucose Levels in Patients Who Failed SSRI:Transition to Basal Bolus Insulin
Failure was defined as 3 consecutive BG values > 240 mg/dL during SSRI
¶
P: NS P: 0.02
¶¶
¶¶
Umpierrez, Diabetes Care 30: 2007
RABBIT 2
• Improved glycemic control with basal / bolus insulin regimen compared to SSRI
• Subset that failed with SSRI controlled with basal / bolus
• No difference in hypoglycemia – (3% of patients in each arm)
Umpierrez, Diabetes Care 30: 2007
Effect of Structured Insulin Orders and an Insulin Management Algorithm -
UCSD• 400 bed academic center• All adult monitored stays on Med / Surg wards
with dx of DM or Documented Hyperglycemia n = 9,314 > 7 readings n = 5,530
• What is effect of implementing a structured insulin order set?
• What is the incremental effect of an insulin management protocol?– Insulin Use Patterns– Glycemic Control – Hypoglycemia
Maynard et al, JHM January 2009; 4: 3-15
The Use of Basal Insulin Increases(sliding scale only regimens decline)
Percent Sliding Scale Insulin Only
0
10
20
30
40
50
60
70
80
Per
cent
10/20/03
New Order Set
01/20/04
CPOE - TH
72% of 477 insulin regimens SSI only in May-Oct 2003 vs 26% of 499 in Mar-Aug 2004
% of 9,314 Patient-Stays with Uncontrolled Hyperglycemia
A Win / Win Situation5,530 patients with DM or Hyperglycemia and > 7
POC Glucose readings TP3:TP1
RR Uncontrolled Patient-Day
0.77 (0.74 - 0.80)
RR Uncontrolled Patient-Stay (70% controlled vs 60%)
0.73 (0.66 - 0.81)
RR Hypoglycemic Patient-Day (prevents 208 / year)
0.68 (0.59 – 0.80)
RR Hypoglycemic Patient-Stay
0.77 (0.64 – 0.92)
Maynard et al, JHM January 2009; 4: 3-15
Methods for Managing Methods for Managing Hospitalized Non-ICU Patients Hospitalized Non-ICU Patients
With DiabetesWith Diabetes
• Basal/bolus therapy (MDI)Basal/bolus therapy (MDI)
– Long-acting and rapid-acting insulinLong-acting and rapid-acting insulin
– NPH and Regular insulinNPH and Regular insulin
• Sliding Scale Short-Acting Insulin Sliding Scale Short-Acting Insulin
Blo
od
glu
co
se
(mg
/dL
)
Duration of Therapy (days)
Detemir + NovologNPH + Regular
DEAN-Trial
Basal/bolus regimen: Detemir was given once daily and Novolog before meals.NPH/regular regimen: NPH and Regular insulin were given twice daily, 2/3 A.M., 1/3 P.M.
Data are ± SEM
HypoglycemiaHypoglycemia
• Detemir/Aspart Group:Detemir/Aspart Group:– 22 patients (32.8%) had ≥ 1 BG < 60 mg/dL22 patients (32.8%) had ≥ 1 BG < 60 mg/dL– 3 patients (4.5%) had a < 40 mg/dL (0.2%)3 patients (4.5%) had a < 40 mg/dL (0.2%)
• NPH/Regular Group:NPH/Regular Group:– 16 patients (25.4%) had ≥ 1 BG < 60 mg/dL 16 patients (25.4%) had ≥ 1 BG < 60 mg/dL – 1 patient (1.6%) had a BG < 40 mg/dL1 patient (1.6%) had a BG < 40 mg/dL
ADA, 68th Scientific Sessions, 2008; JCEM, in press
RABBIT-2 vs. DEAN Trials
Days of Insulin therapy
Blo
od
Glu
co
se
(m
g/d
L)
120
140
160
180
200
220
240
SSRIGlargie + GlulisineDetemir + AspartNph + Regular
Admit 1 2 3 4 5 6 7-10
Umpierrez et al, ADA, 68th Scientific Sessions, 2008; JCEM, in press Umpierrez et al, Diabetes Care 30:2181–2186, 2007
Blood Glucose Concentration During SSRI, NPH-regular, and Basal Bolus Regimen in Medical Patients with Type 2
Diabetes
DEAN Trial
Percent of Glucose values within target (< 140 mg/dl)
RABBIT-2 Trial
% %38%
66%
48%45%
*
* P < 0.01
Umpierrez et al. JCEM, in press Umpierrez et al. Diabetes Care 30:2181–86, 2007
%
25.4
32.8
Rate of Hypoglycemia(# patients with BG < 60 mg/dl)
33
%
DEAN TrialRABBIT-2 Trial
Umpierrez et al. JCEM, in press Umpierrez et al. Diabetes Care 30:2181–86, 2007
Summary – Ward Glycemic Control
• Optimal Glycemic Target Uncertain – My bias: Fasting should likely be < 150 mg/dL– Upper limit of no sugars > 180 mg/dL reasonable
• Basal / Bolus regimens with Glargine / RAA-insulin more effective than sliding scale and present no higher risk of hypoglycemia
• Well executed order sets / protocols can improve glycemic Well executed order sets / protocols can improve glycemic control control and reduceand reduce hypoglycemia. hypoglycemia.
