A short history of glucose control in critical illness

A short history of glucose control in critical care

Tom Pratt

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

The discovery of insulin

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

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.

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.

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.

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.

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.

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

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

1978 2015

Arthur Riggs Keiitchi Itakura

Genentech produce the first synthetic human insulin

The Leuven papers

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

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

2001 2015

Leuven 1

• 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

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

Diabetes Leuven2-h post-prandial 200 mg/dL 11.1 mmol/L

Leuvenconventional

treatment↑↑↑ 180 mg/dL 10 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

2001 2015


Participant recruitment poorly documented in Leuven 1 Note very high use of insulin in treatment arm

2001 2015


2001 2015

Crit Care Med 2004; 32: 858-73

Tight glycemic control even proposed as core quality of care measure for the Medicare program

• 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

2001 2015


2001 2015


Mortality of control group much lower than might be expected for a general ICU

NEJM 2008; 358: 125-39

2005

• P - Adult patients with severe sepsis or septic shock in 18 academic tertiary hospitals in Germany



• 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)

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

2006

Leuven 2

• P - All adult patients admitted to medical ICU in a University teaching hospital and expected to stay >48 hours



• O - All cause in hospital mortality

2006


2006


2:1 screening to recruitment ratio seems very low for a large trial

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)

2006

ICU mortality

0%

10%

20%

30%

40%


26.8%

8%

24.2%

4.6%


2006

In-hospital mortality

0%

10%

20%

30%

40%


10.9%7.2%


2006

In-hospital mortality

0%

10%

20%

30%

40%


40%

10.9%

37.3%

7.2%


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

The second wave

Diabetes Leuven2-h post-prandial 200 mg/dL 11.1 mmol/L

Leuvenconventional



↓↓↓




intensivetherapy

80 mg/dL 4.4 mmol/L

NEJM 2001; 345: 1359-67 / WHO 2006

Diabetes Leuven Glucontrol2-h post-prandial 200 mg/dL 11.1 mmol/L

Leuvenconventional


Glucontrolgroup 1


↓↓↓




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

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

2009


2009


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

2009

• P - All adult patients admitted to the ICUs of 42 hospitals in North America, Australia and New Zealand


• 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

2009

NEJM 2009; 360: 1283-97

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

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

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

• 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

“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

–Jasper Carrott

“Laughter is the best medicine - unless you’re a diabetic, then insulin comes pretty high on

the list”

A short history of glucose control in critical illness

Health & Medicine

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