Introduction
Current standard of care
Major recent advances and common beliefs that have been contradicted by recent trials
Provision of early EN and PN
Study | Population | Number of patients | Intervention/control | Main findings | Trial title |
---|---|---|---|---|---|
EDEN [7] | Patients with acute lung injury requiring mechanical ventilation | 1000 | Trophic enteral feeding (10 ml/h,10–20 kcal/h) compared to full enteral feeding | No difference in ventilator-free days, 60-day mortality, or infectious complications | Early versus delayed enteral feeding to treat people with acute lung injury or acute respiratory distress syndrome |
PermiT [8] | Critically ill patients | 894 | Permissive underfeeding (40–60% of calculated caloric requirements) compared to standard enteral feeding (70–100%) | No difference in 90-day mortality | Permissive underfeeding versus target enteral feeding in adult critically ill patients |
EPaNIC [11] | Critically ill adults in whom caloric targets cannot be met by enteral nutrition alone | 4640 | Early PN (initiated within 48 h after ICU admission) compared to late PN (not initiated before day 8) | Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation | Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients |
PEPaNIC [12] | Critically ill children with an expected stay of 24 h or more in the ICU and a medium malnutrition risk (using score the Screening Tool for Risk on Nutritional Status and Growth—STRONGkids score) | 1440 | Early PN (initiated within 24 h after ICU admission) compared to late PN (not initiated until day 8) | Late PN was associated with similar mortality, but less infections, shorter ICU stay, and higher likelihood of an earlier live discharge from the ICU | Impact of early parenteral nutrition completing enteral nutrition in pediatric critically ill patients |
Early PN [13] | Critically ill adults with relative contraindications to early EN | 1372 | Early PN (within 24 h of ICU admission) compared to standard care | No difference in 60-day mortality. Early PN strategy resulted in fewer days of invasive ventilation but not significantly shorter ICU or hospital stays | Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition |
Impact of SPN on infection rate, duration of mechanical ventilation & rehabilitation in ICU patients [14] | Patients who received less than 60% of EE from EN at ICU day 3 | 305 | EN alone compared to EN with supplemental PN | Supplemental PN was associated with a decrease of late infections compared to EN alone | |
CALORIES [16] | Patients who could be fed through either the parenteral or the enteral route | 2388 | Early EN compared to early PN for the first 5 days | No difference in 30-day mortality | Trial of the route of early nutritional support in critically ill adults |
REGANE [26] | Adults requiring invasive mechanical ventilation | 322 | Intervention group (GRV = 500 ml) compared to control group (GRV = 200 ml) | No difference in diet volume ratio (diet received/diet prescribed), and pneumonia | Gastric residual volume during enteral nutrition in ICU patients |
NUTRIREA1 [25] | Adults requiring invasive mechanical ventilation | 452 | No routine monitoring of GRV compared to routine monitoring | No difference in pneumonia | Study of impact of not measuring residual gastric volume on nosocomial pneumonia rates |
REDOXS [29] | Mechanically ventilated patients with multiorgan failure | 1223 | 2-by-2 factorial trial, patients were randomized to receive supplements of glutamine, antioxidants, both, or placebo | Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure | Reducing deaths due to oxidative Stress |
OMEGA trial [30] | Patients with acute lung injury requiring mechanical ventilation | 272 | Enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared to placebo | Supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary endpoint of ventilator-free days or other clinical outcomes and might be harmful | Early versus delayed enteral feeding and omega-3 fatty acid/antioxidant supplementation for treating people with acute lung injury or acute respiratory distress syndrome (The EDEN-omega study) (EDEN-Omega) |
