A short history of glucose control in critical illness
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Transcript of A short history of glucose control in critical illness
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A short history of glucose control in critical care
Tom Pratt
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1.1, 1.3, 1.6, 4.1, 4.8
Treatment strategies for abnormalities of fluid, electrolyte, acid-base and glucose balance
3.5, 3.9 Principles of blood glucose control: indications, methods, monitoring of safety and efficacy
4.1, 4.7 Physiology of fluid, electrolyte, acid-base and glucose control
4.8 Recognises and manages electrolyte, glucose and acid-base disturbances
4.8 Pathophysiological consequences, signs and symptoms of disordered fluid, electrolyte, acid-base and glucose balance
4.8 Effect of critical illness upon homeostatic mechanisms and causes of homeostatic disturbances
4.8, 4.9 Principles of blood glucose control: indications, methods, monitoring of safety and efficacy
4.8, 4.9 Institute and manage a regimen to control blood glucose within safe limits
6 Perioperative management of patients with diabetes; blood glucose control;
Curriculum 2014
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1.1, 1.3, 1.6, 4.1, 4.8
Treatment strategies for abnormalities of fluid, electrolyte, acid-base and glucose balance
3.5, 3.9 Principles of blood glucose control: indications, methods, monitoring of safety and efficacy
4.1, 4.7 Physiology of fluid, electrolyte, acid-base and glucose control
4.8 Recognises and manages electrolyte, glucose and acid-base disturbances
4.8 Pathophysiological consequences, signs and symptoms of disordered fluid, electrolyte, acid-base and glucose balance
4.8 Effect of critical illness upon homeostatic mechanisms and causes of homeostatic disturbances
4.8, 4.9 Principles of blood glucose control: indications, methods, monitoring of safety and efficacy
4.8, 4.9 Institute and manage a regimen to control blood glucose within safe limits
6 Perioperative management of patients with diabetes; blood glucose control;
Curriculum 2014
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The discovery of insulin
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1869 2015
Paul Langerhans (1847-1888)
Langerhans’ undergraduate MD thesis described dissection of a rabbit pancreas. He identifies “small cells of almost perfect homogeneous content and of a polygonal form, with round nuclei without nucleoli, mostly lying together in pairs or small groups”, but their role is unknown
1874 diagnosed with TB and abandoned academic studies
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1889 2015
Oskar Minkowski (1858-1931)
Joseph von Mering (1849-1908)
In order to investigate the function of the pancreas they undertook pancreatectomy in previously house-trained dogs, resulting in polyuria and incontinence. Noticing that the urine attracted flies they tested the it and found it to contain sugar.
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1900 2015
Eugene Lindsay Opie (1873-1971)
A medical student at the time, Opie observed consistent morphological alterations in the islets of Langerhans of diabetic patients. Would also go on to describe the pathology of gallstone pancreatitis.
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1916 2015
Israel Kleiner (1885-1966)
Nicolae Paulescu (1869-1931)
George Ludwig Zeulzer (1870-1949)
1906 20151916 2015
All developed pancreatic extracts used successfully in animals, though not humans, but in all cases their work was interrupted by WW1.
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Frederick Banting (1891-1941)
E Clark Noble (1900-1978)
1921 2015
Charles Best (1899-1978)
Banting, a surgeon, believed that through selective arterial and ductal ligation it should be possible to isolate the islet cells and hence produce a purer pancreatic extract. He convinced J. R. R. McLeod to allow him use of his lab over the summer holidays and was ‘loaned’ two medical students to assist. As only one was required at a time they tossed a coin to see who took the first session.
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Frederick Banting (1891-1941)
1921 2015
Charles Best (1899-1978)
Best won the toss and his work with Banting was so productive that he stayed the entire summer.