• Detemir/aspart resulted in equivalent glycemic control to a Detemir/aspart resulted in equivalent glycemic control to a split-mixed NPH and regular regimen (but hypoglycemia split-mixed NPH and regular regimen (but hypoglycemia higher than with RABBIT 2 regimen and UCSD regimens) higher than with RABBIT 2 regimen and UCSD regimens)
Hypoglycemia
Precipitating factors
Etiologic factor % of hypo cases
Reduction in enteral intake 40
Insulin adjustment 6.1
Steroid withdrawal 0.4
Unclear 43
“Diverse causes” 10.4
Medication error noneVarghese P, et al. J Hosp Med. 2007; 2:234-240)
Hypoglycemia follow-up
1/3 with documented BG rechecked within 60 minutes
< 50% with documented euglycemia within 2 hours of low
Average time to documented resolution was 4 hrs, 3mins (median 2 hrs, 25mins)
Varghese P, et al. J Hosp Med. 2007; 2:234-240)
Provider Response to Insulin-Induced Hypoglycemia in Hospitalized
Patients
• Case series – 52 patients
• Delays in treatment
• Suboptimal adjustment of regimens common
Garg, et al. J Hosp. Med. 2007; 2:258-260
Iatrogenic Hypoglycemia – Risk Factors, Treatment, and
Prevention• 130 ward inpatients monitored for glucose
• 65 consecutive cases with iatrogenic hypoglycemic day
• Matched 1:1 with controls (monitored, similar hospital day, not hypoglycemic)
• Examine risk factors for hypoglycemia
• Study hypoglycemia treatment and adjustments made to prevent recurrence
Maynard et al, Diabetes Spectrum 2008 Vol 21:4 241-247.
Hypoglycemia – 65 cases
Severe (≤ 40 mg / dL) 11 17%
Nutrition / insulin mismatch 32 49%
Absent documentation 19 29%
Time next value (minutes) 60 (8 – 600)
Time to resolution (minutes) 180 (10 – 1,260)
Temporary harm 2 3%
Hypoglycemic Cases vs Controls
Univariate Unadjusted Statistically Different
Lower weight: 73.4 vs 89.7 Kg
Lower BMI: 26 vs 31
More CKD / ESRD: 35% vs 17%
More CHF: 37% vs 15%
Hypoglycemia: Take Home Points
Suboptimal response to hypoglycemia is the rule– Nurses and physicians!
• Opportunities for prevention often missed.• Make a change after hypoglycemic event. • Mere Existence of a hypoglycemia protocol does
not guarantee good management
• SC insulin protocols promoting basal / bolus regimens can achieve improved control safely ---hypoglycemia can even be reduced.
Society of Hospital MedicineBig Picture Context
• DM / Hyperglycemia very common
• Controversy over exact glycemic target distracts from larger issues
• Chaos and avoidable hyper- and hypo-glycemia are the rule
• Alternatives (SSI, laissez faire) don’t work and can be dangerous
• Standardization / team approach / protocols / order sets / metrics
Inpatient DM Resources
http://www.aace.com/resources/igcrc/
http://www.hospitalmedicine.org/ResourceRoomRedesign/GlycemicControl.cfm
SHM Glycemic Control Mentored Implementation Program
Questions / Comments
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