Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365: DOI: /NEJMoa

2 APPENDIX: ONLINE MATERIAL EARLY VERSUS LATE PARENTERAL NUTRITION IN CRITICALLY ILL ADULT PATIENTS Michael P. Casaer M.D., Dieter Mesotten M.D., Ph.D, Greet Hermans M.D., Ph.D, Pieter J. Wouters R.N, M.Sc., Miet Schetz M.D., Ph.D, Geert Meyfroidt M.D., Ph.D, Sophie Van Cromphaut M.D., Ph.D, Catherine Ingels M.D., Philippe Meersseman M.D., Jan Muller M.D., Dirk Vlasselaers M.D., Ph.D., Yves Debaveye M.D., Ph.D, Lars Desmet M.D., Jasperina Dubois M.D., Aime Van Assche M.D., Simon Vanderheyden, B.Sc.(Econ), Alexander Wilmer M.D., Ph.D, Greet Van den Berghe M.D., Ph.D. From the department of Intensive Care Medicine (M.P.C, D.M., P.J.W, M.S., G.M, S.V.C., C.I., Y.D., J.M., D.V., L.D., S.V., G.V.d.B.), and the Medical Intensive Care Unit, department of Internal Medicine (G.H, Ph.M, A.W.) of the University Hospitals of the Catholic University of Leuven, Leuven, Belgium, from the departments of Anesthesia and Intensive Care (J.D, A.V.A.) of the Jessa Hospitals, Hasselt, Belgium. The authors received the international Stoutenbeek Award 2009 for the quality of the EPaNIC study protocol. The protocol and statistical analysis plan are published in Trials 2011,12:21. 1

3 Running head: Early versus late parenteral nutrition in adults Corresponding author: Greet Van den Berghe, MD, PhD Department of Intensive Care Medicine University Hospital Leuven, University of Leuven, B-3000 Leuven, Belgium Phone : (+32) or (+32) Fax : (+32) greet.vandenberghe@med.kuleuven.be AUTHORS' CONTRIBUTIONS MPC, GH, AW and GVdB designed the EPaNIC study. MPC and GVdB developed the statistical plan which was reviewed and approved by an independent statistician with special expertise in statistics of clinical trials and by all authors. PJW designed the database, supervised and monitored data entry by the study nurses and assistants, checked the database for accuracy and exported the data for statistical analysis. DM and SV performed the analysis of the incremental healthcare related costs. GVdB and MPC performed the statistical analysis and drafted the manuscript. GVdB vouches for the data and the analysis. Other authors recruited patients and supervised accurate execution of the complex study protocol. All authors read and approved the final manuscript. 2

4 Online Figure 1 3

5 Legend : The panels depict the amount of carbohydrate (top panel), protein (second panel), and lipid (third panel), and total energy (fourth panel) from day 1 through day 16, expressed as gram/kg.day and kcal/kg respectively, administered via the enteral (left panels), parenteral (middle panels) and both (right panels) routes. The lower panels depict the percentages of the calculated nutritional goal (calculated as specified in online-table 3) administered from day 1 through day 16, via the enteral (left panel), parenteral (middle panel) and both (right panel) routes. The data on total energy intake include oral nutrition. Panels showing macronutrient composition of EN do not include oral nutrition, because for the hospital meals in the participating units exact macronutrient composition was not available. Nutrition after ICU discharge was at the discretion of the attending physicians on the regular wards. Boxes represent interquartile ranges and the horizontal lines within the boxes represent the medians. If no horizontal line is present within the boxes, the median value touches the 25 th percentile. The red color depicts the Late PN group and the blue color the Early PN group. 4

6 Online Figure 2: survival up to 90 days after enrollment Legend : Vital status at 90 days after randomization was obtained from the Belgian National Registry for all Belgian citizens. The non-belgian citizens (N=83), who left the hospital alive before day 90 (N=69) were included in this analysis but censored at hospital discharge. Log-rank p-value was

