Why tight glycaemic control may not be appropriate in ... Tight glycemmic... · Why tight glycaemic control may not be appropriate in hospital settings D Mesotten MD, PhD Katholieke

Why tight glycaemic control may notbe appropriate in hospital settings

D Mesotten MD, PhDKatholieke Universiteit Leuven

Department of Intensive Care MedicineUniversity Hospitals Leuven

Belgium

FDA public MeetingBlood Glucose Meters

16-17 March 2010

Blood glucose

Mor

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y

hypo normal for age “renal threshold”

adaptive?

innocent bystander?

contributing toadverse outcome?

Association blood glucose mortality

The Leuven hypothesis

TGC

Blood glucose

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“Hyperglycaemia is not adaptive”“Don’t Touch”

• Prospective randomized single centre trial in surgicalICU patients

• N=1548 mechanically ventilated / 12 months• TGC = insulin infusion for BGL 80-110mg/dL (4.4-

6.1mmol/L)• Conventional = only insulin when BGL >215mg/dL

(>12 mmol/L) and stopped when <180mg/dL (<10mmol/L) (“do not touch”)

• ICU mortality: 8.0% 4.6%• Glycaemia <40 mg/dL: 0.8% 5.1%

Leuven S-ICU study

Leuven S-ICU studyIC

U S

UR

VIV

AL

(%)

80

90

100ALL (1548) PATIENTS

p = 0.005

DAYS AFTER INCLUSION0 20 40 60 80 100120

Intensive

Conventional

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

HO

SP

ITA

L S

UR

VIV

AL

(%)

80

90

100

70

p = 0.01

100

0 40 80 120

Long-stay patientsp = 0.007

90

80

0 100 200

Long-stay patientsp = 0.02100

90

80

70

DAYS AFTER INCLUSION0 50 100 150 200

Intensive

Conventional

ALL (1548) PATIENTS

• Prospective randomized single centre trial inmedical ICU

• Powered for 4% ARR in long-stay patients

• n= 1200 n=767 long-stay / 3 years

• Same design as S-ICU study

• ICU mortality ITT: 26.8% 24.2%

• ICU mortality long stay: 38.1% 31.3%

• Hypoglycaemia: 3.1% 18.7%

Leuven M-ICU study

Leuven M-ICU study

.

20

40

60

80

100

hosp

ital s

urvi

val (

%)

0 100 200 300 500400

0 10 20 30

40

60

80

100

Days

first 30 days

p = 0.3

Intention-to-treat(N=1200)

Intensive

Conventional

40

60

80

100

0 10 20 30

first 30 days

0 100 200 300

Days50 150 250 350

20

40

60

80

100

p = 0.02

Intensive

Conventional

500

Long-stay (>3d)(N=767)

Predefined target population

Van den Berghe G et al. N Engl J Med. 2006; 354: 449-461

Mixed M-ICU/S-ICU population(N=2748)

Van den Berghe G et al. Diabetes 2006; 55: 3151-9

0.1.2.3.4.5

0 100 200 300 400 500 600

p = 0.006

In ICU at least 3 days (N = 1389)

Cumulative risk for in-hospital mortality

Hosp mort 38% -> 30%Intensive

Conventional

0

.1

.2

.3

0 100 200 300 400 500 600

p = 0.02

Intention-to-treat (N = 2748)

24% -> 20%- 4% - 8%

Leuven P-ICU study• Prospective randomized single centre

• TGC = normal for age

– infants : 50-80 mg/dL (2.8 - 4.4 mmol/L)

– children : 70-100 mg/dL (3.9 - 5.6 mmol/L)

• “Do not touch” = only insulin for glucose>215mg/dL (12 mmol/L)

• Primary end-point = length of stay

• Powered for effect on inflammation (CRP)

• N=700 (75% cardiac surgery)

Leuven P-ICU study

0 20 40 60 80 100

Cumulative incidence of PICU death (%)

1

0

2

3

456

p = 0.038

days after admission

Usual careTGC

N = 700

Vlasselaers et al. Lancet 2009;373: 547-56

5.7%

2.6%

3.1%

Hypoglycaemia 1 25%

Conclusion I

TGC

Blood glucose

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Compared with “do not touch” strategyachieved tight glycaemic control

improves the outcome of ICU patients

“Do nottouch”