MetaPlus [31] | Mechanically ventilated critically ill patients | 301 | High-protein EN enriched with glutamine, omega-3 fatty acids, selenium, and antioxidants compared to standard high-protein EN | The intervention did not reduce infectious complications or improve other clinical endpoints and may have been harmful as suggested by an increased adjusted 6-month mortality | High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU |
Route of early feeding
Nutritional risk assessment
Gastric residual volume (GRV)
Immune-modulating nutrition
Glucose control
Remaining areas of uncertainty
1. Evaluation of energy expenditure and monitoring of nutritional effects in different phases of critical illness and across patients with different nutritional risks |
1.1 Does nutrition guided by measuring energy expenditure affect patient outcome as compared to estimated energy expenditure (EE) by predictive equations? 1.2 What is the approach for estimating EE that is associated with improved outcomes? 1.3 What is the most appropriate energy target expressed as a proportion of (time-dependent) EE and should energy intake match the EE? 1.4 How to assess the burden/beneficial effect of feeding on metabolism and cellular integrity in a clinically useful, continuous point of care measurement monitoring? 1.5 Is there a role for biomarkers in monitoring feeding? 1.6 How to identify patients at highest nutritional risk in its acute and chronic components? 1.7 Does nutrition risk assessment alter the timing of initiation, rate of increase, or ultimate goals of nutrition therapy? 1.8 What is the role of existing nutritional risk scores including nutritional and non-nutritional variables (e.g., NRS-2002 or combination of NUTRIC + PANDORA?) [21] 1.9 How to define and monitor for refeeding syndrome and what is the optimal caloric and protein intake in these patients? |
2. Method of administration of enteral and parenteral nutrition |
2.1 What is the optimal timing for initiation of artificial feeding? 2.2 What is the optimal strategy for management for enteral feeding? 2.3 How should feeding strategy vary at different stages of critical illness and recovery? 2.4 What is the effect of continuous feeding vs intermittent feeding on protein synthesis and on patient-centered outcomes? 2.5 What is the role of alternative lipid emulsions in PN? |
3. Substrate requirements: proteins, carbohydrates, and micronutrients |
3.1 What is optimal protein dose to facilitate recovery of critically ill patients in general and nutritionally high-risk patients in particular (mortality and physical function) and does it need to be combined with some sort of muscle use/exercise? 3.2 Is there any interrelationship between calorie and protein “dose”? 3.3 What is the amount of substrate that is actually absorbed in critically ill patients given gut dysfunction and malabsorption? 3.4 What is the role of whey-based protein (high in leucine) in muscle synthesis and facilitating recovery from critical illness? 3.5 What combinations of amino acids are optimal: should they mimic “normal” intake or be aimed at inducing metabolism or supporting host defense? 3.6 What is the role of small peptide vs polymeric formulae in patients at high risk of intolerance? 3.7 What is the appropriate amount of micronutrients to be provided in ICU patients? |
4. Nutrition and functional recovery |
4.1 What is the best way to measure the effect of nutrition on physical recovery outcomes of survivors of ICU? 4.2 Is there a role for bedside measures to monitor the impact of feeding practices on muscle (such as blood, urine, or muscle imaging) and how to correlate these measures with long-term functional and vital outcomes? 4.3 What is the effect of combination of ranges of proteins + physical activity + monitoring of muscle mass/function? |
5. Management of intestinal and gastric feeding intolerance |
