intensive insulin therapy in the medical icu
TRANSCRIPT
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?