Bin Du - Glycemic Control in Critically Ill Patients - Magic or Myth

Glycemic Control in the Critically IllMagic or Myth?

Bin Du, MDMedical Intensive Care Unit

Peking Union Medical College Hospital

Hyperglycemia in Critically Ill Patients

0.8% 1.7%

10.0%

0%

10%

20%

Normoglycemia Known diabetes New hyperglycemia

10.0% 11.0%

31.0%

0%

20%

40%


Total In-patient MortalityNon ICU Mortality

ICU Mortality

Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87(3): 978-82

More than 80 to 90% ICU patients with BS > 126 mg/dl No DM history in about 60%

In 1548 patients in SICU, 98.7% had a BS level > 110 mg/dl

1.7% 3.0%

16.0%

0%

10%

20%


Factors Related to Hospital Death

Predictive Factor OR (95%CI)

Age, per decade 2.2 (1.2 4.2)

Maximal daily SOFA score > 8 9.6 (7.8 11.9)

Poor glycemic control 1.5 (1.1 2.0)

Average cumulative insulin 100 U/d 3.8 (1.8 7.7)

Defined as glucose values of 144 mg/dL or less for less than 5% of total hospital stay time

Rady MY, Johnson DJ, Patel BM, Larson JS, Helmers RA. Influence of individual characteristics on outcome of glycemic control in intensive care unit patients with or without diabetes mellitus. Mayo Clin Proc. 2005;80:1558-1567.

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

Hyperglycemia and Prognosis

0

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80-99 100-119 120-139 140-159 160-179 180-199 200-249 250-299 >300Mean Blood Glucose in ICU (mg/dl)

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1826 consecutive ICU patients 10/99 thru 4/02, Stamford CT

Hyperglycemia: Potential Risks

Impairment of immune function Reduction of neutrophil function Attenuation of complement binding Disruption of monocyte phagocytic function Defect of PMN

Proinflammatory & prothrombotic effects Altered cell membrane

Insulin: Potential Benefits

Regulates vasomotor function and contractility of the myocardium

Stimulates nitric oxide production Improves endothelial function Lowers cytokines Improves protein balance and fat metabolism

Intensive Insulin Therapy in Surgical ICU

Randomization

Control Group IIT Group

Blood glucose at initiation of insulin therapy > 215 mg/dL > 110 mg/dL

Blood glucose during insulin therapy

180 200 mg/dL(10.0 11.1 mmol/L)

80 110 mg/dL(4.4 6.1 mmol/L)

Use of insulin in 39% Use of insulin in 99%

Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367

Intensive Insulin Therapy in Surgical ICU

Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367

-34%

-46%-41%

-50%-44%

-60%

-40%

-20%

0%Mortality Sepsis Dialysis Transfusion Polyneuropathy

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Intensive Insulin Therapy in Medical ICU

van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006; 354: 449-61

Intensive Insulin Therapy in Medical ICU

van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006; 354: 449-61

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IIT: Meta-analysis (n = 35)

35 trials included in the meta-analysis Reduction in death 15%

(RR 0.85; 95% CI 0.75-0.97) Subgroup analysis

Surgical ICU(RR 0.58; 95% CI 0.22-0.62)

Glucose goal(RR 0.71; 95% CI 0.54-0.93)

All patients with diabetes mellitus(RR 0.73; 95% CI 0.58-0.90)

Pittas AG, Siegel RD, Lau J. Insulin Therapy for Critically Ill Hospitalized Patients: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2004;164: 2005-2011

SSC Guideline: Glycemic Control

Use IV insulin to control hyperglycemia in patients with severe sepsis following stablization in the ICU

(1B) Aim to keep blood glucose < 150 mg/dl (8.3

mmol/L) using a validated protocol for insulin dose adjustment

(2C)Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36(1): 296-327. Erratum in: Crit Care Med 2008; 36(4): 1394-1396.

Intensive vs. Conventional : VISEP

Conventional Intensive

HES

290 247

Ringers Lactate

Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125-139.

Intensive vs. Conventional : VISEP

Conventional(n = 290)

Intensive(n = 247)

28-day mortality 26.0% 24.7%

90-day mortality 35.4% 39.7%

Severe hypoglycemia (%) 12 (4.1%) 42 (17.0%)

p < 0.001

Brunkhorst FM, Kuhnt E, Engel C, Meier-Hellmann A, Ragaller M, Quintel M, Weiler N, Grundling M, Oppert M, Deufel T, et al. Intensive insulin therapy in patient with severe sepsis and septic shock is associated with an increased rate of hypoglycemia - results from a randomized multicenter study (VISEP) [abstract]. Infection 2005;33: 19-20.