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Leonard Thompson (1908-1935)
1922 2015
First patient to receive Banting’s extract was Leonar Thompson, then age 14 and dying of diabetes. He received a Bovine extract, the first dose of which almost killed him due to a severe immune reaction. A modified formula proved more successful and Thompson lived to age 27
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1950 20151969 2015
Frederick Sangar (1918-2013)
Dorothy Hodgekin (1910-1994)
Sangar determined insulin’s DNA sequence in 1950 Hodgekin identified the tertiary structure of the insulin molecule using x-ray crystallography in 1969
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1978 2015
Arthur Riggs Keiitchi Itakura
Genentech produce the first synthetic human insulin
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The Leuven papers
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1991 20151995 2015
Stress Level
Urine Nitrogen (g/day)
Plasma Lactate
(mmol/L)
Plasma Glucose (mg/dL)
Insulin Resistance
Oxygen Consumption (mL/min/m2)
LOW <10 <1.5 <150 No <140MID 10-20 1.5-3.0 150-250 Some 140-180
HIGH >20 >3.0 >250 Yes >180
Mizock. Am J Med 1995; 98: 75-84
Stroke outcome
Mean glucose (mmol/L) P-value Alive at 6
monthsMean glucose
(mmol/L) P-value
GOOD 4.75 (4.53-4.99)0.02
Yes 5.01 (4.85-5.19)0.03
POOR 5.43 (3.48-6.35) No 5.67 (5.11-6.46)
O’Neill et al. Stroke 1991; 22: 842-7
Growing body of evidence that glucose and outcome are linked, and that stress hyperglycaemia is a maladaptive response
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1999 2015
Malmberg. JACC 1995; 26: 57-65 / Malmberg. Circulation 1999; 99: 2626-32 / Scott. Stroke 1999; 30: 793-9
Conflicting results of tight glycemic control in acute CVS disease; AMI (DIGAMI) good, Stoke (GIST) unclear
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2001 2015
Leuven 1
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• P - All ventilated patients admitted to a mixed surgical/medical ICU in a University teaching hospital
• I - Intensive insulin therapy to maintain a blood glucose level of 80-110 mg/dL (4.4-6.1 mmol/L)
• C - Insulin therapy to maintain a blood glucose level of 180-200 mg/dL (10.0-11.1 mmol/L)
• O - All cause mortality during intensive care stay
2001 2015
Van den Berghe et al. NEJM 2001; 345: 1359-67
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• P - All ventilated patients admitted to a mixed surgical/medical ICU in a University teaching hospital
• I - Intensive insulin therapy to maintain a blood glucose level of 80-110 mg/dL (4.4-6.1 mmol/L)
• C - Insulin therapy to maintain a blood glucose level of 180-200 mg/dL (10.0-11.1 mmol/L)
• O - All cause mortality during intensive care stay
2001 2015
Van den Berghe et al. NEJM 2001; 345: 1359-67
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Diabetes2-h post-prandial 200 mg/dL 11.1 mmol/L
↑↑↑
Impaired glucose tolerance
↓↓↓
140 mg/dL 7.8 mmol/L
Fasting 126 mg/dL 7.0 mmol/L
IFG 110 mg/dL 6.1 mmol/L
WHO 2006
Diabetic diagnostic thresholds as per WHO
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Diabetes Leuven2-h post-prandial 200 mg/dL 11.1 mmol/L
Leuvenconventional
treatment↑↑↑ 180 mg/dL 10 mmol/L
Impaired glucose tolerance
↓↓↓
140 mg/dL 7.8 mmol/L
Fasting 126 mg/dL 7.0 mmol/L
IFG 110 mg/dL 6.1 mmol/LLeuven
intensivetherapy
80 mg/dL 4.4 mmol/L
NEJM 2001; 345: 1359-67 / WHO 2006
It could be argued that the Leuven 1 paper compared normoglycaemia to a diabetic state
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2001 2015
Van den Berghe et al. NEJM 2001; 345: 1359-67
Participant recruitment poorly documented in Leuven 1 Note very high use of insulin in treatment arm
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2001 2015
Van den Berghe et al. NEJM 2001; 345: 1359-67
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2001 2015
Crit Care Med 2004; 32: 858-73
Tight glycemic control even proposed as core quality of care measure for the Medicare program
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• Single-centre study
• Predominance of surgical patients
• Early use of glucose infusions and TPN
• Risk of hypoglycaemia
• High nursing intensity
2001 2015
Devos and Preiser. Crit Care 2004; 8: 427-9 / Angus and Abraham. Am J Respir Crit Care Med 2005; 172: 1358-9
Significant early criticisms
