Intensive versus Conventional Glucose Control in Critical Ill PatientsN Engl J Med 2009; 360:1283-1297.

雙和醫院劉慧萍藥師

Introduction

Hyperglycemia Common in acutely ill patients, including ICU patients Increased morbidity and mortality

Randomized, controlled trial of critically ill surgical patients showing that tight glucose control reduced hospital mortality Guidelines recommend tight glucose control in all critically ill

adults Tight glucose control not used frequently

Conflicting results among trials Increased risk of severe hypoglycemia

Goal of this trial To test the hypothesis that intensive glucose control reduces

mortality at 90 days

Methods (I)

Study Design A parallel-group, multi-center, randomized,

controlled trial performed at 42 hospitals, 38 academic tertiary care hospitals, and 4 community hospitals

Follow-up 90 days

Patient Population Patients expected to require treatment in the ICU

on 3 or more consecutive days

Methods (II)

Randomly assigned to 2 groups Intensive glucose control

Glucose target- 81 to 108 mg/dL Conventional control

Glucose target 180 mg/dL≦ Insulin administered if glucose level >180 mg/dL an

d reduced and discontinued insulin if glucose level <144 mg/dL

Control of blood glucose was achieved with the use of an intravenous infusion of insulin in saline

Methods (III)

Time of discontinued intervention Patients started eating Discharged from ICU

Resumed if the patient readmitted to ICU within 90 days

Time of discontinued permanently Death 90 days after randomization

Data Collection

Demographic and clinical characteristics Including APACHE II score

All blood glucose measurements Insulin administration Red-cell administration Blood cultures positive for pathogenic organisms Type and volume of all enteral and parenteral nutrition and additi

onal IV glucose administration Corticosteroid administration Organ failure Use of mechanical ventilation Renal replacement therapy

Outcome MeasurementPrimary outcome

Death from any cause within 90 days after randomization

Examined in subgroups Operative and nonoperative With and without diabetes With and without trauma With and without sepsis Treated and not treated with corticosteroids APACHE II score 25 or more and less

Outcome Measurements

Secondary outcomes Survival time during the first 90 days Cause-specific death Duration of mechanical ventilator and renal-replacement

therapy Stays in the ICU and hospital

Tertiary outcomes Death from any cause within 28 days after randomization Place of death Incidence of new organ failure Positive blood culture Receipt of red-cell transfusion Volume of the transfusion

Definition

Operative admission Admitted to ICU directly from the operating or recovery roo

m Diabetes

Based on medical history Trauma

Admitted to ICU within 48 hours after admission to hospital for trauma

Previous treatment with corticosteroids Systemic corticosteroids for 72 hours or more immediately

before randomization Serious adverse events

Blood glucose 40 mg/dL or less

ResultsStudy Participants

Recruited period December 2004 ~

November 2008

Baseline Characteristics

ResultsInsulin Administration and Treatment Effects Intensive group vs. conventional group

Receiving insulin 2931/3014 (97.2%) vs. 2080/3014 (69.0%) p < 0.001

Mean insulin dose 50.238.1 vs. 16.929.0 units/day p < 0.001

Mean time-weighted blood glucose level 11518 vs. 14423 mg/dL p < 0.001

ResultsNutrition and Concomitant Treatment

Intensive v.s. conventional group Nutrition during the first 14 days

Mean daily amount of nonprotein calories administration 891490 v.s. 872500 kcal; p = 0.14

Enteral nutrition- 624496 vs. 623496 kcal Parenteral nutrition- 173359 vs. 162345 kcal IV glucose- 93.488.8 v.s. 87.293.5 kcal

Corticosteroids 1042/3010 (34.6%) vs. 955/3009 (31.7%); p = 0.02

ResultsOutcome Measurements

829 of 3010 patients (27.5%) in the intensive-control group had died as compared with 751 of 3012 patients (24.9%) in the conventional group

Majority of deaths occurred in the ICU Intensive v.s. conventional group

546/829 (65.9%) v.s. 498/751 (66.3%) The absolute difference in mortality was 2.6 percent

points (95% CI, 0.4 to 4.8) The odds ratio for death with intensive control was 1.

