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Journal Club - Early versus Late Parenteral Nutrition in Critically Ill Adults

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Journal Club and article review presented at the Miami VA during my Pharmacy Surgery Elective Rotation.

Journal Club and article review presented at the Miami VA during my Pharmacy Surgery Elective Rotation.

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  • 1. Early versus Late Parenteral Nutrition in Critically Ill Adults N Engl J Med 2011 Authors: Casaer MP, Mesotten D, Hermans G, et. al.Joy A. Awoniyi, PharmD. CandidateFlorida Agricultural and Mechanical UniversityAugust 2, 2011Surgery Elective RotationPreceptor: Dr. Lisa Joseph
  • 2. Background• Parenteral Nutrition provides caloric requirements when other routes of administration are not possible • Short Bowel Syndrome • Bowel Obstruction • Chron’s Disease • Ulcerative Colitis• Starvation or underfeeding in intensive care unit patients is associated with increased morbidity and mortality• 20-40% of critically ill patients show evidence of protein- energy malnutrition• Optimal timing for the initiation of parenteral nutrition in critical care is a major area of uncertainty
  • 3. Guideline Differences European Society of Society of Critical CareEnteral and Parenteral Medicine and American Nutrition. 2009 Society of Parenteral and Enteral Nutrition. 2009“All patients who are notexpected to be on normal “Use of parenteral nutritionnutrition within 3 days should be reserved andshould receive parenteral initiated only after the firstnutrition within 24 to 48 7 days of hospitalizationhours if enteral nutrition is (when EN is notcontraindicated or if they available).”cannot tolerate enteralnutrition.”
  • 4. Objectives EPaNIC Study Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients• To compare the effect of late initiation of parenteral nutrition with early initiation on rates of death and complications in adults in the ICU who are at risk but not chronically malnourished• To investigate whether preventing a caloric deficit during critical illness by providing PN early in disease course would reduce the rate of complication or whether withholding PN for 1 week would be clinically superior
  • 5. Methods Study Design Study Population• Prospective • 4640 Underwent Randomization• Randomized • 2313 – Early Initiation • 2328 – Late Initiation• Controlled • Patients stratified• Parallel-group according to diagnostic• Multi-centered categories • Subjects were not blinded
  • 6. Methods Inclusion Criteria Exclusion Criteria• Score of 3 or more on • Short-bowel syndrome the Nutritional Risk Screening • Home ventilation• 18 years or older • Pregnant or Lactating• BMI of at least 17 • Enrollment in another trial • Readmission to the ICU
  • 7. Baseline Characteristics• Well matched between groups (Table 1) • Sex, Age, Weight, BMI • Disease States: Diabetes Mellitus, Dialysis-dependent Kidney Failure, Cancer, Nutritional Risk Screening Score • Emergency Admission• Severity of Illness by APACHE II Scoring • Scale of 0 to 71• Sepsis diagnosed by the ACCP Society of Critical Care Medicine Criteria • Score calculated by trained experts
  • 8. Study Procedure All Patients• Enteral Nutrition if unable to eat by Day 2 • Twice daily increase in infusion rate • Prokinetic agents • Duodenal feeding tubes• Parenteral administration early in the ICU stay to avoid micronutrient depletion on re-feeding • Trace elements • Minerals • Vitamins
  • 9. Study Procedure Early Initiation Group• Day 1: 20% IV Glucose Solution • Target total daily energy intake of 400 kcal• Day 2: 20% IV Glucose Solution • Target total daily energy intake of 800 kcal• Day 3: Initiation of PN • Target: 100% of caloric goal (EN and PN)• Maximum caloric goal for all patients: 2880 kcal per day.
