Blood Sugar Control in ICU

Muhammad Asim Rana MBBS, MRCP, FCCP, SF-CCM, EDIC

Department of Critical Care MedicineKing Saud Medical City

Riyadh Saudi Arabia

Introduction

• Hyperglycemia is common in critically ill patients .

• Current literature shows conflicting results on the effects of more intensive glucose controls versus conventional glucose control in critically ill patients.

Case Study 1• 32 years male without any prior medical history, admitted

to surgical ICU after an assault with head & chest injuries • Second day routine labs showed random blood sugar to be

more than 10mmols• Repeated labs failed to show a fall below 8.5mmols

• Is he a diabetic?• What should be our plan to control the blood sugar?

Why control of blood sugar is necessary?

Case Study 2• 52 years male with prior medical history of HTN on Rx,

admitted to surgical ICU post laparotomy for bowel perforation & septic shock

• Labs showed random blood sugar to be more than 8.0mmols• Repeated attempts failed to control blood sugar on subcut

insulin

• Are we on right track?• What should be our plan to control the blood sugar?

Why control of blood sugar is necessary?

Remember

• Hyperglycemia commonly ensues, even in patients who do not have pre-existing diabetes mellitus.

• The rationale behind the use of insulin therapy in critically ill patients is that severe injury or infection alters carbohydrate metabolism, which results in insulin resistance.

Three Types of Hyperglycemic Patient

• Known history of diabetes• Existing, but unrecognized, diabetes• Stress hyperglycemia

Clement et al. Diabetes Care. 2004;27:553-591.

Hyperglycemia Adversely Affects Outcomes

• Hyperglycemia impacts• Mortality• Morbidity • Rate of infections• Length of stay in ICU (LOS)

Why blood sugar control is important ?

~2x

Mor

talit

y Ra

te (%

)

Mean Glucose Value (mg/dL)

Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.

N=1826 ICU patients.

0

5

10

15

20

25

30

35

40

45

80-99 100-119 120-139 140-159 160-179 180-199 200-249 250-299 >3000

5

10

15

20

25

30

35

40

45

0

5

10

15

20

25

30

35

40

45

Hyperglycemia and Mortality in the MICU

~4x~3x

Blood Glucose (mg/dL)

<150 150- 175

200- 225

175- 200

>250225- 250

P<0.0001

*P<0.001

PostopMortality

BG <200n=662

1.8%

BG >200

n=1369

5.0% *

Post

op M

orta

lity

(%)

Adjusted for 19 clinical and operation variables

Furnary AP et al. Circulation. 1999:100 (Suppl I): I-591.

1.4 1.72.1

3.8

5.8

8.6

0

2

4

6

8

10

Hyperglycemia: A Predictor of Mortality Following CABG in Diabetics

CABG, coronary artery bypass graft.

First Postop Glucose >200• 2x LOS• 3x Vent duration• 7x mortality !!!

OMG !!!!

… THE HISTORY OF ICMThe milestone study which revolutionized …

Wake up… here comes…

Intensive Insulin Management in Medical-Surgical ICU

Krinsley JS. Mayo Clin Proc. 79:992-1000, 2004.

Mean BG Levels(mg/dL)

P < 0.001

Hospital Mortality (%)

P < 0.002

29.3% Reduction

Baseline group (n = 800) Glucose management group (n = 800)

Study Setting Population Clinical Outcome

Furnary, 1999 ICU DM undergoing open heart surgery 65% infection

Furnary, 2003 ICU DM undergoing CABG 57% mortality

Krinsley, 2004 Medical/surgical ICU Mixed, no Cardiac 29% mortality

Malmberg, 1995 CCU Mixed 28% mortalityAfter 1 year

Van den Berghe, 2001* Surgical ICU Mixed, with CABG 42% mortality

Lazar, 2004 OR and ICU CABG and DM 60% A Fib post op survival 2 yr

*RCT, randomized clinical trial.

Kitabchi & Umpierrez. Metabolism. 2008;57:116-120.

Benefits of Tight Glycemic Control: Observational Studies and Early Intervention Trials

Intensive Insulin Therapy in Critically Ill Patients: The Leuven SICU Study

• Randomized controlled trial: • 1548 patients admitted to a surgical ICU, receiving mechanical

ventilation. Patients were assigned to receive either:

• Conventional therapy: IV insulin only if BG >215 mg/dL• Target BG levels: 180-200 mg/dL• Mean daily BG: 153 mg/dL

• Intensive therapy: IV insulin if BG >110 mg/dL• Target BG levels : 80-110 mg/dL• Mean daily BG: 103 mg/dL

Van den Berghe et al. N Engl J Med. 2001;345:1359-1367.

Intensive Insulin Therapy in Critically Ill Patients: SICU

*

*

*

*

*

*

*P<0.01

Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. Relative Risk Reduction (%)

34%

46%

41%

Intensive Glucose Management in RCT

Trial N Setting Primary Outcome

ARR RRR Odds Ratio(95% CI)

P-value

Van den Berghe2006

1200 MICU Hospital mortality

2.7% 7.0% 0.94* (0.84-1.06)

N.S.

HI-52006

240 CCU AMI 6-mo mortality

-1.8%* -30%* NR N.S.

Glucontrol2007

1101 ICU ICU mortality

-1.5% -10% 1.10*(0.84-1.44)

N.S.