5.1 What is the role of novel pro-motility agents? 5.2 Does the acceleration of gastric emptying to increase nutrient delivery to the small intestine during gastric feeding result in improved clinical outcomes? 5.3 What is the association between small bowel feeding and non-occlusive bowel disease/necrosis? |
6. Immune-modulating nutrition |
6.1 What is the role of glutamine in glutamine-deficient patients and conditions (like burn-injured patients)? 6.2 What is the role of moderate-dose glutamine in patients receiving exclusive PN after the first week in ICU and in absence of renal or hepatic failure? 6.3 What is the role of high-dose IV selenium in cardiac surgery patients? 6.4 What is the role of high-dose IV fish oils in inflammatory conditions, like sepsis and cardiac surgery? 6.5 What is the role of high-dose zinc supplementation in critically ill adults? 6.6 What is the role of vitamin D supplementation in critically ill patients? 6.7 Is there a role of pharmacological agents in promoting retention of muscle mass and improved physical outcomes (e.g., growth hormone, ghrelin agonists, anabolic steroids, and others)? 6.8 Is there a role for arginine/fish oil formula in severe acute pancreatitis? 6.9 Should pharmaconutrition be used alone or in combination with other EN or PN? 6.10 What is the effect of timing of immune-modulating nutrition: pre ICU, early, late etc.? 6.11 How does the effect of immune-modulating nutrition relate to the actual immune status? |
7. Glucose control |
7.1 Should glucose targets differ by diabetic status? Should glucose targets differ according to previous glycemic control in patients with pre-existing diabetes? 7.2 What are the prospects for precision glycemic control? 7.3 Should glucose control differ by feeding strategy and by glucose measurement strategy? 7.4 What is the role of insulin glargine in glucose control in critically ill patients? 7.5 What is role for GLP-1 and its agonists in blood glucose control during critical illness? 7.6 What is the optimal strategy to control blood glucose with avoidance of hypoglycemia and glycemic fluctuations? |
Evaluation of EE and monitoring of nutritional effects in different phases of critical illness and across patients with different nutritional risks
Method of administration of EN
Substrate requirements: proteins and carbohydrates
Protein and functional recovery
Management of intestinal and gastric feeding intolerance
Top ten studies/trials to be done in the next 10 years
Clinical trial design considerations
Outcomes
Study size
Time course of the disease and type of critical illness
Patients
Study design
Top ten trials
NCT number | Title | Recruitment | Interventions | Sponsor/collaborators | Enrollment | Start date | Completion date | Acronym |
---|---|---|---|---|---|---|---|---|
Evaluation of energy expenditure and monitoring of nutritional effects in different phases of critical illness and across patients with different nutritional risks | ||||||||
NCT02897713 | Feasibility, safety, and outcomes of intensive enteral nutrition in patients with mechanical ventilation | Recruiting | Intensive enteral nutrition, routine enteral nutrition | Shanghai Zhongshan Hospital Shanghai 6th People’s Hospital Shanghai Tongji Hospital, Tongji University School of Medicine Shanghai 10th People’s Hospital Shanghai Jinshan Hospital Shanghai Minhang Central Hospital Renji Hospital Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine Xinhua Hospital, Shanghai Jiao Tong University School of Medicine Shanghai East Hospital Xuhui Central Hospital, Shanghai Tongren Hospital, Shanghai | 400 | Nov-16 | Mar-18 | – |
NCT02022813 | Impact of supplemental parenteral nutrition in ICU patients on metabolic, inflammatory, and immune responses | Recruiting | Supplemental parenteral nutrition (SPN) | Centre Hospitalier Universitaire Vaudois University of Geneva, Switzerland | 30 | Apr-14 | Dec-16 | SPN2 |
NCT02306746 | The augmented versus routine approach to giving energy trial | Recruiting | TARGET protocol EN 1.5 kcal/ml, TARGET protocol EN 1.0 kcal/ml | Australian and New Zealand Intensive Care Research Centre | 4000 | Jun-16 | Apr-18 | TARGET |
