INSULIN THERAPY IN ICU

• Dr SANJAY KALRA, D.M. [AIIMS]

OUR VISIONTo be a globally-acknowledged centre of excellence for clinical care, education & training, and research

in diabetology and endocrinology.

EVOLUTION OF INSULINOLOGY

• 1922 – DISCOVERY OF INSULIN

• 1993 – tight glycemic control is beneficial in T1DM – DCCT

• 1998 - tight glycemic control is beneficial in T2DM – UKPDS

• 1997-99 – GIK infusion in diabetic MI

• 2001 – insulin in ICU patients

EVOLUTION OF CRITICAL CARE

• 1940 – FIRST COMMERCIAL VENTILATOR [SPIROPULSATOR]

• 1942 – Penicillin

• 2001 – INSULIN in ICU patients

HYPERGLYCEMIA IN THE CRITICALLY ILL

• No clear guidelines for defining hyperglycemia in the critically ill

• Wide variation in reported incidence: 3 to 71% (Capes, 2000)

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)

‘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)

‘STRESS DIABETES’

• INSULIN RESISTANCE

• Even in previously non-diabetic persons

• At receptor, post-receptor level

• In liver, skeletal muscle, heart (Mizock, 2001)

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

The ‘fight, flight, fright mechanism’: hyperglycemia may help

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

Hyperglycemia: deleterious effects enter the arena

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)

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

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

IN-HOSPITAL HYPERGLYCEMIA

Normo-glycemia

Known diabetes

New hyper-glycemia

Total mortality

1.7% 3.0% 16%

Non-ICU mortality

0.8% 1.7% 10%

ICU mortality

10% 11% 31%

The JURY: stress diabetes is dangerousThe JURY: stress diabetes is dangerous

THE LEUVEN STUDY

• 1548 mechanically-ventilated patients admitted to ICU after surgery/trauma

• INTENSIVE THERAPY GROUP: aim for blood glucose 80-110 mg%

• CONVENTIONAL APPROACH: aim for blood glucose 180-200 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

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)

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%

? 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?due to both

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

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)

Is it the nurse or the injection which saved me ?

Is it the nurse or the injection which saved me ?

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)

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)

RISKS

• Hypoglycemia– Associated with

sedation, ventilation, blunted responses, erratic feed

– Brain damage– Arrhythmias– Commonest after 1

week

Watch out for low sugars

Watch out for low sugars

ALGORITHM

• Measure BG on arrival in ICU– >220: insulin 2-4 U/h– 110-220: insulin 1-2 U/h– <110: continue BGM q4h; do not start

insulin

ALGORITHM

• Measure BG q1-2h until within normal range– >140: increase dose by 1-2 U/h– 110-140: increase by 0.5-1 U/h– <110: adjust by 0.1-0.5 U/h

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

IF THERE IS NO PUMP

• 500 ml NS + 50 U insulin infusion

• 1 U = 10 ml NS

• 1 U/hr = 10 microdrops/min

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

QUESTIONS UNANSWERED

• ? medical ICU patients• ? children• ? surgical patients in

general ward• ? non-ventilated

patients• ? how lo do we go

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

Who Moved My Cheese ?

WHO KILLED MY ICU PATIENT ?WHO KILLED MY ICU PATIENT ?

CONCLUSION

• AIM FOR BETTER GLYCEMIC CONTROL WITH EXOGENOUS INSULIN

• ACHIEVE REDUCTION IN MORTALITY & MORBIDITY