Intensive versus Conventional Glucose Control in Critical Ill Patients N Engl J Med 2009; 360: 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 and 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 additional IV glucose administration Corticosteroid administration Organ failure Use of mechanical ventilation Renal replacement therapy

Outcome Measurement Primary 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 room 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

Results Study Participants Recruited period  December 2004 ~ November 2008

Baseline Characteristics

Results Insulin Administration and Treatment Effects Intensive group vs. conventional group  Receiving insulin 2931/3014 (97.2%) vs. 2080/3014 (69.0%) p <  Mean insulin dose 50.2  38.1 vs  29.0 units/day p <  Mean time-weighted blood glucose level 115  18 vs. 144  23 mg/dL p < 0.001

Results Nutrition and Concomitant Treatment Intensive v.s. conventional group  Nutrition during the first 14 days Mean daily amount of nonprotein calories administration  891  490 v.s. 872  500 kcal; p = 0.14  Enteral nutrition- 624  496 vs. 623  496 kcal  Parenteral nutrition- 173  359 vs. 162  345 kcal  IV glucose  88.8 v.s  93.5 kcal  Corticosteroids 1042/3010 (34.6%) vs. 955/3009 (31.7%); p = 0.02

Results Outcome 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)

Results Outcome 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)

Results Survival Time

Results Outcomes 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.

Results Comparison 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)

Results Serious 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 were 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 needed

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 Adults A Meta-analysis JAMA. 2008; 300:

Data Sources MEDLINE (1950-June 6, 2008) The Cochrane Library Clinical trial registries Reference lists Abstracts from conferences from both the American Thoracic Society ( ) and the Society of Critical Care Medicine ( )

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- term mortality ( ≦ 30-day), septicemia, new need for dialysis, or hypoglycemia Exclusion criteria  Intervention conducted primarily during the intraoperative period 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 mg/dL  According to recommendation for glucose control in critically ill patients American Diabetes Association  Close to 110mg/dL Surviving Sepsis Campaign  <150mg/dL ICU setting  Surgical ICU  Medical ICU  Mixed medical-surgical ICU

Search Results

Results Primary Outcome No significant difference in hospital mortality between tight glucose control and usual care strategies (21.6% vs. 23.3%; 95% CI, )

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?

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