7 Online Table 1. Baseline Patient Characteristics (Expanded) Late PN group Early PN group P Value (N=2328) (N=2312) Male sex - n. (%) 1486 (63.8) 1486 (64.3) 0.75 Age - yr (mean ± SD) 64 ± ± Weight kg (mean ± SD) 75 ± ± BMI (kg/m2) categories n. (%) 0.34 < (6.1) 134 (5.8) 20-< (38.2) 854 (36.9) 25-< (37.1) 852 (36.9) 30-< (17.4) 430 (18.6) (1.2) 42 (1.8) Diabetes mellitus n. (%) 417 (17.9) 391 (16.9) 0.36 Dialysis dependent kidney failure prior to ICU admission n. (%) 35 (1.5) 34 (1.5) 0.92 Cancer n. (%) 457 (19.6) 437 (18.9) 0.52 NRS categories n. (%) (45.1) 1014 (43.9) (37.0) 851 (36.8) (8.9) 231(10.0) (7.4) 178 (7.7) 7 38 (1.6) 38 (1.6) Sepsis upon admission n. (%) 505 (21.7) 510 (22.1) 0.76 Emergency admission n. (%) 970 (41.7) 956 (41.4) 0.82 APACHE II score upon admission (mean ± SD) 23 ± ± Diagnostic category at ICU admission n. (%) 0.99 Cardiac surgery 1408 (60.5) 1410 (61.0) Complicated abdominal or pelvic surgery 178 (7.6) 170 (7.4) Transplantation 163 (7.0) 165 (7.1) Trauma, burns or reconstructive surgery 107 (4.6) 99 (4.3) Complicated pulmonary or esophageal surgery 83 (3.6) 86 (3.7) Respiratory disease 71 (3.1) 72 (3.1) Complicated vascular surgery 69 (3.0) 65 (2.8) Gastroenterologic or hepatic disease 61 (2.6) 55 (2.4) Complicated neurosurgery 54 (2.3) 61 (2.6) Hematological or oncological disease 16 (0.7) 18 (0.8) Neurological disease 15 (0.6) 14 (0.6) Cardiovascular disease 10 (0.4) 8 (0.4) Renal disease 10 (0.4) 8 (0.4) Neurological presentation of medical disease 7 (0.3) 10 (0.3) Metabolic disorder 4 (0.2) 2 (0.1) Other 72 (3.1) 69 (3.0) 6

8 Footnote : BMI denotes body mass index; NRS denotes Nutritional Risk Screening, with higher scores indicating higher risk of malnutrition, ranging from 0 to APACHE-II denotes Acute Physiology And Chronic Health Evaluation-II, with higher scores reflecting more severe critical illness, ranging from 0 to

9 Online-table 2. A. Parenteral Nutrition Composition Oliclinomel N7E Oliclinomel N7 Clinimix N14G30E* Clinimix N17G35E* Glucose 5% + E Glucose 5% Volume 1000ml 1000ml 1000ml 1000ml 1000ml 1000ml Lipids (gram) Amino Acids (gram) Glucose (gram) Sodium mmol Potassium (mmol) Calcium (mmol) Magnesium (mmol) Phosphate (mmol) Acetate (mmol) Chloride (mmol) Footnote : * Administered to 13 patients with contraindications for IV lipids. Summarized data from the "Summary of product characteristics" (versions April 2005 and February 2001) provided by Clintec Parenteral (Maurepas, France). 8

