The intensive care medicine research agenda in nutrition and metabolism

Intensive Care Medicine, Apr 2017

Purpose The objectives of this review are to summarize the current practices and major recent advances in critical care nutrition and metabolism, review common beliefs that have been contradicted by recent trials, highlight key remaining areas of uncertainty, and suggest recommendations for the top 10 studies/trials to be done in the next 10 years. Methods Recent literature was reviewed and developments and knowledge gaps were summarized. The panel identified candidate topics for future trials in critical care nutrition and metabolism. Then, members of the panel rated each one of the topics using a grading system (0–4). Potential studies were ranked on the basis of average score. Results Recent randomized controlled trials (RCTs) have challenged several concepts, including the notion that energy expenditure must be met universally in all critically ill patients during the acute phase of critical illness, the routine monitoring of gastric residual volume, and the value of immune-modulating nutrition. The optimal protein dose combined with standardized active and passive mobilization during the acute phase and post-acute phase of critical illness were the top ranked studies for the next 10 years. Nutritional assessment, nutritional strategies in critically obese patients, and the effects of continuous versus intermittent enteral nutrition were also among the highest-ranking studies. Conclusions Priorities for clinical research in the field of nutritional management of critically ill patients were suggested, with the prospect that different nutritional interventions targeted to the appropriate patient population will be examined for their effect on facilitating recovery and improving survival in adequately powered and properly designed studies, probably in conjunction with physical activity.

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The intensive care medicine research agenda in nutrition and metabolism

Intensive Care Med The intensive care medicine research agenda in nutrition and metabolism Yaseen M. Arabi 0 Michael P. Casaer Marianne Chapman Daren K. Heyland Carole Ichai Paul E. Marik Robert G. Martindale Stephen A. McClave Jean‑Charles Preiser Jean Reignier Todd W. Rice Greet Van den Berghe Arthur R. H. van Zanten Peter J. M. Weijs 0 Intensive Care Department, MC 1425, College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU‐ HS), King Abdullah International Medical Research Center (KAIMRC) , P.O. Box 22490, Riyadh 11426 , Kingdom of Saudi Arabia Full author information is available at the end of the article Purpose: The objectives of this review are to summarize the current practices and major recent advances in critical care nutrition and metabolism, review common beliefs that have been contradicted by recent trials, highlight key remaining areas of uncertainty, and suggest recommendations for the top 10 studies/trials to be done in the next 10 years. Methods: Recent literature was reviewed and developments and knowledge gaps were summarized. The panel identified candidate topics for future trials in critical care nutrition and metabolism. Then, members of the panel rated each one of the topics using a grading system (0-4). Potential studies were ranked on the basis of average score. Results: Recent randomized controlled trials (RCTs) have challenged several concepts, including the notion that energy expenditure must be met universally in all critically ill patients during the acute phase of critical illness, the routine monitoring of gastric residual volume, and the value of immune‑ modulating nutrition. The optimal protein dose combined with standardized active and passive mobilization during the acute phase and post‑ acute phase of critical illness were the top ranked studies for the next 10 years. Nutritional assessment, nutritional strategies in critically obese patients, and the effects of continuous versus intermittent enteral nutrition were also among the highestranking studies. Conclusions: Priorities for clinical research in the field of nutritional management of critically ill patients were suggested, with the prospect that different nutritional interventions targeted to the appropriate patient population will be examined for their effect on facilitating recovery and improving survival in adequately powered and properly designed studies, probably in conjunction with