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Intensive versus Conventional Glucose Control in Critical Ill Patients

Intensive versus Conventional Glucose Control in Critical Ill Patients. N 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

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Intensive versus Conventional Glucose Control in Critical Ill Patients

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  1. Intensive versus Conventional Glucose Control in Critical Ill Patients N Engl J Med 2009; 360:1283-1297. 雙和醫院 劉慧萍藥師

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. ResultsStudy Participants • Recruited period • December 2004 ~ November 2008

  11. Baseline Characteristics

  12. 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 • 50.238.1 vs. 16.929.0 units/day • p < 0.001 • Mean time-weighted blood glucose level • 11518 vs. 14423 mg/dL • p < 0.001

  13. ResultsNutrition 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- 93.488.8 v.s. 87.293.5 kcal • Corticosteroids • 1042/3010 (34.6%) vs. 955/3009 (31.7%); p = 0.02

  14. 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)

  15. 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)

  16. ResultsSurvival Time

  17. 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.

  18. 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)

  19. 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

  20. 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

  21. 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

  22. 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.

  23. Benefits and Risks of Tight Glucose Control in Critically Ill AdultsA Meta-analysis JAMA. 2008; 300:933-944.

  24. 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)

  25. 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

  26. 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

  27. 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 patients • American Diabetes Association • Close to 110mg/dL • Surviving Sepsis Campaign • <150mg/dL • ICU setting • Surgical ICU • Medical ICU • Mixed medical-surgical ICU

  28. Search Results

  29. 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)

  30. 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

  31. 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?

  32. Thank You for Attention

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