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Systematic Reviews of the Literature and Meta-analyses: ….problems or panacea?

Systematic Reviews of the Literature and Meta-analyses: ….problems or panacea?. Daren K. Heyland, MD, FRCPC, MSc. Queen’s University, Kingston, Ontario. Updated Jan 2009 Summarizes >200 trials studying 21283 patients 34 topics 17 recommendations.

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Systematic Reviews of the Literature and Meta-analyses: ….problems or panacea?

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  1. Systematic Reviews of the Literature and Meta-analyses:….problems or panacea? Daren K. Heyland, MD, FRCPC, MSc Queen’s University, Kingston, Ontario

  2. Updated Jan 2009 • Summarizes >200 trials studying 21283 patients • 34 topics 17 recommendations www.criticalcarenutrition.com

  3. Clinical Practice Guidelines evidence integration of values + Validity Homogeneity Safety Feasibility Cost practice guidelines

  4. In Search of Truth...…Does it work? • Begins with a hypothesis or question • Does Drug X reduce the incidence of problem Y in patients with condition Z • Application of experimental or observational methods to determine the answer • Results of our observations leads to conclusions that are correct (truth) or incorrect (due to bias or chance)

  5. Levels of Evidence less bias/strong inferences • Systematic reviews • RCT’s • Cohort Studies • Case Control • Case Series more bias/weaker inferences

  6. 198 RCT’s Reviewed in Critical Care Nutrition Guidelines

  7. PLOS 2008;5: e4

  8. Learning Objectives • Will be able to appraise and incorporate results of systematic reviews into clinical decision making. • understand the role of systematic reviews in research and policy settings. • List the strengths and weakness of meta-analyses

  9. Overview • Definition and Classification • Usefulness • Methodological Quality • Making Inferences • Conclusions

  10. Systematic Review… • Form of scientific investigation to assess the effectiveness of healthcare interventions • Integrative research • Subjects= original or primary studies • Employs methods that limit bias and reduce random error

  11. Systematic Reviews and Meta-analysis Systematic Reviews Narrative Reviews Meta-analysis

  12. Number of Systematic Reviews Published

  13. The Frailties of Narrative Reviews • If the original studies of thrombolytics therapies had been subject to a systematic review, the treatment effect would have been apparent in the 1970s instead of 1980s. • Narrative reviews omitted effective therapies and endorsed ineffective therapies. Antman JAMA1992;268;240 and Lau NEJM 1992;327:248

  14. Clinical Decision Making and Systematic Reviews • Case Scenario • 77 y.o. male with presumptive Dx of Urosepsis • PMHX: MI, Prostate • BMI 21 • After initial resuscitation • FiO2 = 100%, PO2 = 55 • MAP = 65, CVP 13, levophed 20 mcg/kgk/min • rising Cr, 20 ml of urine, acidemic • High NG drainage • Going to start on EN but not likely to tolerate Role for early supplemental PN?

  15. Clinical Decision Making and Systematic Reviews • Problem • 100s of citations across scores of journals published over the last 20 years In diverse patient populations or diverse settings with variable or inconsistent results! How do you make sense of this all?

  16. Impact of Caloric Debt Adequacy of EN Caloric Debt •  Caloric debt associated with: •  Longer ICU stay •  Days on mechanical ventilation •  Complications •  Mortality Rubinson CCM 2004; Villet Clin Nutr 2005; Dvir Clin Nutr 2006; Petros Clin Nutr 2006

  17. 2007 International Nutrition Practice Survey • Point prevalence survey of nutrition practices in ICU’s around the world conducted Jan. 27, 2007 • Enrolled 2772 patients from 158 ICU’s over 5 continents • Included ventilated adult patients who remained in ICU >72 hours

  18. Hypothesis • There is a relationship between amount of energy and protein received and clinical outcomes (mortality and # of days on ventilator) • The relationship is influenced by nutritional risk • BMI is used to define chronic nutritional risk

  19. What Study Patients Actually Rec’d • Average Calories in all groups: • 1034 kcals and 47 gm of protein Result: • Average caloric deficit in Lean Pts: • 7500kcal/10days • Average caloric deficit in Severely Obese: • 12000kcal/10days

  20. Relationship Between Increased Calories and 60 day Mortality Legend: Odds of 60-day Mortality per 1000 kcals received per day adjusting for nutrition days, BMI, age, admission category, admission diagnosis and APACHE II score.