physical activity. Nutrition; Metabolism; Critical care; Intensive care; Protein; Calorie - Introduction The last decade has seen much needed increases in the number of methodologically sound studies in the field of nutrition therapy of the critically ill, adding to the expanding body of knowledge and highlighting or inducing many uncertainties and controversies [ 1 ]. In this review of the research agenda for intensive care medicine nutrition and metabolism in adults, we summarize the current practices, major recent advances in the field, and common beliefs that have been contradicted by recent trials. We then highlight key remaining areas of uncertainty and suggest recommendations for the top 10 studies/trials to be done in the next 10 years. Current standard of care Recent randomized clinical trials have questioned several previously accepted but poorly supported concepts in nutrition therapy of critically ill patients. Based on the current available evidence, defining a universally accepted standard of care is difficult. Existing clinical practice guidelines by different societies/organizations have provided detailed evidence-based assessment of available evidence. Although the resulting recommendations have similarities, significant differences exist that reflect lower levels of evidence and differences in the methodology of guideline development [ 2 ]. In practice, considerable variations also exist. The use of routes of nutrition [enteral nutrition (EN) or parenteral nutrition (PN)] and the dose of calories and protein all vary across centers and countries (Supplemental References). For the evaluation of energy expenditure (EE), different predictive equations are used. Indirect calorimetry is infrequently used, reflecting the limited supportive evidence, the limited availability, and the difficulties in performing and interpreting the measurement in critically ill patients (Fig. 1) [ 3, 4 ]. Major recent advances and common beliefs that have been contradicted by recent trials Provision of early EN and PN The value of early initiation of EN is supported by physiologic data. Over the first week of ICU admission, most critically ill patients experience the non-nutritional benefits of EN by virtue of the gastrointestinal responses [maintaining gut integrity, supporting the diversity of the microbiome, and sustaining gut-associated lymphoid tissue (GALT) and secretory IgA production], immune responses [sustaining mucosa-associated lymphoid tissue  (MALT) at distant sites, stimulating Th2 anti-inflammatory lymphocytes and T-regulatory cells], and metabolic responses [increasing incretin release, and reducing generation of advanced glycation end products (AGEs)] (Supplementary References). Meta-analyses of randomized controlled trials (RCTs) demonstrate that early EN is associated with reduction in mortality and infections compared to withholding early EN, although the included individual clinical trials are heterogeneous and not adequately powered [ 5 ]. Additionally, the definition of early nutrition remains arbitrary and has ranged from 3 to 7 days in different interventional studies. Nevertheless, the notion that EE must be met universally in all ICU patients during the acute phase of critical illness has been challenged. Indeed, a number of trials in general ICU patients and in selected populations (acute respiratory failure, acute lung injury, refeeding syndrome) show that restricted feeding strategies described as “permissive or trophic” during the early phase of critical illness result in similar outcomes compared with standard caloric intake (Table  1) [ 6–10 ]. However, “standard” caloric intake in these trials met only 70–80% of EE. The protein intakes also differed between the study arms in most studies [ 6, 7 ], but not all [8]. So it remains uncertain whether the provision of energy to fully match EE has clinical benefit. Along with the lack of benefit of early aggressive EN, the use of supplemental PN in the first week to achieve caloric targets for all patients has now been challenged. The EPaNIC study, conducted in critically ill adults in whom caloric targets could not be met by EN alone, showed that late initiation of PN (i.e., after a week of critical illness) was associated with faster recovery and fewer complications, as compared with early initiation [ 11 ]. Interestingly, the similarly designed PEPaNIC trial in critically ill children showed similar results [ 12 ]. The Early PN trial