Glycemic Control in ICU: More RCTs

Glucontrol Trial Prospective, randomized, single-blinded clinical trial BG 80 110 mg/dL vs. 140 180 mg/dL Primary outcome: mortality Secondary outcome: LOS, incidence of hypoglycemia Sample size: 3500 patients Prematurely terminated in March, 2006 after enrolment

of 1101 patients Significantly higher incidence of adverse events in intensive

insulin therapy group

Shorr AF. Building the Evidence Base for Clinical Decision Making in the ICU. http://www.medscape.com/viewarticle/555169. accessed on July 30, 2007

Glycemic Control in ICU: Glucontrol

8.6

2.4

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Intensive insulin Control

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Shorr AF. Building the Evidence Base for Clinical Decision Making in the ICU. http://www.medscape.com/viewarticle/555169. accessed on July 30, 2007

IIT in ICU: Data From Columbia

Prospective, randomized, non-blinded, single-center clinical trial A medical/surgical ICU in a university hospital Randomization

Intensive insulin therapy: 80 110 mg/dl Standard insulin therapy: 180 200 mg/dl

Primary outcome 28-day mortality: 36.6% vs. 32.4% (p > .05)

Secondary outcome Prevalence of severe hypoglycemia: 8.3% vs. 0.8% (p < .001)

De La Rosa GD, Donado JH, Restrepo AH, et al. Strict glycemic control in patients hospitalized in a mixed medical and surgical intensive careunit: a randomized clinical trial. Crit Care 2008; 12: R120.

Intensive Insulin Therapy in DMADVANCEACCORD

The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2559.The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572.

Real Life Might Be Quite Different

Why Glycemic Control Ineffective

Comparison of different protocols Blood glucose measurement Titration of insulin

Efficacy of protocol in glycemic control Blood glucose target Patient population that may benefit

Glycemic Control in ICU (n = 7)

Author Study Design Setting Case No. End-point

van den Berghe Prospective randomized SICU 1548 Mortality

Krinsley Before-and-after M/SICU 1600 Mortality

Kanji Before-and-after M/SICU 50 Protocol evaluation

Laver Prospective cohort M/SICU 27 Protocol evaluation

Goldberg Prospective cohort MICU 52 Protocol evaluation

van den Berghe Prospective randomized MICU 1200 Mortality

Brunkhorst Prospective randomized M/SICU 537 Mortality

Glycemic Control in ICU (n = 7)

Author Sample Device Protocol Target

van den Berghe Arterial ABL 700 Leuven 4.4 6.1

Krinsley Plasma Vitros 950/250 Stamford < 7.7

Kanji Capillary AccuCheck Ottawa 4.5 6.1

Laver Arterial (most) AccuCheck Bath IIP 4.0 7.0

Goldberg Fingertip One Touch Yale IIP 5.5 7.7

van den Berghe Arterial/Capillary ABL 700/HemoCue Leuven 4.4 6.1

Brunkhorst Arterial/capillary HemoCue Leuven 4.4 6.1

Glucose Measurements: Various Techniques

Setting: Medical ICU in university teaching hospital Patients: 49 consecutive admissions

Age 63.9 18.8, male 29/49 (59%), DM 15/49 (31%) APACHE II 20.3 7.2 ICU mortality 15/49 (31%)

Glucose measurement Venous blood/Blood chemistry Capillary blood/Surestep TM Arterial blood/Surestep TM Arterial blood/ABL 735 Arterial blood/Blood chemistry

Peng J, Liu Y, Meng Y, et al. Factors influencing accuracy of blood glucose measurements in critically ill patients. Crit Care 2008; 12 (Suppl 2): P163Liu Y, Wu D, Song X, et al. Accuracy of point-of-care blood glucose measurements in the medical ICU. Crit Care 2008; 12 (Suppl 2): P167

Discrepancy with Reference Method

0 2 4 6 8 10 12 14 16 18 20-10-8-6-4-202468

10

The reference glucose (mmol/l)

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Point-of-care blood glucose testing in acute and chronic care facilities, approved guideline 2002, 2nd edition (document C30-A2), CLSI: http://www.nccls.org, accessed 9 January 2007

> 0.83 mmol/L (15 mg/dl) difference for laboratory values <

4.12 mmol/L (75 mg/dl)

> 20% difference for laboratory level 4.12

mmol/L (75 mg/dl)


Methods Mean SD (mmol/l) Bias SD (mmol/l) Discrepancy (%)

Venous/Blood chemistry 7.4 2.7 NA NA

Capillary/Surestep TM 9.1 2.7 1.7 1.4 66.2 (96/145 )

Arterial/Surestep TM 8.9 2.5 1.6 1.4 60.9 (84/138 )

Arterial/ABL-735 8.5 2.9 1.2 1.2 40.0 (58/145 )