Improved mitochondrialultrastructure and function(Vanhorebeek The Lancet 2005 &

Crit Care Med 2008)Strict bloodglucose control

with IITresults in:

Reduced endothelial activation(Langouche JCI 2005)

Improved leukocyte functionReduced inflammation (Ellger Diabetes 2006)

Improved cardiacfunction

(Ellger Diabetes 2006) Improved kidney function(Schetz et al JASN 2008; Vanhorebeek KI 2009)

• Single centre

• High study inclusion rate SICU 95%,MICU 60%, PICU 68%

• Passionate PI + nursing staff dedicatedto TGC

• Glucose measurements predominantlyarterial + blood gas analyzer

• Insulin infusion: central line + syringepump

The setting of the Leuven studies

STANDARDISATION: Proof-of-concept design

EXPERIENCE

PASSION

ADEQUATETECHNOLOGY

Follow-up studies on TGC

• Multi-centre studies– VISEP N Engl J Med 08

– GLUCONTROL Intensive Care Med 09

• Single-centre studies– Arabi et al Crit Care Med 09

– De La Rosa et al Crit Care 09

Flaws:

- VISEP + GLUCONTROL stopped early forhypoglycaemia

- Inadequate separation of glycaemic levels(target not reached)

- All underpowered to detect a mortalitydifference

Follow-up studies on TGC

The NICE-SUGAR trial• Sufficiently powered RCT with multi-centre

design• N=6104, expected to require ICU treatment for

>3days• Powered for 3.8% ARR in 90d mortality,

assuming baseline mortality of 30%• TGC = insulin infusion for BGL 81-108 mg/dL

(4.5-6.0 mmol/L)• Conventional = insulin infusion for BGL > 180

mg/dL (10 mmol/L) and stopped if < 144 mg/dL(8 mmol/L)

Mortality in NICE-SUGAR

The NICE-SUGAR investigators. N Engl J Med 2009; 360: 1283-97

Conventional glucose control 24.9%

Intensive glucose control 27.5%

+ 2.6%

How to explain the different outcome ?

Leuven NICE-SUGAR

DESIGNsetting Single centre MulticentreIntervention target 80-110 mg/dL 80-110 mg/dL

Control target 180-215 144-180

Mean morning BG control 152 ±32 145 ±26Mean morning BG TGC 105 ±24 118 ±35

more overlap

Van den Berghe G et al. J Clin Endocrinol Metab 2009; 94: 3163-70

The study hypothesis

BLOOD GLUCOSE

MO

RTA

LITY


The LEUVEN hypothesis

“Do not touch”

TGC

The NICE-SUGAR comparison

Inter-mediate

Post-hoc analysis of Leuven studies

Van den Berghe G et al. Diabetes 2006, 55: 3151-3159

Cumulative risk for in-hospital mortalityIntention-to-treat analysis (n=2748)

mean BG > 150 mg/dLmean BG 110-150 mg/dLMean BG < 110 mg/dLIntensive

Conventional

- 4%

0

.1

.2

.3

0 100 200 300 400 500 600

p = 0.02 0

.1

.2

.3

0 100 200 300 400 500 600

p = 0.0005

**

*

- 3%

- 1%

The study hypothesisThe study hypothesis

BLOOD GLUCOSE

MO

RTA

LITY


The LEUVEN hypothesis

“Do not touch”

TGC

The NICE-SUGAR comparison

Inter-mediate

1% ARR= 70.000 patients!!

How to explain the different outcome ?Leuven NICE-SUGAR

INTERVENTIONInstructions guideline + “if-then” algorithm

intuitive decision

Insulin only infusion infusion + bolus

syringe pumps all types of pumps

Sampling site arterial arterial/capillary

Measuring tool blood gas analyzer diverse methods


“with the use of POC glucose meters orblood gas analyzers or laboratory analyzersin routine use at each hospital”.