found that early PN (i.e., within the first hours of admission in ICU) to critically ill adults with relative contraindications to early EN was not associated with a significant clinical benefit [ 13 ]. Another study enrolled patients who received less than 60% of EE from EN at ICU day 3 and found that supplemental PN was associated with a decrease of late infections compared to EN alone [ 14 ]. Of note, common infections, including pneumonia and bloodstream infections, did not decrease [ 14 ]. While these studies are somewhat conflicting, it would appear that there is no benefit in providing nutrition parenterally early in the ICU stay. The underlying mechanisms and potential consequences of an increased provision of nutrients during the early phase of critical illness are currently investigated. A pre-planned secondary analysis  of 600 patients included in the EPaNIC trial, with prospective assessment of functional weakness, revealed that tolerating a substantial macronutrient deficit during the first week of critical illness reduced ICU-acquired weakness (ICU-AW). In addition, muscle biopsies indicated that activation of autophagy might explain the protective effect on weakness of delaying PN delivery [ 15 ]. Hyperglycemia during feeding may occur since the endogenous production of glucose cannot be fully inhibited by exogenous caloric supply [ 3 ]. Nutrient delivery may lead to the development of refeeding syndrome or may counteract potentially adaptive early anorectic response of severe illness, particularly in severely ill patients, identified by high “nutritional risk” as discussed below. Irrespective of the underlying mechanisms, the optimal amount of calories and proteins in the early phase of critical illness remains unknown. Patient Admitted to the ICU • How to identify patients at highest nutritional risk? • What is the role of the existing nutritional risk scores? • Does nutrition guided by measuring EE affect patient outcome? • What is the approach for estimating EE that is associated with improved outcome? • What is the optimal calorie dose? • What is the optimal protein dose? “Take steps to improve tolerance to gastric feeding” • What is the role of novel pro-motility agents? • Which patients benefit from post-pyloric feeding tube placement? “Implement enteral feeding protocol” • What is the optimal timing for initiation of artificial feeding? • What is the optimal strategy for managing EN? “Do not use gastric residual volumes as part of routine care” “Start PN when EN is not feasible or sufficient in high-risk patients” • Does gastric residual monitoring have a role in the identification of patients with gastrointestinal dysfunction? • What is the role of pro-motility agents? • Does improving gastric emptying result in improved clinical outcomes? • What is the optimal timing of initiating PN? • What is the optimal caloric dose of PN? • What is the optimal composition of PN? Lipids? Micronutrients? • Who is at “high risk”? Does it mean more risk of harm by underfeeding or more risk of harm by EN/PN??? M N iillttraeT ‑lllfrrrtssyyvaaaEeeeeeeeunddd ‑iiftt/ycaaaae3onndgdgm iiilttttsxaaaeeuoonnnndppm iilfrrttttcaaeeeeuoohngppw iiljrrrrrttsyycaaeeuuuoonngp ‑i(rrtssssyTEEeeeohnddNDm ‑))(tsyaaEEeeuogdgNDOmm ‑iiiilrrrttttaeeeuoonnnnhgpH ‑‑iiirtceeeuonhhnddwmmm iilrrttttsssvaaaeuunnnnddg ‑iiiilrrrttttaeeeuoonnnnhhgp iiiilftssccaaeoooonnnnndm ItehCU iiifsannngd ‑ilffttttyaaee3uoonnnppm ‑,,iiiillsγcccaaaeonnnddd iiiirtttsxvaaeooonnndddpm iifrrttyaeeoohnndppm ‑ilfrrrrtttsyvaaeeeeooonhd iiillttscccaaeuoonnhdgmm lfraeuhbm iiirrtttcveeeeeuoonhnnnddd iiiilfttsscccaeuooonnpm iiillrrrtccvaeeooohnpm itsyvaaaeeeeonnnhnddpbm lfrtsssyaaaeeuuhnggdbm ‑ijrttsscaaeee6uonnhdddm ilrttyaom M S T ‑f3n , tod on icad raep il/tttrrcveeooonnn illrtttsaaeeeuonnppm ‑,iiillfttsγyccaaeonnd iittsxcaaaoonnnddm lcaeopb In E s t n e i t a p   f o r e b m 27 u 2 N ry ‑ila ju tn in e ng lva lu ic te an cau ceh h m iltaounp iitttsaenw iirreunqg iton o P P d e u iltceaT1onnb tySud il[]rtaE30AGOM , ith iscad tsn ‑ihg edw fttya iad rhd x irch ‑a3g ito and en e an ta EN ,om and tso iten ien , ihg lagm iseunm rcaeodpm irtEeonpN o ‑rp tu le H Route of early feeding The CALORIES trial was a pragmatic RCT that compared early EN to early PN for the first 5 days in an unselected critically ill population. The majority of patients in both arms did not reach EE targets and no difference on short-term outcome was found [ 16 ]. A recent metaanalysis