Arerial/Blood chemistry 7.9 2.7 0.6 1.2 23.7 (33/139)Peng J, Liu Y, Meng Y, et al. Factors influencing accuracy of blood glucose measurements in critically ill patients. Crit Care 2008; 12 (Suppl 2): P163Liu Y, Wu D, Song X, et al. Accuracy of point-of-care blood glucose measurements in the medical ICU. Crit Care 2008; 12 (Suppl 2): P167


Kanji S, Buffie J, Hutton B, Bunting PS, Singh A, McDonald K, Fergusson D, McIntyre LA, Hebert PC. Reliability of point-of-care testing for glucose measurement in critically ill adults. Crit Care Med 2005; 33: 2778-2785

% Agreement % Agreement in hypoglycemia

Arterial/Glucose Meter 69.9% 55.6%

Arterial/ABG or Chemistry 76.5% 64.9%

Capillary/Glucose Meter 56.8% 26.3%


Conclusion The magnitude of the differencesbydifferent

methodsled to frequent clinical disagreements regarding insulin dose titration

Kanji S, Buffie J, Hutton B, Bunting PS, Singh A, McDonald K, Fergusson D, McIntyre LA, Hebert PC. Reliability of point-of-care testing for glucose measurement in critically ill adults. Crit Care Med 2005; 33: 2778-2785

Glycemic Control in ICU: Protocol

Wilson M, Weinreb J, Soo Hoo GW. Intensive Insulin Therapy in Critical Care. A review of 12 protocols. Diabetes Care 2007; 30: 1005-1011

Ineffective Glycemic Control by Protocol

Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, OBrian PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, McMahon MM. Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery. A Randomized Trial. Ann Intern Med 2007; 146: 233-243

BG 4.4 5.6 mmol/L BG < 11.1 mmol/L


Insulin Control Difference P value

Intraoperative

Baseline BG 6.2 1.2 6.2 1.7 0 (-0.3 to 0.3) 0.98

Post-CPB BG 6.8 1.3 8.2 1.9 -1.4 (-1.8 to -1.1) < 0.001

ICU

Baseline BG 6.3 1.6 8.7 2.3 -2.4 (-2.8 to -1.9) < 0.001

BG at 24 h 5.7 0.9 5.8 1.2 -0.1 (-0.3 to 0.2) 0.72Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, OBrian PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, McMahon MM. Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery. A Randomized Trial. Ann Intern Med 2007; 146: 233-243


Medical ICU at university teaching hospital 55 consecutive admissions 3 phases Control: personal judgment Intervention 1: BG 4.5 7.5 mmol/L without protocol Intervention 2: BG 4.5 7.5 mmol/L with protocolAccording to protocol by Meynaar

Meynaar IA, Dawson L, Tangkau PL, et al. Introduction and evaluation of a computerised insulin protocol. Intensive Care Med 2007; 33: 591-596


Control(n = 17)

Intervention 1(n = 20)


Male sex 11 11 10

Age 64.6 16.5 69.6 11.2 60.8 19.7APACHE II 22.5 7.5 24.1 10.8 22.7 11.0History of DM 6 9 4

Medical admission 17 19 17

Major reason for ICU admission

Respiratory 6 10 7

Septic shock 5 5 4

LOS 4.4 2.2 3.8 2.0 4.4 1.9


Control(n = 17)



BG at ICU admission 9.4 4.8 10.5 6.5 9.7 3.4Mean BG level 8.6 [7.5, 10.0] 8.5 [7.4, 9.3] 7.1 [6.3, 8.3]

Within target BG

Time (h) 6.6 [2.4, 11.4] 7.2 [3.2, 10.8] 11.0 [ 6.9, 19.1]

(%) 27.4 [9.8, 47.6] 30.3 [13.3, 45.1] 46.0 [28.8, 79.4]

Above target BG

Time (h) 17.1 [10.9, 21.5] 15.9 [10.8, 20.6] 10.1 [2.4, 16.6]

(%) 71.1 [45.5, 89.4] 66.2 [44.9, 85.9] 42.2 [10.1, 69.1]

HGI (mmol/L) 1.52 [0.69, 2.77] 1.30 [0.76, 2.14] 0.25 [0.03, 1.03]


Control(n = 17)



Below BG level

Time (h) 0.0 [0.0, 0.0] 0.0 [0.0, 1.1] 0.0 [0.0, 2.2]

(%) 0.0 [0.0, 0.0] 0.0 [0.0, 4.4] 0.0 [0.0, 9.3]

Severe hypoglycemia (< 2.2 mmol/L)

Episode (%) 1 (0.4) 2 (0.4) 3 (0.6)

Hospital-days (%) 1 (1.3) 2 (2.6) 2 (2.5)

IIT: Risk Factor for Hypoglycemia

van den Berghe 7.50 (4.50 12.50)

Pittas 3.4 (1.9 6.3)

Glycemic Control in ICU: Guideline?