Timing and administration of enteral and parenteral nutrition | ||||||||
NCT02358512 | Intermittent versus continuous feeding in ICU patients | Recruiting | Enteral feeding | Guy’s and St Thomas’ NHS Foundation Trust University College, London The Whittington Hospital NHS Trust | 116 | Feb-15 | Dec-17 | – |
NCT02159456 | Continuous versus intermittent enteral feeding in critically ill patients | Recruiting | Continuous enteral feeding via infusion pump, intermittent enteral feeding via gravity-based infusion | Seoul National University Hospital | 70 | May-14 | Apr-17 | – |
NCT02853799 | Comparison of the effects of intermittent and continuous enteral feeding on glucose-insulin dynamics in critically ill medical patients | Not yet recruiting | Osmolite 1.2 cal/ml enteral feeds | San Antonio Military Medical Center | 20 | Aug-16 | Oct-17 | – |
Substrate requirements: proteins and carbohydrates | ||||||||
NCT01934595 | Optimal protein supplementation for critically ill patients | Recruiting | Beneprotein | University of Oklahoma | 100 | Sep-13 | Sep-16 | – |
NCT02755155 | Optimization of therapeutic human serum albumin infusion in selected critically ill patients | Not yet recruiting | Human serum albumin infusion 4%, human serum albumin infusion 20% | University Hospital, Strasbourg, France | 550 | Sep-16 | May-19 | AlbAlsace |
NCT02503527 | Efficacy and safety study of a low-carbohydrate tube feed in critically ill patients under insulin therapy | Recruiting | Diben 1.5 kcal HP, Fresubin HP Energy Fibre (1.5 kcal) | Fresenius Kabi OE Clinical Trial Center (KKS) Universität Innsbruck International Medical Research-Partner GmbH dsh statistical services GmbH | 40 | Sep-15 | Sep-17 | – |
NCT02106624 | A trial to assess the effect of high nitrogen intake in critically ill patients | Recruiting | Nitrogen supply | Shanghai Zhongshan Hospital | 80 | Mar-15 | Aug-17 | – |
NCT02678325 | The basal enteral high protein study | Recruiting | Standardized high protein enteral nutrition, standardized normal protein enteral nutrition | University Hospital, Basel, Switzerland | 90 | May-16 | Oct-16 | – |
NCT02584907 | Fat based enteral nutrition for blood glucose control in ICU | Recruiting | High fat enteral nutrition | Shahid Beheshti University | 88 | Oct-15 | Jan-17 | – |
NCT02763553 | Does a ketogenic diet cause ketosis in patients on intensive care? | Not yet recruiting | Ketogenic feed, standard feed | University Hospitals Bristol NHS Foundation Trust | 10 | Dec-16 | Mar-17 | – |
NCT01833624 | Efficiency of a small-peptide enteral feeding formula compared to a whole-protein formula | Recruiting | Peptamen® AF, Sondalis® HP | Centre Hospitalier Universitaire de Besancon Nestlé© Foundation | 206 | Jun-12 | Aug-17 | NUTRI_REA |
NCT02865408 | Amino acid nutrition in the critically ill | Not yet recruiting | Peptamen 1.5% via enteral, Prosol 20% IV to 1.75 g/kg/day, Prosol 20% IV to 2.5 g/kg/day | McGill University Health Center | 30 | Sep-16 | Sep-19 | AA-ICU |
Nutrition and functional recovery | ||||||||
NCT02509520 | Assessing the effects of exercise, protein, and electric stimulation on intensive care unit patients outcomes | Recruiting | MPR and high protein supplement (HPRO), MPR and neuromusc electric stimulation (NMES)|, MPR and NMES and HPRO | University of Maryland | 60 | May-15 | Jul-17 | ExPrEs |
NCT02773771 | Strategies to reduce organic muscle atrophy in the intensive care unit | Not yet recruiting | Beta-hydroxy-beta-methylbutyrate, Placebo, Vital HP®
| Massachusetts General Hospital | 60 | Jan-17 | Jan-19 | STROMA-ICU |
NCT02822170 | Nutrition and exercise in critical illness: a randomized trial of combined cycle ergometry and amino acids in the ICU | Not yet recruiting | Amino acid supplementation plus early in-bed cycle ergometry exercise | Clinical Evaluation Research Unit at Kingston General Hospital | 142 | May 2017 | May 2021 | NEXIS Trial |
