1. INSULIN THERAPY IN ICU
Dr SANJAY KALRA, D.M. [AIIMS]

2. OUR VISION To be a globally-acknowledged centre of excellence for clinical care, education & training, and research in diabetology and endocrinology.

3. EVOLUTION OF INSULINOLOGY
1922 – DISCOVERY OF INSULIN
1993 – tight glycemic control is beneficial in T1DM – DCCT
tight glycemic control is beneficial in T2DM – UKPDS
– GIK infusion in diabetic MI
2001 – insulin in ICU patients

4. EVOLUTION OF CRITICAL CARE
1940 – FIRST COMMERCIAL VENTILATOR [SPIROPULSATOR]
1942 – Penicillin
2001 – INSULIN in ICU patients

5. HYPERGLYCEMIA IN THE CRITICALLY ILL
No clear guidelines for defining hyperglycemia in the critically ill
Wide variation in reported incidence: to 71% (Capes, 2000)

6. HYPERGLYCEMIA IN THE CRITICALLY ILL
Aim of treatment until recently: lower blood glucose to <220 mg% (Boord, 2001) in fed, critically ill patients
Avoid osmotic diuresis and fluid shift
Avoid infections
Moderate hyperglycemia was thought to be beneficial for brain and blood cells, that rely solely on glucose for energy (McCowen, 2001)

7. ‘STRESS DIABETES’ Increase in hepatic gluconeogenesis
Increased levels of
Glucagon (Hill, 1991)
Cortisol (Khani, 2001)
Growth hormone
Cytokines IL-1 (Flores, 1990), IL-6, TNF
Increase in hepatic glycogenolysis
Increased levels of
Adrenaline
Noradrenaline (Watt, 2001)
Cytokines IL-1, IL-6, TNF (Sakurai, 1996)

8. ‘STRESS DIABETES’ INSULIN RESISTANCE
Even in previously non-diabetic persons
At receptor, post-receptor level
In liver, skeletal muscle, heart (Mizock, 2001)

9. ACUTE vs. CHRONIC CRITICAL ILLNESS
ACUTE PHASE commonly seen
Efficient neuro-endocrine adaptation
Body provides endogenous energy to cover period of temporary starvation by gluconeogenesis, glycogenolysis
The ‘fight, flight, fright mechanism’: hyperglycemia may help

10. ACUTE vs. CHRONIC CRITICAL ILLNESS
CHRONIC PHASE is a different paradigm (Berghe, 1998); more frequent now
No efficient adaptive response; fall in GH, catecholamine, cytokine, cortisol (van den Berghe, 2001)
Starvation is not a major concern
Hyperglycemia: deleterious effects enter the arena

11. PRESENT SCENARIO
30% of tertiary level ICU patients need >5 days of intensive care (Takala, 1999)
>20% do not survive
Commonest culprit: septic shock (Parrillo, 1993)
Polyneuropathy and skeletal muscle wasting lead to prolonged mechanical ventilation, with reduced survival (Leitjen, 1994)

12. PRESENT SCENARIO
Increasing ICU admissions; longer survival in ICU means more costs
Compare the cost of insulin with that of 4th gen antibiotics or ventilatory support

13. IN-HOSPITAL HYPERGLYCEMIA
An independent marker of in-hospital mortality in patients with undiagnosed diabetes (Umpierrez, 2002)
Diabetes detected in 38% (12% previously unknown) of 2030 consecutive adult indoor patients. No glycemia measured in 7% patients
Survival least in newly-diagnosed diabetics (18.3x  mortality vs. 2.7x in known diabetics)
42% new diabetics vs. 77% old diabetics treated with insulin

14. IN-HOSPITAL HYPERGLYCEMIA
Normo-glycemia
Known diabetes
New hyper-glycemia
Total mortality
1.7%
3.0%
16%
Non-ICU mortality
0.8%
10%
ICU mortality
11%
31%
The JURY: stress diabetes is dangerous

15. THE LEUVEN STUDY
1548 mechanically-ventilated patients admitted to ICU after surgery/trauma
INTENSIVE THERAPY GROUP: aim for blood glucose mg%
CONVENTIONAL APPROACH: aim for blood glucose mg%; begin insulin only if BG > 215 mg% (van den Berghe, 2001, 2003)
Continuous infusion of 50 U insulin in 50 ml 0.9% NaCl given thru’ pump. Whole-blood arterial glucose tested at 1-4 hour intervals