  21. RESULTS: WHO IS AT RISK?

  22. RCT Level of Evidence that More EN= Improved Outcomes • RCTs of aggressive feeding protocols • Results in better protein-energy intake • Associated with reduced complications and improved survival • Taylor et al Crit Care Med 1999; Martin CMAJ 2004 • Meta-analysis of Early vs Delayed EN • Reduced infections: RR 0.76 (.59,0.98),p=0.04 • Reduced Mortality: RR 0.68 (0.46, 1.01) p=0.06 www.criticalcarenutrition.com

  23. More is Better! Our Field of Dream If you feed them (better!) They will leave (sooner!)

  24. ICU patients are not all created equal…should we expect the impact of nutrition therapy to be the same across all patients?b

  25. What if you can’t provide adequate nutrition enterally? … to TPN or not to TPN, that is the question!

  26. Current practice in nutritional support in septic patients: Results of national, prospective multicenter German Study Point prevalence study 454 ICUs from 310 hospitals in Germany 399 patients septic patients included Median APACHE II 26 68% had no GI pathology 46% in shock Overall mortality 55.2% • Elke CCM 2008;36:1762

  27. Current practice in nutritional support in septic patients: Results of national, prospective multicenter German Study Point prevalence study 454 ICUs from 310 hospitals in Germany 399 patients septic patients included Median APACHE II 26 68% had no GI pathology 46% in shock Overall mortality 55.2% P=0.005 Multivariate analysis: PN independent predictor for mortality (OR 2.09, 95% CI 1.29-3.37)

  28. Early Supplemental PN is Associated with Increased Infection in Critically Ill Trauma Patients • Retrospective, multicenter, cohort study of 597 severely injured patients • Compared those that rec’d PN within 7 to those who did not. • Also compared early PN group to subgroup of ‘EN tolerant’ (tolerated 1000 kcal any day during first week) • Adjusted for differences in key baseline demographics Sena J Am Coll Surg 2008;207:459

  29. Early Supplemental PN is Associated with Increased Infection in Critically Ill Trauma Patients Differences not due to differences in glycemic control

  30. Prospective Studies of Supplemental PNEffect on Mortality www.criticalcarenutrition.com

  31. What if you can’t provide adequate nutrition enterally? … to TPN or not to TPN, that is the question! Maximize EN delivery prior to initiating PN

  32. Use of Supplemental PN in Sepsis? • Results of meta-analysis • Results of single RCTs of Septic Patients • Results of observational studies • Consideration of Individual Patient Characteristics

  33. Using Systematic Reviews in Clinical Practice • Summarizes large body of knowledge • Answers specific clinical question • Less likely to be biased than narrative reviews • More accurate and precise estimate of treatment effect

  34. Using Systematic Reviews in Research Setting • Research Question: • What is the effect of Glutamine and Antioxidant supplementation on survival in critically ill patients? • Methods: • A meta-analysis

  35. Effect of Glutamine in Critically Ill: A Systematic Review of the Literature • Comprehensive search • Selection criteria • Randomized • Surgical or critically ill adults • Glutamine (EN or PN) vs. placebo • Clinically important outcomes 20 RCT’s

  36. Effect of Glutamine: A Systematic Review of the Literature Mortality Updated Jan 2009, see www.criticalcarenutrition.com

  37. Effect of Glutamine: A Systematic Review of the Literature Infectious Complications Updated Jan 2009, see www.criticalcarenutrition.com

  38. Effect of Glutamine: A Systematic Review of the Literature Hospital Length of Stay Updated Jan 2009, see www.criticalcarenutrition.com

  39. Results of Subgroup Analysis PN>>>EN?

  40. REducing Deaths from OXidative Stress:The REDOXS study antioxidants Factorial 2x2 design glutamine R Concealed Stratified by 1200 ICU patients R placebo Evidence of site organ failure antioxidants Fed enterally R placebo placebo

  41. Using Systematic Reviews in Research Setting • Summarizes what is known; identifies gaps • Background of grant proposals • Generates hypotheses • Estimate of treatment effect N • Subgroup analysis

  42. Using Systematic Reviews in Policy Making As an ICU, should you make an arginine-supplemented diet available for general use in your institution?

  43. Meta-analyses of Arginine-supplemented Diets • 22 RCTs of IEDs • All arginine-containing IED, not just IMPACT/IMMUNAID • Non english, more recently published studies • Excluded duplicates • Excluded single agents Heyland JAMA 2001;286:944

  44. Overall Effect on Mortality • RR 1.10 (0.93-1.31)

  45. Overall Effect on Complications • RR 0.66 (0.54-0.80)

  46. 1.18 (0.88,1.58)

  47. Effect of Arginine-supplemented Diets in the Critically Ill Patient Mortality Updated Jan 2009, see www.criticalcarenutrition.com

  48. Effect of Arginine-supplemented Diets in the Critically Ill Patient Infectious Complications Updated Jan 2009, see www.criticalcarenutrition.com

  49. Effect of Arginine-supplemented Diets in the Critically Ill Patient Hospital Length of Stay Updated Jan 2009, see www.criticalcarenutrition.com

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