Management of intestinal and gastric feeding intolerance | ||||||||
NCT02528760 | To determine the role of prokinetics in feed intolerance in critically ill cirrhosis | Recruiting | Metaclopramide, erythromycin, placebo | Institute of Liver and Biliary Sciences, India | 162 | Sep-15 | Feb-17 | – |
NCT01934192 | Nutritional adequacy therapeutic enhancement in the critically ill: a randomized double blind, placebo-controlled trial of the motilin receptor agonist GSK962040 | Finished recruiting | Novel motilin agonist vs. placebo | Clinical evaluation research unit at Kingston General Hospital | 150 | August 2013 | July 2016 | The NUTRIATE study |
NCT02459275 | PEP uP protocol in surgical patients | Recruiting | PEP uP protocol | Clinical Evaluation Research Unit at Kingston General Hospital | 100 | Jul-15 | Sep-17 | – |
NCT02609620 | Safety & initial efficacy of the LunGuard PFT Sys. on Enteral-Fed, sedated and mechanically ventilated patients peristaltic feeding tube | Not yet recruiting | Peristaltic feeding tube, ConvaTec levin duodenal tube | LunGuard Ltd. | 20 | Dec-15 | Oct-16 | PFT |
NCT02705027 | Comparison of two endoscopically placed nasojejunal probes | Recruiting | Freka®-Trilumina versus Freka®-EasyIn | Ruhr University of Bochum | 64 | Aug-12 | Aug-16 | – |
NCT02515123 | Promotion of esophageal motility to prevent regurgitation and enhance nutrition intake in ICU patients | Recruiting | E-motion system, sham E-motion system | E-Motion Medical Ltd. Clinical Evaluation Research Unit at Kingston General Hospital | 140 | Feb-16 | Dec-17 | PROPEL |
Immune-modulating nutrition | ||||||||
NCT02738762 | Glutamine supplementation | Not yet recruiting | Glutamine supplementation | Medical Centre Leeuwarden | 80 | Jun-16 | Mar-17 | – |
NCT01162928 | Parenteral nutrition with intravenous and oral fish oil for intensive care patients | Recruiting | Nutriflex Omega special + Oxepa, Nutriflex Lipid special + Pulmocare | B. Braun Melsungen AG | 100 | May-13 | Jan-18 | – |
NCT02189538 | Effect of n-3 PUFA from fish in enteral nutrition of major burn patients | Recruiting | ω-3 PUFA, low fat enteral diet | Centro Nacional de Quemados, Uruguay | 100 | Jan-13 | Feb-17 | OmegaBurn |
NCT02868827 | Cholecalciferol supplementation in critically ill patients with severe vitamin D deficiency | Not yet recruiting | Cholecalciferol, milk (Nestle) | King Abdullah Medical City | 430 | Oct-16 | Dec-18 | – |
NCT01704430 | Glutamine to improve outcomes in cardiac surgery | Recruiting | Glutamine, maltodextrin | University of Alberta | 100 | Sep-12 | Jul-16 | GLADIATOR |
NCT02594579 | Effect of vitamin D3 supplementation on muscle mass in ICU patient | Not yet recruiting | Vitamin D3, placebo | Mahidol University | 40 | Oct-15 | Dec-16 | – |
NCT00985205 | A randomized trial of ENtERal glutamine to minimize thermal injury | Recruiting | Enteral glutamine vs. placebo | Clinical Evaluation Research Unit at Kingston General Hospital | 2700 | Jul-15 | July 2021 | The RE_ENERGIZE trial |
NCT02002247 | SodiUm SeleniTe administration IN cardiac surgery: a multicenter, randomized controlled trial of high-dose sodium-selenite administration in high-risk cardiac surgical patients | Recruiting | High-dose intravenous Selenium vs. placebo | Clinical Evaluation Research Unit at Kingston General Hospital | 1400 | Oct-15 | October 2019 | SUSTAIN CSX®-trial |
NCT02864017 | Immuno nutrition by l-citrulline for critically ill patients | Recruiting | Enteral nutrition, l-citrulline, placebo | Rennes University Hospital | 120 | Sep-16 | Oct-18 | Immunocitre |
Others | ||||||||
NCT01477320 | Enteral nutrition as stress ulcer prophylaxis in critically ill patients | Recruiting | Pantoprazole 40 mg IV daily and tube feed, placebo and tube feed | Abbott nutrition University of Louisville | 198 | Aug-13 | Oct-17 | – |
Topic # | Candidate research topic | Average score |
---|---|---|