  • 10. Study Procedure Late Initiation Group• Day 1-7: 5% Glucose solution in a volume equal to parenteral nutrition• Day 8: Parenteral nutrition administration if enteral nutrition proved insufficient
  • 11. Study Procedure Administration and Monitoring• Patient-data-management system used to calculate daily volumes of EN and PN for each patient• After discharge from the ICU, nutritional management at the discretion of attending physicians• Continuous Insulin infusion • Glucose goal: 80-110 mg/dL• Blood Gas analyzer to monitor ABG every 1-4hours
  • 12. Data Collection• Intensive care treatments and procedures• New bacterial or fungal infections• Chemical Analysis Results • Blood • Urine • Hematologic Studies • Inflammation markers• Total Energy Intake by EN and PN
  • 13. Data Collection• Therapy Interruptions• Feeding Related Complications• Functional Status before discharge• Direct Health Care costs • Patient invoices • Analyzed from healthcare payer perspective• Government and patient costs• Vital Status 90 days after randomization
  • 14. Outcome Measures Primary Endpoint Safety Endpoints• Duration of • Vital Status dependency on • Proportion alive at ICU intensive care discharge in 8 days or less • Number of ICU days • Rates of ICU and Hospital • Time to discharge from the deaths ICU • Rates of survival up to 90 • Defined as time patients days were ready for ICU discharge, to avoid bias • Rates of complications and hypoglycemia
  • 15. Outcome Measures Secondary Endpoints• Number of patients with new infections • Infection site • Duration of Antibiotic Therapy• Inflammation (C-reactive Protein max)• Time to final weaning from mechanical ventilatory support• Duration of hospital stay and time to discharge• Functional status • Distance walked in 6 minutes • Proportion of patients independent in all ADLs
  • 16. Outcome Measures Secondary Endpoints• Rate of acute renal injury • RIFLE Criteria (Risk, Injury, Failure, Loss, End-stage) • Doubling of the SrCr level from admission• Proportion of patients requiring renal replacement therapy • Duration of the therapy in the ICU• Need for and duration of pharmacologic or mechanical hemodynamic support
  • 17. Outcome Measures Secondary Endpoints• Proportion of patients presenting with liver dysfunction • Total Bilirubin >3mg/dL • GGT >79.5Units/L • Alkaline phosphatase >405 Units/L • ALT >123 • AST>114• Incremental Healthcare costs from randomization to discharge
  • 18. Statistical Analysis• Sample size • Ability to detect a between-group change of 1 day in the ICU stay • Power at least 80% • Ability to detect a change of 3% in the rate of death • Power of at least 70%• Intention-to-treat Analysis• Two-sided p value of less than 0.05 to indicate statistical significance• Use of JMP Software for analysis
  • 19. Statistical AnalysisVariable Test UsedData Comparison • Chi-squared Test • Student’s T-Test • Non-parametric testing • Median Test • Wilcoxon Rank-sum Test • Mann-Whitney U TestHealthcare Costs • Student T TestsTime-To Event • Analysis: Kaplan Meier Methods • Effect Size: Cox-proportional Hazards
  • 20. Results Study Intervention• Insulin Requirements to reach target • Late: 31 IU (Interquartile 19-48) • Early: 58 IU (Interquartile 40-85)• Glucose Level • Late: 102 ± 14 mg/dL • Early: 107 ± 18 mg/dL• P <0.001
  • 21. Results Safety Outcomes20.0% 18.2%18.8%18.0%16.0%14.0% 11.2% 11.2%12.0% 10.4% 10.9%10.0% Late 8.0% 6.1% 6.3% 6.0% Early 4.0% 2.0% 0.0% Death in ICU Death In Death Within 90 Nutrition-related Hospital Days Complications
  • 22. Results Statistically Significant Safety p = 0.007 Outcomes p = 0.00176.0% 75.2% 4.0% 3.5%75.0% 3.5%74.0% 3.0%73.0% 2.5% 71.7% 1.9%72.0% Late 2.0%71.0% Early 1.5%70.0% 1.0%69.0% 0.5% 0.0% Discharged Alive in 8 days Hypoglycemia during intervention
  • 23. Results Primary Outcome Duration of dependency on Intensive Unit careMedian days Duration greater than 3 • Late – 3 (2-7) days • Early – 4 (7-9) • Late – 48% • P = 0.02 • Early – 51.3% • P= 0.02Hazard Ratio for time Todischarge from the ICU • 1.06 • 95% CI between 1.00 and 1.13 • P= 0.04
  • 24. Results Kaplan-Meier EstimatesProportion Discharged from ICU Proportion discharged alive from ICU
  • 25. Results Kaplan-Meier EstimatesDischarged from Hospital Discharged Alive from Hospital