Is the evidence enough?

Strict glycemic control Grade C Single-center clinical trial

No, not quite

Angus DC, Abraham E. Intensive insulin therapy in critical illness: when is evidence enough? Am J Respir Crit Care Med 2005; 172: 1358-1359

IIT: More Questions Than Answers

Target BG level Inconsistent results of RCTs Lack of multicenter RCTsRisk of severe hypoglycemiaWorkload for euglycemia

Bellomo R, Egi W. Glycemic control in the intensive care unit: why should we wait for NICE-SUGAR. Mayo Clin Proc 2005; 80: 1546-1548

Glycemic Control in ICU: Underlying Dis.

No Glycemic Control

(n = 4459)

Glycemic Control

Nondiabetic(n = 1743)

Diabetic(n = 1083)

Maximal daily SOFA score 3 (0 8) 7 (4 11) 5 (1 10)

Mechanical ventilation 652 (15) 1179 (67) 390 (36)

BG (mg/dL) 118 (97 153) 134 (110 181) 170 (121 238)

Stay time with BG 144 mg/dL (%) 93 (32 100) 71 (18 91) 30 (0 81)

Hospital death (%) 5 (4 6) 10 (9 12) 6 (4 7)

LOS (day) 4.4 (1.2 11.3) 8.0 (4.2 22.0) 6.7 (2.3 15.6)



ConclusionDifferent BG range for glycemic control in

diabetic and nondiabetic patients Higher in diabetic patients?

One size does not fit all



Different Thresholds for Glycemic Control in Diabetic Physiologic readjustment to higher glucose level in

diabetic patients Greater increments necessary for hyperglycemia to exert its

adverse effects Less intense injury sufficient to increase glucose in

diabetic patients Hyperglycemia in diabetics not a reflection of severity-of-

illness

Bellomo R, Egi W. Glycemic control in the intensive care unit: why should we wait for NICE-SUGAR. Mayo Clin Proc 2005; 80: 1546-1548

Glycemic Control in Trauma Patients

Collier et al Before-and-after study > 700 trauma patients No benefit of strict glucose control

van den Berghe et al Subgroup analysis (trauma) Higher mortality in intensive insulin therapy: 12.1%

(4/33) vs. 8.6% (3/35)Collier B, Diaz J Jr, Forbes R, et al. The impact of a normoglycemic management protocol on clincial outcomes in the trauma intensive care unit.JPEN J Parenter Enteral Nutr. 2005;29:353-359.Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367.

Summary

Hyperglycemia as independent prognostic factor for critically ill patients

Significantly less hyperglycemia with protocol Significantly more hypoglycemia with protocolNo evidence of improvement of outcome in

patients with strict glycemic control

Glycemic Control in the Critically IllMagic or Myth?Hyperglycemia in Critically Ill PatientsFactors Related to Hospital DeathHyperglycemia and PrognosisHyperglycemia: Potential RisksInsulin: Potential BenefitsIntensive Insulin Therapy in Surgical ICUIntensive Insulin Therapy in Surgical ICUIntensive Insulin Therapy in Medical ICUIntensive Insulin Therapy in Medical ICUIntensive Insulin Therapy in Medical ICUIIT: Meta-analysis (n = 35)SSC Guideline: Glycemic ControlIntensive vs. Conventional : VISEPIntensive vs. Conventional : VISEPGlycemic Control in ICU: More RCTsGlycemic Control in ICU: GlucontrolIIT in ICU: Data From ColumbiaIntensive Insulin Therapy in DMReal Life Might Be Quite DifferentReal Life Might Be Quite DifferentReal Life Might Be Quite DifferentWhy Glycemic Control IneffectiveGlycemic Control in ICU (n = 7)Glycemic Control in ICU (n = 7)Glucose Measurements: Various TechniquesDiscrepancy with Reference MethodGlucose Measurements: Various TechniquesGlucose Measurements: Various TechniquesGlucose Measurements: Various TechniquesGlycemic Control in ICU: ProtocolGlycemic Control in ICU: ProtocolGlycemic Control in ICU: ProtocolIneffective Glycemic Control by ProtocolIneffective Glycemic Control by ProtocolIneffective Glycemic Control by ProtocolIneffective Glycemic Control by ProtocolIneffective Glycemic Control by ProtocolIneffective Glycemic Control by ProtocolIIT: Risk Factor for HypoglycemiaGlycemic Control in ICU: Guideline?IIT: More Questions Than AnswersGlycemic Control in ICU: Underlying Dis.Glycemic Control in ICU: Underlying Dis.Glycemic Control in ICU: Underlying Dis.Glycemic Control in Trauma PatientsSummary

Bin Du - Glycemic Control in Critically Ill Patients - Magic or Myth

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