Design and rationale of the effect of early nutritional therapy on frailty, functional outcomes and recovery of malnourished medical inpatients trial (EFFORT): a pragmatic, multicenter, randomized-controlled trial

Philipp Schuetz, Rebecca Fehr, Valerie Baechli, Martina Geiser, Filomena Gomes, Alexander Kutz, Pascal Tribolet, Thomas Bregenzer, Claus Hoess, Vojtech Pavlicek, Sarah Schmid, Stefan Bilz, Sarah Sigrist, Michael Brändle, Carmen Benz, Christoph Henzen, Silvia Mattmann, Robert Thomann, Claudia Brand, Jonas Rutishauser, Drahomir Aujesky, Nicolas Rodondi, Jacques Donze, Zeno Stanga, Beat Mueller


Background: Malnutrition is highly prevalent and strongly associated with clincial outcomes of medical inpatients. Still, the benefit of nutritional treatment to prevent adverse outcomes in medical inpatients at risk for malnutrition remains unproven. We describe the trial methods of the largest yet nutritional trial in medical inpatients including the rationale for key design decisions regarding the nutritional strategy, eligibility criteria, choice of control arm, and endpoints.

Methods: The Effect of early nutritional therapy on Frailty, Functional Outcomes and Recovery of malnourished medical inpatients Trial (EFFORT) is an investigator-initiated, non-commercial, open-label RCT to compare the effects of an intensified nutritional therapy (intervention group) with a control group on medical outcomes. We include adult medical inpatients at risk of malnutrition based on a Nutritional Risk Screening 2002 (NRS) score of ≥3 points with an expected length of stay of ≥5 days. An individualized systematic nutritional assessment by study dieticians is done to define nutritional targets and to establish an implementation plan. Patients in the intervention group receive individualized early nutritional therapy based on a previously published consensus algorithm, while control group patients receive standard hospital nutrition. The study is powered to compare clinical outcomes (composite adverse outcome and mortality) in the 2 study arms as well as to address several mechanistical questions.

Conclusion: EFFORT aims to close important gaps in the literature regarding the controversy about benefit and possible harm of nutritional therapy in medical inpatients at risk for malnutrition.

Trial Registration: NCT02517476; registered July 30, 2015.


Nutrition, Trial, Intervention

Full Text:



Kubrak C, Jensen L. Malnutrition in acute care patients: a narrative review. Int J Nurs Stud. 2007;44:1036-54.

Felder S, Lechtenboehmer C, Bally M, Fehr R, Deiss M, Faessler L, et al. Association of nutritional risk and adverse medical outcomes across different medical inpatient populations. Nutrition. 2015;31:1385-93.

Aeberhard C, Birrenbach T, Joray M, Muhlebach S, Perrig M, Stanga Z. Simple training tool is insufficient for appropriate diagnosis and treatment of malnutrition: A pre-post intervention study in a tertiary center. Nutrition. 2016;32:355-61.

Casaer MP, Hermans G, Wilmer A, Van den Berghe G. Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial): a study protocol and statistical analysis plan for a randomized controlled trial. Trials. 2011;12:21.

Villet S, Chiolero RL, Bollmann MD, Revelly JP, Cayeux RNM, Delarue J, et al. Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr. 2005;24:502-9.

Schuetz P. Food for thought: why does the medical community struggle with research about nutritional therapy in the acute care setting? BMC Med. 2017;15:38.

Schutz P, Bally M, Stanga Z, Keller U. Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target? Swiss Med Wkly. 2014;144:w13957.

Bally MR, Blaser Yildirim PZ, Bounoure L, Gloy VL, Mueller B, Briel M, et al. Nutritional Support and Outcomes in Malnourished Medical Inpatients: A Systematic Review and Meta-analysis. JAMA Intern Med. 2016;176:43-53.