that included the results of the CALORIES trial comparing EN to PN found no effect on overall mortality [ 17 ]. However, EN was associated with lower infective complications and shorter ICU length of stay (LOS) [ 17 ]. Nutritional risk assessment It has been generally accepted that a small percentage of patients, those at highest nutritional risk, may require the nutritional benefits of therapy where full macro- and micronutrient provision maximizes protein synthesis, supports lean body mass, and corrects nutrient deficiencies. Hence, there has been increasing work to define nutritional risk assessment in nutrition therapy [ 18 ]. The NUTRIC (The Nutrition Risk in Critically ill) score was proposed to identify those who will benefit the most from nutrition therapy or be harmed the most by ongoing inattention to nutrition. The clinical utility of this score has been examined in three multi-institutional databases. These studies demonstrate that patients with high NUTRIC scores have reduced mortality with increased nutrition intake compared to patients with low NUTRIC scores where no such relationship between intake and mortality exists [ 18, 19 ]. Of note, the variables included in this score mainly reflect the severity of disease and are not direct measures of nutritional status. A post hoc analysis of the PermiT trial showed that permissive underfeeding was associated with similar mortality compared with standard feeding in patients with high and low nutritional risk as assessed by the NUTRIC score and several other nutritional risk tools [20]. Other scores have also been developed, such as the Nutrition Risk Screening-2002 (NRS-2002) score and the PatientAnd Nutrition-Derived Outcome Risk Assessment Score (PANDORA); the latter has yet to be validated in the critically ill population [ 21, 22 ]. The role of nutritional assessment using an objective measurement of body composition or more specifically muscle mass (using CT, ultrasound, or bioelectric impedance) requires further study (Supplementary References). Although these parameters identify increased risk of death, it is unclear if these are modifiable by nutrition or if they just reflect disease severity. The uncertainty about the optimal approach for nutritional assessment is further complicated by the controversy regarding whether patients with severe undernutrition would benefit or alternatively suffer from high energy and protein intakes. In patients with hypophosphatemia within 72  h of initiation of nutrition, restricted versus standard caloric intake resulted in no difference in the primary endpoint of the number of days alive after ICU discharge, but with more patients alive at day 60 [ 23 ]. Post hoc analysis of the PermiT trial suggested that patients with low prealbumin levels might have better outcomes with restricted calories [ 20 ]. Post hoc analysis of the EPaNIC trial showed that the beneficial effect of a delay in the initiation of PN was generalized across different strata of severity of illness including those who were most severely ill [ 24 ]. Interestingly, the PEPaNIC trial showed that early PN provoked more harm in children at increased nutritional risk according to their Screening Tool for Risk on Nutritional Status and Growth (STRONGkids) score [ 12 ]. Another aspect of nutritional assessment is how to differentiate the acute (catabolic) phase and the post-acute (anabolic) phase. There is a need for a dynamic marker to identify patients “readiness for enhanced feeding”. Such a marker would allow an adaptation of the nutritional strategy to the clinical evolution based on endocrinological or metabolic signals rather than starting enhanced energy/ protein intake at a predefined number of days. Gastric residual volume (GRV) The role of GRV measurement to monitor tolerance of patients on EN has been challenged. Although GRVs are generally considered to indicate gastric emptying rate, volumes aspirated are also affected by the rate of feed administration, the technique of aspiration, gastric secretion, and duodeno-gastric reflux. Increasing the limit of monitored GRV from 200 to 500  ml (REGANE study) or adopting a no routine monitoring of GRV strategy (NUTRIREA1 study) among adults requiring mechanical ventilation did not increase pneumonia [ 25, 26 ]. However, these studies included predominately patients admitted for medical (as opposed to surgical) reasons and were underpowered to assess the impact on other clinical