1 | Effects of high vs low protein dose combined with standardized active and passive mobilization during the acute phase of critical illness on (mortality and) recovery (physical function, ICU length of stay) of severely ill patients (treated with mechanical ventilation and vasoactive drugs during the acute phase). The study should include a priori stratification by nutritional risk | 3.71 |
2 | Effects of high vs low protein dose combined with standardized active and passive mobilization post-acute phase of critical illness on (mortality and) recovery (physical function, ICU length of stay, MV duration) of severely ill patients (treated with mechanical ventilation and vasoactive drug during the acute phase). The study should include a priori stratification by nutritional risk | 2.93 |
3 | Comparative study of different nutritional assessment tools to identify the best tool that differentiates the response to caloric and protein intake | 2.93 |
4 | Effects of permissive underfeeding (calories) with and without high-dose protein supplementation in critically ill obese on (mortality and) physical function | 2.57 |
5 | Effects of continuous versus intermittent (infuse 20–30 min, off 90 min, repeat q 2 h) feeding on mechanistic markers as a prerequisite to a larger RCT | 2.36 |
6 | Best feeding strategy for sepsis patients with respect to calories and proteins | 2.36 |
7 | Effects of high vs low energy dose with standardized active and passive mobilization post-acute phase of critical illness on (mortality and) recovery (physical function, ICU length of stay) of severely ill patients (treated with mechanical ventilation and vasoactive drug during the acute phase) | 2.29 |
8 | Effects of continuous versus intermittent (infuse 20–30 min, off 90 min, repeat q 2 h) feeding on (mortality and) physical function | 2.21 |
9 | What bedside assessment of muscle mass can accurately identify low muscle mass, be used to monitor nutrition success, and predict for function recovery? | 2.14 |
10 | A pragmatic RCT of standardized parenteral supplementation of daily requirements of all micronutrients until full EN is achieved in critically ill patients on mortality and/or functional recovery | 2.14 |
11 | RCT evaluating the effects of prokinetic use on the recovery of critically ill patients with persistent intolerance to EN | 2.00 |
12 | Effects of high vs low energy dose with standardized active and passive mobilization during the acute phase of critical illness on (mortality and) recovery (physical function, ICU length of stay) of severely ill patients (treated with mechanical ventilation and vasoactive drug during the acute phase) | 1.93 |
13 | Effects of stepwise increases in caloric provision during the first week on the complication rate and physical function | 1.93 |
14 | Whey-based protein (high in leucine) (with or without some form of exercise) compared to soy or casein-based protein on mortality and physical function | 1.86 |
15 | Revisiting liberal versus strict glucose control in a setting of tolerated early hypocaloric feeding, strict separation of the glucose levels obtained in the liberal and strict arm in non-diabetic and diabetic critically ill patients on mortality, organ function, and functional status | 1.79 |
16 | Effects of permissive underfeeding (calories) with high-dose protein supplementation in critically ill diabetic patients on (mortality and) physical function | 1.71 |
17 | Nutrition and physical activity guided by muscle mass assessment on (mortality and) long-term physical function | 1.50 |
18 | RCT of small peptide vs polymeric in patients at high risk of intolerance on (mortality and) recovery (physical function, ICU length of stay) and nutritional adequacy (intake) | 1.36 |
19 | Use of resolvins and/or protectins in critically ill patients. The main outcomes are mortality and physical function | 1.29 |
20 | The effect of GLP-1 and its agonists in hyperglycemic critically ill patients on mortality on mortality, organ function, and functional status | 1.14 |
21 | The effect of insulin glargine in hyperglycemic critically ill patients on mortality, organ function, and functional status | 1.07 |