Schuetz P, Blaser Yildirim PZ, Gloy VL, Briel M, Bally MR, Schuetz P. Early nutritional therapy for malnourished or nutritionally at-risk adult medical inpatients. Cochrane Metabolic and Endocrine Disorders Group, 2017;9; CD011096.

Feinberg J, Nielsen EE, Korang SK, Halberg Engell K, Nielsen MS, Zhang K, et al. Nutrition support in hospitalised adults at nutritional risk. Cochrane Database Syst Rev. 2017;5:CD011598.

Deutz NE, Matheson EM, Matarese LE, Luo M, Baggs GE, Nelson JL, et al. Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: A randomized clinical trial. Clin Nutr. 2016;35:18-26.

Gomes F, Schuetz P, Bounoure L, Austin P, Ballesteros-Pomar M, Cederholm T, et al. ESPEN guidelines on nutritional support for polymorbid internal medicine patients. Clin Nutr. 2018;37:336-53.

Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365:506-17.

Owen HC, Vanhees I, Gunst J, Van Cromphaut S, Van den Berghe G. Critical illness-induced bone loss is related to deficient autophagy and histone hypomethylation. Intensive Care Med Exp. 2015;3:52.

Fucho R, Martinez L, Baulies A, Torres S, Tarrats N, Fernandez A, et al. ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis. J Hepatol. 2014;61:1126-34.

Casaer MP, Van den Berghe G. Nutrition in the acute phase of critical illness. N Engl J Med. 2014;370:2450-1.

Friedli N, Stanga Z, Sobotka L, Culkin A, Kondrup J, Laviano A, et al. Revisiting the refeeding syndrome: Results of a systematic review. Nutrition. 2017;35:151-60.

Schuetz P. "Eat your lunch!" - controversies in the nutrition of the acutely, non-critically ill medical inpatient. Swiss Med Wkly. 2015;145:w14132.

Kondrup J, Johansen N, Plum LM, Bak L, Larsen IH, Martinsen A, et al. Incidence of nutritional risk and causes of inadequate nutritional care in hospitals. Clin Nutr 2002;21:461-8.

Kondrup J, Allison SP, Elia M, Vellas B, Plauth M, Educational, et al. ESPEN guidelines for nutrition screening 2002. Clin Nutr. 2003;22:415-21.

Norman K, Kirchner H, Freudenreich M, Ockenga J, Lochs H, Pirlich M. Three month intervention with protein and energy rich supplements improve muscle function and quality of life in malnourished patients with non-neoplastic gastrointestinal disease--a randomized controlled trial. Clin Nutr. 2008;27:48-56.

Buzby GP, Knox LS, Crosby LO, Eisenberg JM, Haakenson CM, McNeal GE, et al. Study protocol: a randomized clinical trial of total parenteral nutrition in malnourished surgical patients. Am J Clin Nutr. 1988;47:366-81.

Mahoney FI, Barthel DW. Functional Evaluation: The Barthel Index. Md State Med J. 1965;14:61-5.

Hermans G, Clerckx B, Vanhullebusch T, Segers J, Vanpee G, Robbeets C, et al. Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit. Muscle Nerve. 2012;45:18-25.

Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53-72.

Ribaudo JM, Cella D, Hahn EA, Lloyd SR, Tchekmedyian NS, Von Roenn J, et al. Re-validation and shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Qual Life Res. 2000;9:1137-46.

Friedli N, Stanga Z, Culkin A, Crook M, Laviano A, Sobotka L, et al. Management and prevention of refeeding syndrome in medical inpatients: An evidence-based and consensus-supported algorithm. Nutrition. 2018;47:13-20.

Bounoure L, Gomes F, Stanga Z, Keller U, Meier R, Ballmer P, et al. Detection and treatment of medical inpatients with or at-risk of malnutrition: Suggested procedures based on validated guidelines. Nutrition. 2016;32:790-8.