16. RESULTS: MORTALITY
Strict glycemic control reduced intensive care mortality by 42% (8.0% to 4.6%, p=0.036)
Best results in prolonged critical illness: mortality reduced from 20.2% to 10.6% (p = 0.005)
Even moderate hyperglycemia (120 – 220 mg%) led to higher mortality. Principal cause of death: Multiple organ failure
Autopsy-proven septic focus less common in intensive group (8 vs. 33 deaths, p=0.02)

17. RESULTS: MORBIDITY Intensive insulin therapy reduced the
Duration of ventilatory support
Duration of intensive care stay
Need for blood transfusions
Incidence of septicemia by 46%
Excessive inflammation (CRP)
Need for >10 days antibiotics by 35%
Critical illness polyneuropathy
Acute renal failure by 42%

18. ? A PANACEA FOR ICU Exact mechanisms remain uncertain ? Due to insulin
? Due to good glycemic control
Both daily dose of insulin and mean glucose level increased mortality
?due to both

19. DIGAMI TRIAL
Diabetics with acute MI randomized to conventional or intensive groups
GIK infusion x 48 hours followed by SC insulin x 3 months
Aim: blood glucose < 220 mg%
Insulin led to improvement in (Malmberg 1999)
30-day survival
1 year survival
Reinfarction rates
New cardiac failure

20. Is it the nurse or the injection which saved me ?
INSULIN IN M.I.
GIK infusion in previously non-diabetic individuals with acute MI is life-saving: meta-analysis (Fath-Ordoubadi, 1997)
ECLA Study (Diaz, 1998)

21. INSULIN IN STROKE
GIST (Glucose-Insulin in Stroke Trial) did not show lower glycemia or mortality with GIK regime in acute stroke (Scott, 1999)
However, this study did not target normoglycemia
Hyperglycemia is predictor of mortality in traumatic head injury and stroke (rovlias, 2000)

22. INSULIN & INFECTION
IV insulin infusion reduced post-cardiac surgery deep sternal wounds (0.8% vs. 2% for SC insulin) (Furnary, 1999)
Hyperglycemia leads to failure of skin graft take in burns patients (Gore, 2001)
Relative hyperglycemia, even in non-diabetics, is associated with bacteremia, sepsis (van den Berghe, 2001)

23. Watch out for low sugars
RISKS
Hypoglycemia
Associated with sedation, ventilation, blunted responses, erratic feed
Brain damage
Arrhythmias
Commonest after 1 week
Watch out for low sugars

24. ALGORITHM Measure BG on arrival in ICU >220: insulin 2-4 U/h
<110: continue BGM q4h; do not start insulin

25. ALGORITHM Measure BG q1-2h until within normal range
>140: increase dose by 1-2 U/h
: increase by U/h
<110: adjust by U/h

26. ALGORITHM Measure BG q4h BG nearing normal: adjust dose by 0.1-0.5 U/h
BG normal: do not change
BG falling steeply: reduce dose by 50%; check BG more frequently
BG 60-80: reduce by 50%; recheck within 1 h
BG 40-60: stop infusion; ensure adequate intake
BG<40: stop insulin; give10g glucose bolus IV

27. IF THERE IS NO PUMP 500 ml NS + 50 U insulin infusion 1 U = 10 ml NS
1 U/hr = 10 microdrops/min

28. ALGORITHM Insulin requirements vary a lot
Consider pre-ICU status, caloric intake, severity & nature of illness, infections, corticosteroids
Anticipate improvement in insulin sensitivity and reduction in dose
Check for renal failure
Coordinate with enteral feeding

29. QUESTIONS UNANSWERED ? medical ICU patients ? children
? surgical patients in general ward
? non-ventilated patients
? how lo do we go

30. BE DYNAMIC: don’t be static
Diabetes is a dynamic disease; needs dynamism to manage
Glycemia varies thru’ a diabetic’s life span; so does treatment/insulin requirement
Treatment should be flexible
Be one step ahead of the illness; do not follow its’ complications

32. WHO KILLED MY ICU PATIENT ?
Who Moved My  Cheese ? ?
WHO KILLED MY ICU PATIENT ?

33. CONCLUSION AIM FOR BETTER GLYCEMIC CONTROL WITH EXOGENOUS INSULIN
ACHIEVE REDUCTION IN MORTALITY & MORBIDITY