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2001 2015
Van den Berghe et al. NEJM 2001; 345: 1359-67
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2001 2015
Van den Berghe et al. NEJM 2001; 345: 1359-67
Mortality of control group much lower than might be expected for a general ICU
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NEJM 2008; 358: 125-39
2005
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• P - Adult patients with severe sepsis or septic shock in 18 academic tertiary hospitals in Germany
• I - Intensive insulin therapy to maintain a blood glucose level of 80-110 mg/dL (4.4-6.1 mmol/L)
• C - Insulin therapy to maintain a blood glucose level of 180-200 mg/dL (10.0-11.1 mmol/L)
• O - All cause 28-day mortality and morbidity by SOFA score
Brunkhorst et al. NEJM 2008; 358: 125-39
2005
Multi-centre two-by-two factorial trial Fluid resuscitation with 10% pentastarch (HES 200/0.5) or Hartmann’s Two-stage adaptive design (n=600 for stage one) Intensive insulin therapy terminated after first safety analysis (n=488) Resuscitation fluid trial abandoned after first interim analysis (n=537)
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INSULIN THERAPY FLUID RESUSCITATION
Intensive Conventional HES CSL
↓BM 42/247 (17.0%)
12/290 (4.1%) P<0.001 Renal
failure91/261 (34.9%)
62/272 (22.8%) P=0.002
Mortality 98/247 (39.7%)
102/288 (35.4%) P=0.31 Mortality 107/261
(41.0%)93/274 (33.9%) P=0.09
Brunkhorst et al. NEJM 2008; 358: 125-39
2005
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2006
Leuven 2
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• P - All adult patients admitted to medical ICU in a University teaching hospital and expected to stay >48 hours
• I - Intensive insulin therapy to maintain a blood glucose level of 80-110 mg/dL (4.4-6.1 mmol/L)
• C - Insulin therapy to maintain a blood glucose level of 180-200 mg/dL (10.0-11.1 mmol/L)
• O - All cause in hospital mortality
2006
Van den Berghe et al. NEJM 2006; 354: 449-61
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2006
Van den Berghe et al. NEJM 2006; 354: 449-61
2:1 screening to recruitment ratio seems very low for a large trial
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2006
ICU mortality
0%
10%
20%
30%
40%
Leuven 1 Intensive Leuven 2 Intensive Leuven 1 Conventional Leuven 2 Conventional
8%4.6%
Significant reduction in mortality seen only for patients staying longer than 3 days for ICU (31.3% vs. 38.3%, P=0.05) and in-hospital mortality (43.0% vs. 52.5%, P=0.0009) Compare with insulin-arm of the VISEP trial (safety concerns)
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2006
ICU mortality
0%
10%
20%
30%
40%
Leuven 1 Intensive Leuven 2 Intensive Leuven 1 Conventional Leuven 2 Conventional
26.8%
8%
24.2%
4.6%
Significant reduction in mortality seen only for patients staying longer than 3 days for ICU (31.3% vs. 38.3%, P=0.05) and in-hospital mortality (43.0% vs. 52.5%, P=0.0009) Compare with insulin-arm of the VISEP trial (safety concerns)
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2006
In-hospital mortality
0%
10%
20%
30%
40%
Leuven 1 Intensive Leuven 2 Intensive Leuven 1 Conventional Leuven 2 Conventional
10.9%7.2%
Significant reduction in mortality seen only for patients staying longer than 3 days for ICU (31.3% vs. 38.3%, P=0.05) and in-hospital mortality (43.0% vs. 52.5%, P=0.0009) Compare with insulin-arm of the VISEP trial (safety concerns)
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2006
In-hospital mortality
0%
10%
20%
30%
40%
Leuven 1 Intensive Leuven 2 Intensive Leuven 1 Conventional Leuven 2 Conventional
40%
10.9%
37.3%
7.2%
Significant reduction in mortality seen only for patients staying longer than 3 days for ICU (31.3% vs. 38.3%, P=0.05) and in-hospital mortality (43.0% vs. 52.5%, P=0.0009) Compare with insulin-arm of the VISEP trial (safety concerns)
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2006
0%
10%
20%
30%
40%
28-day mortality 90-day mortality Hypoglycaemia
17%
39.7%
24.7% 25.1%
35.9%
29.9%
Leuven 2 Intensive VISEP Intensive
Rate of hypoglycaemic events significantly higher in Leuven 2, but unlike VISEP this did not lead to termination of the trial
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The second wave
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Diabetes Leuven2-h post-prandial 200 mg/dL 11.1 mmol/L
Leuvenconventional