outcomes. In one study, a 24-h total GRV of greater than 250 ml was shown to predict slow gastric emptying, but the sensitivity and negative predictive value were modest [27]. Immune‑modulating nutrition The use of immune-modulating macronutrients (e.g., glutamine, arginine, and omega-3 fatty acids) and micronutrients (e.g., antioxidant vitamins A, C, and E and the minerals selenium and zinc) used alone (pharmaconutrition) or in combination (immunonutrition) to enrich EN or PN and improve outcomes of ICU patients has been challenged in a number of RCTs [ 28 ]. The REDOXS trial showed an increase in mortality with high doses of enteral and parenteral glutamine (0.6  g/kg per day) [ 29 ]. The OMEGA trial showed that enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants in patients with acute lung injury did not improve the primary endpoint of ventilator-free days or other clinical outcomes and might be harmful [ 30 ]. In the MetaPlus study, highprotein EN enriched with glutamine, omega-3 fatty acids, selenium, and antioxidants did not reduce infectious complications or improve other clinical endpoints when compared to standard high-protein EN and may have been harmful as suggested by an increased adjusted 6-month mortality [ 31 ]. A recent meta-analysis showed that enteral glutamine supplementation does not confer clinical benefit in critically ill patients [ 32 ]. However, in severe burn patients, enteral glutamine supplementation was associated with reduction in hospital mortality and stay [ 32 ]. The danger of providing arginine in the setting of sepsis has been challenged, as multiple studies in septic patients showed no adverse hemodynamic changes in response to intravenous arginine infusion [ 33 ]. The use of arginine/ fish oil formulas may still be beneficial in elective surgical patients, as its use has been shown in four recent meta-analyses to reduce infection and hospital LOS and improve other clinical outcomes (Supplementary References). In severe acute pancreatitis, three small studies in immune-modulating nutrition of varying components showed improved outcomes, but the small numbers enrolled were such that only one reached significance and a meta-analysis was negative (Supplementary References). This last group of patients (severe acute pancreatitis) should be studied further before discounting immune-modulating nutrition across the board. Important questions regarding immune-modulating nutrition remain (Table 1). Glucose control The survival benefit of tight glucose control (TGC) (target 4.4–6.1  mmol/L) observed in an RCT of predominantly (cardiac) surgical patients and an RCT of medical ICU patients [ 34, 35 ] could not be reproduced in other RCTs [36]. The largest trial, NICE-SUGAR, showed increased 90-day mortality with TGC compared to a target of less than 10 mmol/L [ 37 ]. The observed differences in outcome may be related to different targets achieved, different blood glucose analyzing methodology, or the difference in the amount and route of early nutritional intake between the Leuven as compared to the other trials [ 36, 38 ]. After 15  years of intense research in this field, a few assertions are widely accepted: (1) there are three domains of dysglycemia (severe hyperglycemia, moderate hypoglycemia, and high glycemic variability) which are individually and synergistically associated with poor vital outcome; (2) blood glucose control is demanding, difficult to perform, and requires technological improvements in monitoring and therapeutic modalities including automated algorithms and new agents such as long-acting insulin or glucagon-like peptide-1 (GLP-1) agonists; (3) the optimal target could differ over time and according to the pre-existence of diabetes and its control. A study found that markers of inflammation, endothelial injury, and coagulation activation were attenuated in the patients with stress hyperglycemia without diabetes but not in diabetics, suggesting different underlying pathophysiology. In a large observational study, reduced mortality was observed with blood glucose between 80 and 140  mg/dl in non-diabetic patients and 110–180  mg/dl in diabetic patients (Supplementary References). These hypothesis-generating findings are yet to be examined in RCTs. Remaining areas of uncertainty As indicated above, recent trials have highlighted many areas of uncertainty in critical care nutrition. We highlight selected areas here and in Table 2. Evaluation of EE and monitoring of nutritional effects in different phases of critical illness and across patients with different nutritional risks Indirect calorimetry is considered the gold standard in measuring EE in clinical settings [ 39 ] and is recommended, when available, by clinical practice guidelines, although it is acknowledged that the evidence on which this premise is based is limited [ 5, 40 ]. Indirect calorimetry measurements of EE are generally performed during 1–2  h per day and under controlled conditions and therefore do not account for the variation of EE during 24  h.  