Volkert D, Berner YN, Berry E, Cederholm T, Coti Bertrand P, Milne A, et al. ESPEN Guidelines on Enteral Nutrition: Geriatrics. Clin Nutr. 2006;25:330-60.

Vanek VW, Matarese LE, Robinson M, Sacks GS, Young LS, Kochevar M, et al. A.S.P.E.N. position paper: parenteral nutrition glutamine supplementation. Nutr Clin Pract. 2011;26:479-94.

Vanek VW, Borum P, Buchman A, Fessler TA, Howard L, Jeejeebhoy K, et al. A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract. 2012;27:440-91.

Sobotka L, Schneider SM, Berner YN, Cederholm T, Krznaric Z, Shenkin A, et al. ESPEN Guidelines on Parenteral Nutrition: geriatrics. Clin Nutr. 2009;28:461-6.

Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, et al. ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr. 2006;25:285-94.

Mueller C, Compher C, Ellen DM, American Society for P, Enteral Nutrition Board of D. A.S.P.E.N. clinical guidelines: Nutrition screening, assessment, and intervention in adults. JPEN J Parenter Enteral Nutr. 2011;35:16-24.

McMahon MM, Nystrom E, Braunschweig C, Miles J, Compher C, American Society for P, et al. A.S.P.E.N. clinical guidelines: nutrition support of adult patients with hyperglycemia. JPEN J Parenter Enteral Nutr. 2013;37:23-36.

Choban P, Dickerson R, Malone A, Worthington P, Compher C, American Society for P, et al. A.S.P.E.N. Clinical guidelines: nutrition support of hospitalized adult patients with obesity. JPEN J Parenter Enteral Nutr .2013;37:714-44.

Cano NJ, Aparicio M, Brunori G, Carrero JJ, Cianciaruso B, Fiaccadori E, et al. ESPEN Guidelines on Parenteral Nutrition: adult renal failure. Clin Nutr 2009;28:401-14.

Brown RO, Compher C, American Society for P, Enteral Nutrition Board of D. A.S.P.E.N. clinical guidelines: nutrition support in adult acute and chronic renal failure. JPEN J Parenter Enteral Nutr. 2010;34:366-77.

August DA, Huhmann MB, American Society for P, Enteral Nutrition Board of D. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33:472-500.

Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, et al. ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology. Clin Nutr .2006;25:245-59.

Maisonneuve N, Genton L, Karsegard VL, Kyle UG, Dupertuis YM, Pichard C. [Role of impedance measurement in nutritional screening]. Rev Med Suisse Romande. 2004;124:611-5.

Kirkland LL, Kashiwagi DT, Brantley S, Scheurer D, Varkey P. Nutrition in the hospitalized patient. J Hosp Med. 2013;8:52-8.

MacDonald A, Hildebrandt L. Comparison of formulaic equations to determine energy expenditure in the critically ill patient. Nutrition 2003;19:233-9.

Genton L, Pichard C. Protein catabolism and requirements in severe illness. Int J Vitam Nutr Res. 2011;81:143-52.

Potter JM, Roberts MA, McColl JH, Reilly JJ. Protein energy supplements in unwell elderly patients--a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2001;25:323-9.

Milne AC, Potter J, Vivanti A, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev. 2009:CD003288.

Baumann-Hölzle R, Imoberdorf R, Koblet K, Ballmer P, Rühlin M, Bau R, et al. Ernährungsautonomie – ethisches Grundsatzpapier zur Ernährung der Patientinnen und Patienten im Akutspital. Schweizerische Ärztezeitung. 2006;87:33.

Schuetz P, Hausfater P, Amin D, Haubitz S, Fassler L, Grolimund E, et al. Optimizing triage and hospitalization in adult general medical emergency patients: the triage project. BMC Emerg Med. 2013;13:12.

Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489-97.

Tinetti ME, Studenski SA. Comparative effectiveness research and patients with multiple chronic conditions. N Engl J Med. 2011;364:2478-81.

Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA. 2007;297:1233-40.