NO

Glucose meters were designed for the monitoring of bloodglucose levels in diabetics in a home environment and arenot accurate enough to keep BG levels within the narrowrange of TGC

Variation in paired measurement

1.7 mmol/L (30 mg/dL)TGC target range

2.8 mmol/L (50.4 mg/dL)Mixed methods

2.1 mmol/L (37.8 mg/dL)Strip POC

1.1 mmol/L (19.8 mg/dL)Hemocue

1.2 mmol/L (21.6 mg/dL)Laboratory

0.8 mmol/L (14.4 mg/dL)BGA

95% CIMethod of measurement

Duncan Young ISICEM 2009

Blood gas analyzer versus central lab

Kanji et al. Crit Care Med 2005; 33: 2778-2785

1% outsidetargetrange (20% error)

BGM with arterial blood versus central lab



BGM with capillary blood versus central lab



BGM versus ABL blood gas analyzer

• prospective single centre trial

• test the accuracy of 2 POC glucose meters in the settingof TGC in adult ICU-patients

• testing GLYCENSIT statistical procedure

• 452 arterial blood samples of 37 patients

• simultaneous analysis using 3 devices

ABL AccuChek HemoCue

0 50 100 150 200 250 300

350

300

250

200

150

100

50

0

ABL

Accu

Ch

eck

0 50 100 150 200 250 300

350

300

250

200

150

100

50

0

ABLH

em

ocu

e

r = 0.967(CI 0.961-0.973) (p<0.0001)r = 0.983(CI 0.980-0.988) (p<0.0001)

Correlation with ABL blood gas analyzer

AccuChek HemoCue

Vlasselaers D et. al J Diabetes Sci Technol 2008; 2: 932-938

Bland-Altman (ABL blood gas analyzer)

0 50 100 150 200 250 300 350

20

10

0

-10

-20

-30

-40

-50

-60

-70

AVERAGE (ABL+AccuChek/2) (mg/dl

dif

fere

nce

(A

BL

- A

ccu

Ch

ek)

(mg

/dl)

Mean

-6,3

-1.96 SD

-26,5

+1.96 SD

14,0

0 50 100 150 200 250 300 350

30

20

10

0

-10

-20

-30

-40

-50

-60

AVERAGE (ABL+HemoCue/2) (mg/dl)

dif

fere

nce

(A

BL

- H

emo

Cu

e) (

mg

/dl)

Mean

-10,9

-1.96 SD

-29,5

+1.96 SD

7,6

AccuChek HemoCue

14

-6.3

-26.5

7.6

-10.9

-29.5

95% CI= 40.5 mg/dL 95% CI= 37.1 mg/dL Vlasselaers D et. al J Diabetes Sci Technol 2008; 2: 932-938

TGC target range = 30 mg/dL

Hoedemaekers C et. al Crit Care Med 2008; 36: 3062-3066

BGM versus RapidLab blood gas analyzer28.8

-32.4

16.9

-22.3

61.2 mg/dL 39.2 mg/dL

TGC target range30 mg/dL

• Catecholamine therapyHassen MF et al. Diabetes Res Clin Pract 2010;

87: 87-91

• AnaemiaPidcoke HF et al. Crit Care Med 2010; 38: 471-

476

• Drugs e.g. ascorbic acid• Capillary – arterial blood• Unknown factors

Interfering factors for BGM in the ICU

Dungan K et. al Diabetes Care 2007; 30: 403-409

Leuven standing order = measure K+ with each bloodglucose check on ABL + maintain K+ > 4 mEq/L by IVpotassium supplements

Data from paediatric studyTGC : 6% more K+ values < 4 mEq/L

no difference in nr of K+ values < 3.5 or < 3 mEq/L

TGC : 55% more potassium supplements than in the usualcare group (p<0.01)

BGA = glucose + potassium


• Capillary blood sampling = inadequate• All POC glucose meters = inadequate

• So far, only combined measurement ofarterial glucose and potassium in ablood gas analyzer seems appropriate

Conclusion II

For TGC, or any narrow target range in the ICU

Proof-of-concept Confirmation studiesScience Clinical practiceEfficacy EffectivenessStrictly controlled PragmaticInternal validity External validity

Conclusion IIITGC = complex intervention

Underestimated giant step

TGC may not be appropriate in hospital settings

Summary

CONThe current methodology

PROThe scientific concept

Blood glucose

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Why tight glycaemic control may not be appropriate in ... Tight glycemmic... · Why tight glycaemic control may not be appropriate in hospital settings D Mesotten MD, PhD Katholieke