Nevertheless, measuring EE might have a role in preventing overfeeding. Predictive equations are often used instead of direct EE measurement but may over- or underestimate EE and do not account for the variation of EE during critical illness over time [3]. As in clinical practice, most major studies including targeted feeding in the design rely on these predicted values of EE. A more fundamental question is whether calories delivered to patients during the acute phase of their critical illness should match measured or estimated EE despite ongoing endogenous nutrient release, which is not suppressed by feeding and is unmeasurable [ 41 ]. Other important questions remain on to how to assess nutritional risk and how to to determine which patient groups benefit from specific nutritional interventions and which do not or experience harm (Table 2) Method of administration of EN The approach of continuous feeding has been challenged as being unphysiologic [ 42 ]. In animal models and in healthy volunteers, data suggest that protein synthesis is significantly greater after the consumption of a single bolus dose of whey protein than when the whey protein was given as small-pulsed drinks or as a continuous infusion [ 42–44 ]. Intermittent feeding may also have greater anabolic response, increased gastric contractility and emptying, as well as less diarrhea and better absorption owing to slowing of intestinal transit from increased peptide YY release [ 45, 46 ]. However, clinical data supporting this practice are awaited. Substrate requirements: proteins and carbohydrates It remains unclear what constitutes an optimal protein “dose” to facilitate recovery of nutritionally high-risk patients. Current recommendations  are based on very limited evidence. In one trial, a daily intravenous supplement of standard amino acids did not alter the duration of renal dysfunction, and functional outcome at 90  days was unaffected by the large difference in dose of amino acids (0.5–1  kg over 1  week) [ 47 ]. In another study, the administration of amino acids at either 0.8 or 1.2 g/kg in patients receiving PN did not result in a difference in the primary endpoint of handgrip at ICU discharge, although it resulted in slight improvements in other functional outcomes and in nitrogen balance [ 48 ]. The interpretation of these improvements was somewhat complicated by the higher mortality (potentially competing with weakness) in the patients receiving more amino acids [ 49 ]. Another issue to consider is whether there is any interrelationship between calorie and protein “dose”. There is evidence to suggest that if a basal amount of protein is provided, varying the percentage of goal calories delivered may not change outcome. In the PermiT trial [ 8 ] and other studies [ 50 ], restricting calories did not change outcome compared to full feeds when protein provision was equal between groups. On the other hand, data from the International Nutrition Survey 2013 showed that achieving at least 80% of prescribed protein intake (but not energy intake) was associated with increased survival in ICU patients [ 51 ]. Another study showed increased survival with achievement of protein intake of 1.2  g/kg body weight when patients were not overfed with energy (more than 110% of measured EE) [ 52 ]. An earlier small RCT showed that higher protein delivery at 1.4 gm/kg/ day (and reduced calories, 12  kcal/kg) led to better outcome (reduced SOFA score at 48  h) than lower protein doses at 0.76 gm/kg/day (and reduced calories, 14  kcal/ kg) [ 53 ]. Not all proteins are equivalent in their ability to stimulate protein synthesis; whey protein (high in leucine) may increase muscle synthesis compared to soy or casein protein [ 42 ]. An RCT in obese older adults showed that 1. Evaluation of energy expenditure and monitoring of nutritional effects in different phases of critical illness and across