10 Online-table 2. B. Trace elements and Vitamins Addamel Cernevit 10ml 5ml Fe (mg) 1.12 Vitamine A (IE) 3500 Zn (mg) 6.50 Vitamine D3 (IE) 220 Cu (mg) 1.28 Vitamine E (mg) Cr (µg) Vitamine C (mg) 125 Mn (mg) 0.28 Vitamine B1 (mg) 3.51 F (mg) 1.00 Vitamine B2 (mg) 4.14 I (µg) Vitamine B6 (mg) 4.53 Se (µg) Vitamine B12 (µg) 6 Mo (µg) Dexpantothenic Acid (mg) Folic Acid (µg) 414 Biotine (µg) 69 Niacin (mg) 46 Footnote : Patients in both groups receiving nutritional support also received parenteral trace elements and minerals (Addamel Novum, Fresenius Kabi NV, Schelle, Belgium) and vitamins (Cernevit, Baxter, Clintec, Brussels, Belgium) by very slow infusion. Higher doses of Vitamine C, Thiamine, Folate were administered according to the different ICU s practices and clinical indications. 9

11 Online-table 3 : Calculation of caloric target (25) Caloric target = Caloric need x Corrected Ideal Body Weight Formula for calculating Ideal Body Weight (IBW) Female patient [0.91 x (height in cm 152.4)] Male patient 50 + [0.91 x (height in cm 152.4)] Corrected Ideal body weight If BMI < 18.5 (IBW + Actual Body Weight) / 2 If 27 BMI 18.5 IBW If BMI > 27 IBW x 1.2 Caloric need (Kcal/kg/day) Female patient Male patient Age > 60 years Age 60 years Footnote : Caloric target calculations included protein energy 10

12 Online-table 4. Enteral nutrition formula and parenteral nutrition brands (after day 7) used during the study Enteral Nutrition Formulations Company, City Parenteral Nutrition Formulations Company, City Osmolite Abott, Wavre, Belgium OliClinomel N7 Clintec, Brussels, Belgium Nepro Abott, Wavre, Belgium Structokabiven Fresenius Kabi NV, Schelle, Belgium OsmolHical Abott, Wavre, Belgium Pharmacy composed PN Not Applicable Alitra Q Abott, Wavre, Belgium SmofKabiven Fresenius Kabi NV, Schelle, Belgium NutrisonMultif Nutricia, Grimbergen, Belgium Clinimix N17 Clintec, Brussels, Belgium Jevity Fos Abott, Wavre, Belgium Dipeptiven Fresenius Kabi NV, Schelle, Belgium Elemental 028 extra Nutricia, Grimbergen, Belgium KabivenPeri Fresenius Kabi NV, Schelle, Belgium Oxepa Abott, Wavre, Belgium Clinimix N14 Clintec, Brussels, Belgium HiCal Jevity Abott, Wavre, Belgium NutrisonEnergMF Nutricia, Grimbergen, Belgium Suplena Abott, Wavre, Belgium Peptamen Nestlé, Brussels Belgium Footnote : Brands were ranked according predominance of use. Before day 8, patients in the Early PN group only received the study PN, and patients in the Late PN group received glucose 5%. (see also On-line table 2) 11

