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

OUR VISION To 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

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

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% 10% ICU mortality 11% 31% The 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

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

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)

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)

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

ALGORITHM Measure BG on arrival in ICU >220: insulin 2-4 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 KILLED MY ICU PATIENT ? Who Moved My  Cheese ? ? WHO KILLED MY ICU PATIENT ?

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