treatment↑↑↑ 180 mg/dL 10 mmol/L
Impaired glucose tolerance
↓↓↓
140 mg/dL 7.8 mmol/L
Fasting 126 mg/dL 7.0 mmol/L
IFG 110 mg/dL 6.1 mmol/LLeuven
intensivetherapy
80 mg/dL 4.4 mmol/L
NEJM 2001; 345: 1359-67 / WHO 2006
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Diabetes Leuven Glucontrol2-h post-prandial 200 mg/dL 11.1 mmol/L
Leuvenconventional
treatment↑↑↑ 180 mg/dL 10 mmol/L
Glucontrolgroup 1
Impaired glucose tolerance
↓↓↓
140 mg/dL 7.8 mmol/L
Fasting 126 mg/dL 7.0 mmol/L
IFG 110 mg/dL 6.1 mmol/LLeuven
intensivetherapy
Glucontrolgroup 2
80 mg/dL 4.4 mmol/L
NEJM 2001; 345: 1359-67 / WHO 2006 / Intens Care Med 2009; 35: 1738-48
Second wave of papers tested a more liberal glycemic management policy
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2009
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2009
• P - All adult patients admitted to 21 European ICUs
• I - Insulin therapy to maintain a blood glucose level of 7.8-10.0 mmol/L
• C - Insulin therapy to maintain a blood glucose level of 4.4-6.1 mmol/L
• O - All-cause ICU mortality
Preiser et al. Intens Care Med 2009; 35: 1738-48
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2009
Preiser et al. Intens Care Med 2009; 35: 1738-48
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2009
Preiser et al. Intens Care Med 2009; 35: 1738-48
OUTCOME GROUP 1 (7.8-10.0 MMOL/L)
GROUP 2 (4.4-6.1 MMOL/L) P VALUE
ICU MORTALITY 83 (15.3%) 92 (17.2%) 0.410
28-DAY MORTALITY 83 (15.3%) 100 (18.7%) 0.1438
HYPOGLYCAEMIA 2.7 (13%) 8.7 (44%) <0.0001
• Trial halted at first interim analysis due to high rate of unintended protocol violations
• 32% power to detect a 4% difference in mortality
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2009
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2009
• P - All adult patients admitted to the ICUs of 42 hospitals in North America, Australia and New Zealand
• I - Intensive insulin therapy to maintain a blood glucose level of 81-108 mg/dL (4.5-6.0 mmol/L)
• C - Conventional insulin therapy to maintain a blood glucose level below 180 mg (10.0 mmol/L)
• O - All-cause 90-day mortality
NEJM 2009; 360: 1283-97
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2009
NEJM 2009; 360: 1283-97
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2009
NEJM 2009; 360: 1283-97
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2009
NEJM 2009; 360: 1283-97
OUTCOMEINTENSIVE GLUCOSE CONTROL
CONVENTIONAL GLUCOSE CONTROL
P VALUE
90-DAY MORTALITY 829 (27.5%) 751 (24.9%) 0.02
28-DAY MORTALITY 670 (22.3%) 627 (20.8%) 0.02
HYPOGLYCAEMIA 206 (6.8%) 15 (0.5%) <0.001
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Accuracy of point of care testing
Vlasselaers et al. J Diabetes Sci Technol 2008; 2: 932-8
Most glucometers are designed for outpatient use and not intended for tight glucose control. The FDA permits a 20% error in a POC glucometer, vs. 10% for laboratory analysers
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Gem Premiere 4000 vs. laboratory analyser
-3!
-2!
-1!
0!
1!
2!
3!
0! 2! 4! 6! 8! 10! 12! 14! 16! 18! 20!
Diff
eren
ce (m
mol
/L)!
Average (mmol/L)!
0.3 ± 1.4 mmol/L (5.41 ± 25.26 mg/dL)
Blood gas analysers also differ significantly from laboratory results
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• The results of the Leuven 1 trial have not been replicated by subsequent studies
• Tight glycaemic control is labour-intensive and leads to high rates of hypoglycaemia
• The debate is not over…
2015
Summary
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“The question is not whether TGC, minimal GV, and prevention of iatrogenic hypoglycemia are appropriate objectives, but how they are best achieved.”
“…none of the current meta-analyses can unequivocally confirm or refute potential benefits of a tight or very tight glucose control, especially in a specific patient population.”
“This review attempts to re-analyze the current literature and suggests that hope for a benefit from TGC should not be so hastily abandoned.”
2015
Gardner. Indian J Crit Care Med 2014; 18: 807-13
Kuppinger and Hartl. Nutrition 2013; 29: 708-12
Rattan and Nasraway. J Diab Sci Tech 2013; 7: 548-554
TGC = tight glycaemic control GV = glycaemic variation
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–Jasper Carrott
“Laughter is the best medicine - unless you’re a diabetic, then insulin comes pretty high on
the list”