patients with different nutri‑ tional 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 measure‑ ment 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? Underlying nutritional risk/ underlying functional status Inflammation Insulin resistance Catabolism/ anabolism Energy expenditure Rehabilitation GI intolerance Oxidative stress Autophagy Nutritional therapy in the ICU a high whey protein-, leucine-, and vitamin D-enriched supplement compared with isocaloric control preserves appendicular muscle mass during hypocaloric feeding and resistance exercise program [ 54 ]. The implications for critically ill patients are unknown and require further study. While many different combinations of amino acids are theoretically possible, it remains unclear whether these combinations should mimic “normal” intake or be aimed at inducing metabolism or supporting host defense. In contrast to lipids or glucose, an individual amino acid given in excess of demands cannot be simply stored and needs to be metabolized, thereby consuming other amino acids [ 15, 55 ]. Protein and functional recovery Long-term functional recovery of some ICU patients is markedly impaired, e.g., patients with severe ARDS only achieve 76% of a reference value on 6-min walk test for up to 5  years [ 56 ]. The relationship between ICU-acquired weakness (ICU-AW) and delayed functional recovery is only partially established and it is unclear if loss of myofiber mass as compared to loss of myofiber integrity and quality contributes more to the loss of muscle force [ 15, 57 ]. Rates of muscle atrophy and changes in muscle architecture have been quantified and are associated with poor clinical outcomes, although the role of assessment of skeletal muscle mass using computed tomography imaging and ultrasonography and assessment of fat-free mass using bioelectrical impedance analysis remain to be established [ 58, 59 ]. Nevertheless ICU-AW is associated with a longer hospital stay, decreased likelihood to go home after hospital discharge, and reduced long-term survival [ 60 ]. While it is evident that rehabilitation should play an important role, from other areas of research (sports, elderly), it is likely that the combination of protein and exercise will improve physical performance (Fig.  2) [ 61, 62 ]. Surprisingly, withholding PN in patients who received protocolized physiotherapy and passive or active bedcycling reduced the incidence of ICU-AW and enhanced recovery in a 600-patient substudy of the EPaNIC trial [15]. This underscores the fact that general principles that apply in other physiologic conditions may not apply to very early ICU nutrition. While the benefit of early enhanced feeding has long been overestimated, the importance of prolonged often unnoticed and unintentional underfeeding is under addressed, particularly after ICU discharge to the conventional ward [ 63 ]. This deserves much more attention, as patients in this phase of recovery may be more likely to experience benefit by enhanced nutrition possibly in combination with physical exercise. Management of intestinal and gastric feeding intolerance A meta-analysis of 15 RCTs showed that small intestinal feeding compared to gastric feeding improved nutritional intake and reduced the incidence of ICU-acquired pneumonia but did not affect other clinically important outcomes [ 64 ]. However, the indications for small intestinal feeding (when? for whom?) in the ICU remain unclear. Development of novel motility agents beyond erythromycin and metoclopramide remains an area of active investigation. Use of currently available agents is limited by the fear of adverse effects and tachyphylaxis as their efficacy decreases over time (4–5  days). A novel motilin agonist without antibiotic or cardiac effects has recently been shown to accelerate gastric emptying in critically ill patients (Supplementary References). However, the clinical benefits of gastric emptying acceleration and delivery of more nutrition still need to be proven and compared to post-pyloric feeding tubes. Top ten studies/trials to be done in the next 10 years Clinical trial design considerations Outcomes It is important that patient-centered outcomes be emphasized in clinical phase III trials evaluating nutritional interventions; these include mortality, complications (including infections), and functional outcomes (including the ability to perform prior activities and to return to work, muscle strength, walking distance, quality