Intensive Insulin Therapy In The Medical Icu

Intensive Insulin Therapy in the Medical ICU

The New England Journal of Medicine N Engl J Med 2006; 354:449-61Greet van den Berghe et al.

S. Nadery, MCH november 2009

Introduction

IIT Reduced morbidity and mortality In-hospital mortality (11 to 7 % in all) In subgroup (≥ 3 days treated) from 21 to

14 % reduction in mortality From 26 to 17 % among those who

treated at least 5 days Reduction in complications

Several potential mechanisms: Prevention of immune dysfunction Reduction of systemic inflammation Protection of the endothelium/

mitochondrial ultra structure and function

Introduction

Improvement of prognosis in a med. IC? more severely ill have a higher risk of death

Earlier study in a surgical ICU diabetes with acute myocardial infarction observations in diabetes undergoing

coronary-bypass surgery insulin-titrated blood glucose control

at least a few days detectable outcome benefit

Methods

Inclusion: Adult patients Assumed to require at least a third day of

intensive care Exclusion:

Surgical Medical patients able to receive oral

nutrition NTBR on admission

Informed consent Approved by the institutional review March 2002 - May 2005

Study Design

Randomly assigned: Intensive insulin treatment

(intensive-treatment group) Conventional insulin treatment

(conventional-treatment group)

Study Design

Intensive insulin treatment (intensive-treatment group): insulin infusion started when

glucose > 6.1 mmol/l adjusted to maintain

normoglycemia 4.4 to 6.1 mmol per liter

Study Design

Conventional insulin treatment (conventional-treatment group): continuous insulin infusion 50 IU of Actrapid HM [Novo Nordisk] in

50 ml of NaCl 0.9 % use of a pump (Perfusor-FM pump, B.

Braun) when glucose > 12 mmol/l pomp adjusted

for glucose level 10 and 11 mmol/l when glucose < 10 mmol/l: insulin

infusion tapered/ evt. stopped

Study Design

Maximal continuous intravenous insulin infusion at 50 IU per hour

Patient's discharge from IC conventional approach adopted maintenance glucose ≤ 11 mmol/l

Dose of insulin adjusted according: whole-blood glucose levels measured at one-to-four-hour intervals arterial blood or in capillary blood with the use of a point-of-care glucometer

(HemoCue B-glucose analyzerHemoCue)

Study Design

Adjustments were made by the nurses: 2.5 full-time-equivalent nurses per bed Guidelines Hemodynamically stable

Enteral feeding Total of 22 to 30 kcal per kilogram of body

weight per 24 hours 0.08 to 0.25 g of nitrogen per kilogram of

Body weight per 24 hours 20 to 40 percent of nonprotein kilocalories

as lipids Enteral feeding as early as possible

Data collection

Baseline: Demographic and Clinical characteristics

Determine the severity of illness Acute Physiology and Chronic Health

Evaluation (APACHE II system) Simplified Therapeutic Intervention

Scoring System28 (TISS-28) Blood sampling

On admission Every four hours If necessary more frequently Glucose ≤ 2.2 mmol/l hypoglycsmic Blood cultures

Interpreted by an investigator blinded

Outcome Measures

Primary outcome measure: Death in hospital

Sec. outcome measures, predefined: Mortality in ICU and 90-days mortality Days to weaning (mechanical ventilation) Days in the ICU Days in the hospital Initiation of dialysis New kidney injury Days of inotropic or vasopressor support Presence of absence of hyperinflamation Bacteremia/ prolonged AB Presence/absence of hyperbilirubinemia

Outcome Measure

Results

Nutrition & Glucose Control Morbidity Mortality

Nutrition & Glucose Control Hypoglycemia in the intensive-

treatment group > conventional- treatment group

Hypoglycemia mostly only one episode

Severity of hypoglycemia similar in the two groups

Nutrition & Glucose Control No hemodynamic deterioration No convulsions No other events were noted Mortality among pt with hypo:

66.7 % CTG vs 46.4 % ITG P = 0.1 in-hospital mortality was 73.3 % vs 61.9

%, respectively (P = 0.4) Within 24 hour after hypo:

2 pt died in CTG 3 pt died in ITG

Morbidity

Intention-to-Treat Population use of medications other than insulin: no

significant difference 9 pt were treated for septic shock with

activated protein C, 5 in CTG and 5 in ITG (P = 0.8)

644 pt received corticosteroid, 327 in CTG and 317 in ITG (P = 0.8)

Morbidity was reduced in ITG: Newly acquired kidney injury (8.9 to 5.9 %, P = 0.04) Early weaning P = 0.03) Early discharge from ICU (P = 0.04) Early discharge from hospital (P = 0.05)

Morbidity

No significant difference in: Bacteremia (P = 0.5) Prolonged requirement of AB (P = 0.2) Hyperbilirubinemia (P = 0.4) Hyperinflammation (P = 0.1) Cumulative TISS-28 score (P = 0.08) Rates of readmission to ICU (6.3 % in

both groups, similar)

Morbidity

Stays in ICU longer than three days: Among 767 patients, no significant difference

in use of medication other than insulin Among 386 patients in ITG:

Weaning from mechanical ventilation (P = 0.001)

Discharge from ICU (P = 0.002) Discharge from hospital (P = 0.001)

No difference in: Dialysis therapy (P = 0.7) Acquired kidney injury after randomization (P =

0.05) Hyperbilirubinemia (P = 0.04)

Similar in aminotransferase

Morbidity

Stays in ICU longer than three days: No difference in:

Bacteremia Received prolonged AB

Reduction in ITG: Incidence of hyperinflammation (P = 0.03) Cumulative TISS-28 scores (P = 0.02)

• Reflecting a reduction in the costs

Result

Mortality

Intention-to-treat analysis: ICU and in-hospital mortality in 3 days

Not significantly reduced in ITG Mortality ICU at day 3 (P = 0.31) Mortality in-hospital (P = 0.72) From 433 pt stayed less than 3 days:

• 56 pt in ITG died• 42 in CTG died

Beyond the third day of ITG: In-hospital mortality reduced from 52.5 tp

43 % Death from all causes reduced

Beyond the fifth day of ITG: Mortality reduced from 54.9 to 45.9 %

Discussion

Intensive Insulin Therapy: Prevented morbidity, significantly Did not reduce the risk of death Comparing surgical ICU:

No reduction in bacteremia No analysis of other infections than

bacteremie Protection of organ functioning

Among pt stayed > 3 days: Mortality and morbidity ↓ Mortality reduction only in ITG and not in

intention-to-therapy

Discussion

Length of stay Niet predictable Required post-randomization

stratification Risk of bias

Unclear whether IIT caused harm in pt treated < 3 days Previous study No effect on death

Discussion

This intervention (insulin therapy) Not curing but preventing

complications Preventio does not occur if pt has

high risk of death IIT had no effect on mortality

among diabetes Target glucose level not reached

Limitations

Single-center study Diabetes and fail in strict blinding No survival benefit in intention-to-

treat group IIT in all patient Patients < 3 days ICU

Prediction on admission

Conclusions

IIT significantly reduced morbidity

but not mortality. Risk of subsequent death and

disease was reduced In patients treated ≥ 3 days Could not be identified before

therapy Further studies are needed to

confirm these preliminary data

Questions?