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

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

3. Clinical Practice Guidelines Validity Homogeneity Safety Feasibility Cost evidenceintegration of values + 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  Systematic reviews  RCT’s  Cohort Studies  Case Control  Case Series less bias/strong inferences more bias/weaker inferences

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

7. PLOS 2008;5: e4

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

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

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

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

13. Number of Systematic Reviews Published

14. The Frailties of Narrative Reviews u 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. u Narrative reviews omitted effective therapies and endorsed ineffective therapies. Antman JAMA1992;268;240 and Lau NEJM 1992;327:248

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

16. Clinical Decision Making and Systematic Reviews u Problem u 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?

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

18. 2007 International Nutrition Practice Survey u Point prevalence survey of nutrition practices in ICU’s around the world conducted Jan. 27, 2007 u Enrolled 2772 patients from 158 ICU’s over 5 continents u Included ventilated adult patients who remained in ICU >72 hours

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

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

21. Relationship Between Increased Calories and 60 day Mortality BMI GroupOdds Ratio 95% Confidence Limits P-value Overall0.760.610.950.014 <200.520.290.950.033 20-<250.620.440.880.007 25-<301.050.751.490.768 30-<351.040.641.680.889 35-<400.360.160.800.012 >=400.630.321.240.180 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.

22. u RESULTS: WHO IS AT RISK?

23. 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 u 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

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

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

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

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

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

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

30. Early Supplemental PN is Associated with Increased Infection in Critically Ill Trauma Patients Differences not due to differences in glycemic control No Early PNEarly PNOdds Ratio P value Overall Adjusted Nosocomial Infections27%56%2.1 (1.3-3.5) P=0.003 Late ARDS1%8%3.4 (1.0-11.0) P=0.04 Death8%23%1.5 (0.8-3.0) P=0.24 EN tolerant analysis Nosocomial Infections42%69%2.5 (1.1-5.9) P=0.03 Late ARDS2%9%5.4 (1.1-27.4) P=0.04 Death8%19%2.7 (0.8-9.3) P=0.10

31. Prospective Studies of Supplemental PN Effect on Mortality www.criticalcarenutrition.com

32. 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

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

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

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

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

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

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

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

40. Results of Subgroup Analysis PN>>>EN? MortalityInfection EN (n=9) 0.81 (0.48-1.34) P=0.41 0.83 (0.64-1.08) P=0.16 PN (n=17) 0.71 (0.55-0.92) P=0.008 0.76(0.62-0.93) P=0.008

41. 1200 ICU patients Evidence of organ failure R glutamine placebo Concealed Stratified by site R R antioxidants placebo Factorial 2x2 design placebo antioxidants REducing Deaths from OXidative Stress: The REDOXS study Fed enterally

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

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

44. Meta-analyses of Arginine-supplemented Diets o 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

45. Overall Effect on Mortality u RR 1.10 (0.93-1.31)

46. Overall Effect on Complications u RR 0.66 (0.54-0.80)

47. 1.18 (0.88,1.58)

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

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

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

51. Using Systematic Reviews in Policy Making u Greatest generalizability u Consistent with perspective of policy makers u Related to other forms of integrative research

52. Assessing the Validity of Systematic Reviews Validity= fxn { inputs, process, results }

53. u Inputs u selection of studies u clinical homogeneity u explicit, reproducible criteria u methodological quality of studies u outdated/unmeasured co-interventions Assessing the Validity of Systematic Reviews

54. u Process u comprehensive search strategy u publication/timing bias u data excess u language bias u judgements about inclusion explicit/reproducible u data abstraction reproducible Assessing the Validity of Systematic Reviews

55. u Results u few studies u few clinical endpoints u statistical heterogeneity Assessing the Validity of Systematic Reviews

56. Methdological Quality of Meta-analyses lots of bias little bias weak inferences strong inferences Strong clinical recommendations

57. Making Inferences from a Meta-Analysis of RCT’s u Small number of trials u Weak trial methodology u Outdated/unmeasured co-interventions u Surrogate endpoints u Statistical heterogeneity u Fixed effects model u Large number of trials u Strong trial methodology u Current/documented co- interventions u Clinically important endpoints u Statistical homogeneity u Random effects model Weaker InferencesStronger Inferences

58. Meta-analysis vs. Large RCT’s “… if no subsequent randomized, clinical trial, the meta-analysis would have led to the adoption of an ineffective treatment in 32% cases and rejection of useful treatment in 33% cases.” LeLorier NEJM 1997;337:536 “I still prefer conventional narrative reviews … Editorial, NEJM

59. Meta-analysis vs. Large RCT’s RCT #1 RCT #2 RCT #3 RCT #4 RCT #5

60. Meta-analysis vs. Large RCT’s u Argument is with Meta-analysis, not the concept of systematic reviews u Assumes the latest single large trial is the GOLD standard u Assumes RCT and Meta-analysis are measuring the same thing u Differences in Generalizability u Bias exists in both TOOLS.

61. Resolving Discrepancies Between a Meta- analysis and a Subsequent Large RCT  Recent meta-analysis found calcuim supplementation to be effective in preventing preeclampsia  Large RCT found no risk reduction in health nulliparous women  Exploration of heterogeneity across studies  Stratify for high and low baseline risk JAMA 1999;282:664

62. Resolving Discrepancies Between a Meta- analysis and a Subsequent Large RCT JAMA 1999;282:664

63. JAMA 2008;300:933

65. Role of Systematic Reviews in Medical Education u Good source of medical knowledge u Promotes EBM practices u Helps locate original articles u Facilitates critical appraisal of original research u Considered a scholarly research activity

66. Conclusions u Important tool to determine the effectiveness of therapeutic interventions u Need to understand the strengths, weaknesses and limitations u Useful in clinical and policy decision making and research setting u Encourage use of and generation of systematic reviews amongst learners.