13 Online Table 5. Outcome (expanded) * Late PN Early PN P Value (N = 2328) (N=2312) Safety outcome Vital status Discharged live from ICU within 8 days n.(%) 1750 (75.2) 1658 (71.7) ICU mortality n.(%) 141 (6.1) 146 (6.3) 0.76 Hospital mortality n.(%) 242 (10.4) 251 (10.9) day mortality n.(%) 257 (11.2) 255 (11.2) 1 Nutrition related complications n.(%) 423 (18.2) 434 (18.8) 0.62 Vomiting or aspiration n.(%) 284 (12.2) 295 (12.8) 0.59 Feeding tube obstruction n.(%) 71 (3.0) 74 (3.2) 0.80 Problematic diarrhea n.(%) 68 (2.9) 65 (2.8) 0.86 Nasal bleeding n.(%) 18 (0.8) 14 (0.6) 0.59 Central venous catheter obstruction n.(%) 9 (0.4) 15 (0.7) 0.22 Pneumo - hemothorax after CVC placement n.(%) 0 (0.0) 2 (0.1) 0.24 Subclavian artery puncture n.(%) 0 (0.0) 2 (0.1) 0.24 Hypoglycemia Patients with hypoglycemia (< 40mg/dl) during intervention n.(%) 81 (3.5) 45 (2.0) Serious adverse events n.(%) 0 (0) 0 (0) 1 Primary outcome ICU stay (days) median [p25 - p75] $ 3 [2-7] 4 [2-9] 0.02 ICU stay (survivors only) (days) median [p25 - p75] 3 [2-7] 3 [2-8] 0.03 ICU stay (non-survivors only) (days) median [p25 - p75] 11 [5-21] 14 [6-32] 0.21 Patients with ICU stay > median (3 days) n.(%) 1117 (48. 0) 1185 (51.3) 0.02 Time to live discharge from ICU* HR (95% CI) ( ) 0.04 Secondary outcomes Patients with a new infection n.(%) 531 (22.8) 605 (26.2) With a new airway/lung infection n.(%) 381 (16.4) 447 (19.3) With a new blood stream infection n.(%) 142 (6.1) 174 (7.5) 0.05 With a new soft tissue (wound) infection n.(%) 64 (2.8) 98 (4.2) With a new urinary tract infection n.(%) 60 (2.6) 72 (3.1) 0.28 Days on antibiotic treatment when newly infected median [p25 - p75] 12 [6 21] 13 [7-23] 0.11 Inflammation Highest CRP during ICU stay (mg/liter) median [p25 - p75] [ ] [ ] < Mechanical ventilation Days on mechanical ventilation (all patients) median [p25 - p75] 2 [1-5] 2 [1-5] 0.02 Days on mechanical ventilation (survivors only) median [p25 - p75] 2 [1-4] 2 [1-4] 0.04 Days on mechanical ventilation (non-survivors only) median [p25 - p75] 11 [5-19] 12 [5-31] 0.25 Patients with a duration of ventilation > median (2 days) n.(%) 846 (36.3) 930 (40.2) Time to definitive weaning from ventilation* HR (95% CI) ( ) 0.07 Tracheostomy n.(%) 134 (5.8) 162 (7.0)

14 OnlineTable 5. Outcome (Expanded) (Continued.) Late PN Early PN P Value (N = 2328) (N=2312) Kidney failure Modified RIFLE category injury or failure n.(%) 104 (4.6) 131 (5.8) 0.06 Renal replacement therapy n.(%) 201 (8.6) 205 (8.9) 0.77 Duration of renal replacement therapy (days) median [p25 - p75] 7 [3-16] 10 [5-23] New renal replacement therapy n.(%) 177 (7.6) 182 (7.9) 0.73 Duration of new renal replacement therapy (days) median [p25 - p75] 9 [4-16] 10 [5-24] Patients requiring hemodynamic support n.(%) 1923 (82.6) 1920 (83.0) 0.68 Duration of hemodynamic support (days) median [p25 - p75] 2 [1-5] 2 [2-5] 0.33 Liver dysfunction Patients with bilirubine > 3 mg/dl During ICU stay n.(%) 337 (14.5) 298 (12.9) 0.12 During first 8 days in ICU n.(%) 307 (12.2) 241 (10.5) Patients with gamma GT rise > 79.5 IU/liter # During ICU stay n.(%) 583 (32.6) 674 (38.4) <0.001 During first 8 days in ICU n.(%) 460 (26.3) 524 (30.6) Patients with Alkaline Phosphatase rise > 405 IU/liter # During ICU stay n.(%) 357 (19.9) 397 (22.6) 0.05 During first 8 days in ICU n.(%) 205 (11.7) 209 (12.2) 0.63 Patients with hepatocytic cytolysis Patients with ALT rise > 123 IU/liter n.(%) 287 (16.1) 301 (17.1) 0.39 Patients with AST rise > 114 IU/liter n.(%) 410 (22.9) 400 (22.8) 0.96 Hospital stay Hospital stay (days) median [p25 - p75] 14 [9-27] 16 [9-29] Hospital stay (survivors only) (days) median [p25 - p75] 14 [10-25] 15 [9-28] Hospital stay (non-survivors only) (days) median [p25 - p75] 19 [9-45] 21 [8-42] 0.38 Patients with hospital stay > median (15 days) n.(%) 1060 (45.5) 1159 (50.1) Time to live discharge from hospital* HR (95% CI) ( ) 0.04 Functional status at hospital discharge 6 Minutes Walking Distance (6MWD) N = 624 N = 603 Hospital day of assessment of 6MWD median [p25 - p75] 12 [9-18] 12 [8-19] MWD (meter) median [p25 - p75] 277 [ ] 283 [ ] 0.57 Activities of Daily Life (ADL) N = 1060 N = 996 Hospital day of assessment of ADL median [p25 - p75] 13 [9-23] 14 [9-24] 0.12 Patients independent for all ADL activities n.(%) 779 (73.5) 752 (75.5) 0.31 Total incremental healthcare cost, mean [p25 p75] [ ] [ ]