Ghandi2007

399 OR Composite 2% 4.3% 1.0*(0.8-1.2)

N.S.

VISEP2008

537 ICU 28-d mortality

1.3% 5.0% 0.89*(0.58-1.38)

N.S.

De La Rosa 2008

504 SICUMICU

28-d mortality

-4.2% * -13%* NR N.S.

NICE-SUGAR2009

6104 ICU 3-mo mortality

-2.6% -10.6 1.14(1.02-1.28)

< 0.05

*not significant

What is NICE-SUGAR?

N I C E S U G A RNormoglycaemia

Intensive

Care

Evaluation

Survival

Using

Glucose

Algorithm

Regulation

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

Description

• 3054 patients were assigned to the intensive control group and 3050 to the conventional control group.

• 829 patients(27.5%) died in the intensive control group and 751(24.9%) in the conventional-control group which is a difference between surgical vs. medical ICU patients.

• Severe hypoglycemia (<40 mg/dL) was recorded in 6.8% of patients in the intensive control group, vs. 0.5% in the conventional group.

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

Probability of Survival and Odds Ratios for Death, According to Treatment Group

Nice Sugar, NEJM 2009;360:1283

Favors Favors IIT Conventional

Operative Admission

Diabetes

Severe Sepsis

Trauma

Apache Score

Corticosteroids

All deaths at day 90

NICE - SUGAR

• 90 day mortality 27.5% vs 24.9%• Severe hypoglycemia 6.8% vs 0.5%• Glucose control (median) 107 vs 141 mg/dL• Insulin infusion 97% vs 69%

No difference

• 30 day mortality • ICU days• Hospital days• Days of mechanical ventilation• Days of renal replacement• Organ failures

Discussion

Positives:• Large multi-center study.• Robust statistical analysis.• Use of a uniform insulin protocol between sites.• The primary outcome in this in unbiased.• Good representation od critically ill patients• Enrolled more patients than trials that preceded it.

Discussion

Limitations:• More patients in the IIT group received corticosteroids

which could effect the variable were studying• 10% if the IIT discontinued prematurely.• No significant difference in the primary outcome, death.• Inclusion criteria ,i.e., length of stay is a subjective

parameter.• The study was not blinded to the treating personnel

Why the differences?When all the available data are considered, an important step is to establish reasons for the discrepancies in the published literature.

Reasons for discrepancies

• Differences in populations of patients (for example, reasons for admittance to the ICU),

• Insulin-treatment protocols, • Mortality, • Glucose goals, • Glucose concentrations actually achieved • The use of parenteral nutrition• The expertise and experience of nursing staff at a

particular institution could also influence the outcome

Methods used to measure glucose

• Another critical, but frequently overlooked, factor is the method used to measure glucose levels.• Arterial blood gas analyzer• Capillary blood with point of care meters• Differences among precesion of different glucometers

Patient-specific factors

• Some glucose meters are affected by partial pressure of oxygen and hematocrit.

• Reduced tissue perfusion in hypotensive patients results in large differences in glucose concentrations in capillary blood samples, despite minimal alterations in arterial blood samples.

• Another variable is that the glucose concentrations in arterial, venous and capillary blood all differ. • Although these differences are minimal in fasting individuals, postprandial capillary

glucose values are 1.1–1.4 mmol/l higher than those in venous blood. • Finally, as a consequence of differences in water content, glucose

concentrations in plasma are ~11% higher than those in whole blood if the hematocrit is normal.

• Some, or perhaps all, of these factors might have contributed to the results reported by the NICE-SUGAR investigators.

Questions

1. What is the optimal target for the glucose therapy.2. Does a particular sub-set of patients benefits from

tight glucose control3. What about hypoglycemia?4. Strategies for the future management of blood

glucose in the ICU

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/dL

Diabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

Is Hypoglycemia Life-threatening?

Griesdale et al., CMAJ 2009;180:821

Favors IIT Favors ControlHypoglycemic events

Favors IIT Favors Control

All Mixed ICU

All Medical ICU

All Surgical ICU

ALL ICU

0.99 (0.87-1.12)

1.00 (0.78-1.28)

0.63 (0.44-0.91)

0.93 (0.83-1.04)

Points to ponder

• The NICE-SUGAR trial adds to the accumulating data on the use of tight glucose control protocols in patients in the ICU; however, this study does not 'close the case' on these protocols.

• Further large trials are necessary if the question of whether intensive insulin therapy improves the outcomes of selected ICU patients is to be unequivocally resolved.

• As the dose of insulin used in critically ill patients is determined exclusively by their blood glucose value, accurate measurement of glucose concentration is essential to achieve the desired targets and to avoid hypoglycemia.

• In multicenter trials, a particularly important issue is that glucose measurements among institutions are standardized to avoid variability among patients.

• Highly accurate measurements of glucose concentration will, therefore, be necessary in future research

Practice Points

• Intensive insulin therapy to maintain blood glucose concentrations <6.0 mmol/l in patients hospitalized in the intensive-care unit might increase mortality

• Patients enrolled in NICE-SUGAR who received intensive insulin therapy had increased hypoglycemia and cardiovascular mortality compared with patients who received conventional insulin therapy

• Accurate measurement of blood glucose concentration is necessary to achieve the desired target and avoid hypoglycemia

Thank you very much