14 (95% CI, 1.02 to 1.28 ; p = 0.02) Adjusted odds ratio, 1.14 (95% CI, 1.01 to 1.29; p =

0.04)

ResultsOutcome Measurements

Deaths from cardiovascular causes were more common in the intensive-control group (41.6%) than in the conventional-control group (35.8%) (absolute difference, 5.8 percentage points; p = 0.02)

Distributions of proximate causes of death were similar (p = 0.12)

The median survival time was lower in the intensive-control group than in the conventional-control group (hazard ratio, 1.11; 95% CI, 1.01 to 1.23; p = 0.03)

ResultsSurvival Time

ResultsOutcomes Measurements

No significant difference between the two groups in the median length of stay in the ICU or hospital.

No significant difference between the two groups in the number of patients developed new organ failures (p = 0.11)

The number of days of mechanical ventilator and renal replacement therapy, or in the rates of positive blood cultures and red-cell transfusion.

ResultsComparison between Subgroups

No significant difference for comparisons of subgroups Operative and nonoperative patients (p = 0.10) With or without diabetes (p = 0.60) With or without severe sepsis (p = 0.93) APACHE II score 25 and < 25 (≧ p = 0.84)

No significant but indicated a possible trend With trauma and without trauma (p = 0.07) Receiving and not receiving corticosteroids (p = 0.

06)

ResultsSerious Adverse Events

Severe hypoglycemia (blood glucose level 40 mg≦/dL) was recorded in 206 of 3016 patients (6.8%) in the intensive-control group, as compared with 15 of 3014 patients (0.5%) in the conventional-control group (odds ratio, 14.7; 95% CI, 9.0 to 25.9; p < 0.001)

The recorded number of episodes of severe hypoglycemia severe hypoglycemia was 272 in the intensive-control group, as compared with 16 in the conventional-control group.

No long-term sequelae of severe hypoglycemia were reported

Clinical Impact

A goal of normoglycemia for glucose control does not necessarily benefit critical ill patients and may be harmful Lower blood glucose target is not recommended in critically

ill adults. The excess deaths in the intensive-control group we

re predominantly from cardiovascular causes. These differences might suggest that reducing blood glucose levels by the administration of insulin has adverse effects on cardiovascular system. Not examined mechanisms in this trial, further research is n

eeded

Strengths

Standardized, complex management of blood glucose through a computerized treatment algorithm accessible on centralized servers

Patients received predominantly enteral nutrition consonant with current evidence-based feeding guidelines

Longer follow-up period

Limitation

Use of a subjective criterion- expected length of stay in the ICU.

Inability to make treating staff and study personnel unaware of the treatment-group assignments.

Achievement of a glucose level modestly above the target range in a substantial proportion of patients in the intensive group.

Not collect specific data to address potential biologic mechanisms of the trial interventions or their costs.

Benefits and Risks of Tight Glucose Control in Critically Ill AdultsA Meta-analysis

JAMA. 2008; 300:933-944.

Data Sources

MEDLINE (1950-June 6, 2008) The Cochrane Library Clinical trial registries Reference lists Abstracts from conferences from both the

American Thoracic Society (2001-2008) and the Society of Critical Care Medicine (2004-2008)

Study Selection

Inclusion criteria Randomized controlled trial

Adult ICU Intervention group received tight glucose control (goal < 150

mg/dL using insulin) Comparison group received usual care Primary or secondary end points included hospital or short-ter

m mortality ( 30-day), septicemia, new need for dialysis, or h≦ypoglycemia

Exclusion criteria Intervention conducted primarily during the intraoperative p

eriod rather than during ICU stay

Outcome Measures

Primary outcome measure Hospital mortality

Death occurring during the hospital stay or within 30 days following admission

Secondary outcome measure Septicemia New need for dialysis hypoglycemia

Subgroup Analyses

Glucose goal in the tight control group Very tight control

≦ 110mg/dL Moderately tight control

111-150 mg/dL According to recommendation for glucose control in critically ill pa

tients American Diabetes Association

Close to 110mg/dL Surviving Sepsis Campaign

<150mg/dL ICU setting

Surgical ICU Medical ICU Mixed medical-surgical ICU

Search Results

ResultsPrimary Outcome No significant difference in hospital mortality

between tight glucose control and usual care strategies (21.6% vs. 23.3%; 95% CI, 0.85-1.03)

Conclusion

Tight glucose control is not associated with significant reduced hospital mortality or new dialysis but is associated with increased risk of hypoglycemia.

Larger, more definitive clinical trials are needed to reevaluated tight glucose control in critically ill patients

Open Discussion

What are the target range of blood glucose levels in ICU among different hospital?

Should patients in surgical ICU need tighter glucose control?

Thank You for Attention