15 Footnote : * All hazard ratios and 95% confidence intervals (CI) were calculated with the use of Cox proportional-hazard analysis of the effect of late initiation of parenteral nutrition, with adjustment for risk factors. ICU denotes intensive care unit. Data on vital status at 90 days were available for 2289 patients in the late-initiation group and 2268 in the early-initiation group. Hypoglycemia was defined as a glucose level of less than 40 mg per deciliter (2.2 mmol per liter). > 3 times upper limit of normality. # > 1.5 times upper limit of normality. ALT denotes Alanine Transaminase, AST denotes Aspartate Transaminase, gamma GT denotes gamma Glutamyl Transferase, CRP denotes C-Reactive Protein, CVC denotes Central Venous Catheter, ICU denotes Intensive Care Unit. Modified RIFLE classification (Risk of renal dysfunction, injury to the kidney, failure or loss of kidney function and end-stage kidney disease) was used to define new kidney injury or failure as at least a doubling of the creatinine level at admission 31. Values were available for 2264 patients in the late-initiation group and 2248 patients in the early-initiation group. $ The duration of time in the ICU was defined as the time from admission of patients until they were ready for discharge. Patients were considered ready for discharge as soon as all clinical conditions for ICU discharge were fulfilled (i.e. no more need for vital organ support and receipt of at least 2/3 of the caloric requirements as oral feedings) even if they were not actually discharged that day 24. The "ready for discharge" day coincided with the actual day of discharge for all patients except for 104 patients in the late-initiation group and 95 in the early-initiation group.. Total incremental healthcare costs comprised those billed either to the government or the patients. Since the Belgian reimbursement system provides a daily flat compensation for the 14

16 administration of intravenous fluids, including parenteral nutrition, the reported values do not include a deduction of the cost for parenteral nutrition in the late-initiation group. 15

17 Online-table 6. Subgroup Analysis Primary outcome Safety outcome time to alive discharge from ICU discharged alive from ICU within 8 days HR (95% CI) interaction P Value OR (95% CI) interaction P Value Overall (N=4640) ( ) NA ( ) NA A priori defined subgroups BMI (<25 OR 40) (N=1989) ( ) ( ) NRS 5 (N=863) ( ) ( ) Cardiac surgery (N=2818) ( ) ( ) Sepsis admission (N=1015) ( ) ( ) Post-hoc defined subgroup Surgical contraindication for EN* (N = 517) ( ) ( ) Footnote : *This high risk subgroup of patients for whom Early EN was surgically contra-indicated, comprised the admission subgroups Complicated Pulmonary/Esophageal Surgery and Complicated Abdominal-Pelvic Surgery, (N=517, APACHE-II 27±11). Patients predictably received virtually no enteral nutrition [0 (0-163) kcal/day] by day 7. The duration of ICU stay of these patients was 6 (2-16) days in the Late PN group and 7 (3-19) days in the Early PN group. 16