  • 26. Results Secondary Outcome – New Infections30.0%25.0%20.0% Late15.0%10.0% Early 5.0% 0.0%
  • 27. Results More pronounced acute inflammatory response in the late Initiation group (p<0.001) Secondary Outcome - Inflammation200190180170 Late160 Early150140 Max CRP (mg/L)
  • 28. Results Median Duration of Selected Secondary Outcomes 18 16 14 12Time (days) 10 8 Late 6 Early 4 2 0 Mechanical Renal Hospital Stay Ventilation Replacement (p=0.004) (p=0.02) Therapy (p=0.008)
  • 29. Results Mechanical Ventilation Kidney Failure• Percentage of patients • Percentage with Modified requiring MV for >2days RIFLE Category • Late – 36.3% • Late – 4.6% • Early – 40.2% • Early – 5.8% • P = 0.006 • P = 0.06• Hazard ratio for discharge • Percentage requiring Renal alive from hospital: 1.06 Replacement therapy • 95% CI = 1.00-1.13 • Late – 8.6% • Early – 8.9% • P= 0.77
  • 30. Results Hospital Stay Functional Status at Discharge• Percentage in the hospital • Distance on 6 minute walk for >15 days test • Late – 45.5% • Late (624 pts) – 277 meters • Early – 50.1% • Early (603 pts) – 283 meters • P = 0.001 • P = 0.57• Hazards ratio for time to • Percentage of patients discharge alive from the independent in all ADLs hospital: 1.06 • Late (1060 pts) – 73.5% • 95% CI = 0.99 – 1.12 • Early (996 pts) – 75.5% • P= 0.31
  • 31. Results Mean Total • Included in Total Cost Incremental Health Calculation Care Cost • Cost billed to P =0.04 government • Costs billed to€ 18,500 patient 17,973€ 18,000 • From randomization to discharge€ 17,500 Late€ 17,000 16,863 Early • Values do not include deduction of cost of PN€ 16,500 in the late-initiation€ 16,000 group
  • 32. ResultsSubgroup Analysis
  • 33. Study Limitations• No glutamine or immune-modulating compounds• Low protein-to-energy ratio due to standardized, premixed parenteral nutrition products• Subjects and providers were aware of study group assignments
  • 34. Author’s Conclusions“Early initiation of parenteral nutrition appears to be inferior to the strategy of with-holding until Day 8 while providing vitamins, trace elements, and minerals. Late initiation was associated with fewer infections, enhanced recovery, and lower healthcare costs ”
  • 35. Journal Critique
  • 36. Title and Abstract Strong Weak• Title reflective of study • Results regarding acute and objectives inflammation and hypoglycemia not• Abstract well organized addressed in abstract
  • 37. Methods Strong Weak• IRB Approved • Site locations?• Appropriate Study • Trace elements, vitamins Duration and minerals given to both groups• Patients stratified according to 16 diagnostic criteria• 7 Participating ICUs
  • 38. Outcomes and Statistical Analysis Strong Weak• IRB Approved • Too many secondary outcomes• Safety Outcomes included • Intention-to-treat analysis vs per-protocol• Analysis by computer software• Sub-group analysis performed
  • 39. Results Strong Weak• Establishes 1-day • Article mentions few difference in ICU stay results of the stated between groups secondary outcomes • Reader must refer to• Distinguishes results supplementary appendix between overall hospital stay and ICU stay• Graphs and charts provided are helpful
  • 40. Conclusions Strong Weak• Supported by the • Late-initiation group collected data short-comings not addressed• Study limitations • Hypoglycemia addressed • Hyperbulirubinemia
  • 41. Overall ImpressionBenefits of Late Initiation of TPN therapy • Fewer ICU infections • Shorter duration of mechanical ventilation • Shorter course of renal-replacement therapy • Shorter ICU and hospital stay • Reduced Health care costsDisadvantages of Late Initiation of TPN therapy • Higher degree of acute inflammation • Increase in hypoglycemic episodes
  • 42. References• Zeigler TR. “Parenteral Nutrition in the Critically Ill Patient”. N Eng J Med. 2009;361:1088-1097.• Casaer MP, Dieter M, Hermans G, et. al. “Early versus Late Parenteral Nutrition in Critically Ill Adults”. N Eng J Med. 2011;• Singer P, Berger MM, Van den Berghe G, et al. “ESPEN guidelines on parenteral nutrition: Intensive Care”. Clin Nutr 2009;28:387-400.• Martindale RG, McClave SA ,Venek VW, et al. “Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive summary”. Crit Care Med, 2009;37:1757-61.