of life). Surrogate outcomes such as amount of calories/protein delivered, biochemical markers, and glycemic control should not be used as primary outcomes for these largescale clinical trials. Study size Phase III RCTs must be adequately powered and power calculations must be performed using realistic event rates and expected effect size [ 65 ]. The ethics of conducting a study doomed to fail need to be questioned. Time course of the disease and type of critical illness It may be important to distinguish between acute critical illness, subacute critical illness, chronic critical illness, and the relatively stable postoperative ICU patient  (Fig.  2). These different phases of critical illness, or specifically the points of “anabolic switch”, are as yet undefined. It is possible that, when relevant, nutritional support should be individualized on the basis of the patient evolution: as the patient improves clinically and can start rehabilitation, nutrition support should be adapted to the new health state. Patients It is of importance to focus on severe critical illness with patients who experience organ failure (requiring at least invasive mechanical ventilation) and whose outcome depends on nutritional support. The nutritional status of the patients included in the studies should be detailed according to prespecified variables and studies should include a priori stratification by nutritional risk. Specific types of patients should be identified (e.g., those with previous poor nutrition, postoperative, those without organ failure and sepsis). Study design Interpretation of many critical care nutritional observational studies is complicated by the presence of many confounders and competing outcomes. Adequately powered RCTs are the best approach to balance measured and unmeasured confounders. Many previous nutrition trials have been open to bias because they have been unblinded. Top ten trials There is considerable research being conducted in different aspects of nutrition therapy in critically ill patients. Table 3 summarizes open RCTs registered on clinicaltrials.gov as examples of ongoing work. The panel identified the following studies as the top 10 trials/studies for the next 10 years using the methodology outlined in the online supplement (Table 4). 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‑ffffrtcFe3PoonAUm iiiilffrrtttsaeeuoonnnhn ijrrttsaaeuonnbpm ‑illllfrsccaeeeuoohpp iiiillrtttyccaaeonnnm iiillrtttssvaeeeenhpw iiiiftyccvaeenndDm u T t T N P S C P ng G P E C itn ifon 0 2 5 0 7 3 ilta 2 8 8 7 on re tn 76 19 27 62 02 12 ud 76 92 53 82 lce3 unbm aeegm T82502 T43901 T95402 T90620 T50702 T51520 ‑euonm T87302 T26101 T98102 T86802 b T n C C C C C C m C C C C a C a N N N N N N N N N N m T N M I 2 ‑1 g u m u h c o B f o M y t i C l a c i d e h a ll u d b A g n i K N y A I n D R o r A O c L T S U M C C o u C J D d t 2 5 r ‑1 ‑1 ta ep tc S S O o 0 0 r 0 4 n 1 E s r o t ra rta y o e it b lb rs la A e l f iv co o n / y U r it l so rs o n e id o iv h p n a n i r t x e o d b o e lt c s a la iton ,em ,3p n in D e n v m i tren ltau itam I G V t n g e itm iitng t iitn iitng ru ru ye rcu ru c c t e c e e o r e R R N R n n U U l l h a h a rc it rc it p p ae s ae s s o s o e H e H R l R l n ra n ra io e io e t n t n a e a e lu G lu G va n va n E to E to l s l s a g a g ic n ic n in iK in iK l l s o u b o e n c ve la a .p r t s n v i lu o e m s u g b o i l e d n ra c ‑ le e la h e tn p ig S E H 5 0 2 5 8 9 0 0 T 9 1 0 2 r e b o t c 7 4 2 2 0 0 2 0 T A G – – ‑R la l a E ir ir N t N ‑t E E I ® _ Z A X ST S eh ER IG T U C S ‑i c o n u m rte m I n u io Lo rt f i io R m t irt ”O fro u n o ed “n i : ta vo ille yg m m isv rttae lfam ree s in re h “ rc R )w t o a O n u y e ” o n it s n it tt rs ng ito irt o e i la u b iv w it -n bA nU llo en on o v n f l ily teh ica ,ed ad ob IV ce g la r m ,p 0 R 0 d d ,2 ”O on 4 e e 8 s n le fe fe 2 s ( r e s zao eb eb eb illn ep r u u m la co p t t o d d tan an an P h c r a e s R e O h ” T la . r u i o m n r e o s f“ , t R l u O d ” a y | rg l ” l e i n l y “e l a R ic O it ” r c d “ e e R f O “ ” R it O n ” u g in re ed ca e e f v l i a s r n te te “en i“n R R ”O ”O g re in a d c e e v fe i “ s t s n il R e O t e ”n i“n th g an iz n h m is c o u e d m an 16 “ ve itc rs o ir e N “c th n | o o s f ”s ie o r d s io tu ie n s d e l u “s an ts d o d an it n n a ”s e ly lt rv la u e u d t n n “a i a | in s m r“o re i o a d f “p tu s ed R 8 O 5 ch ” W “p re ‑ a ed ilte ‑iilrtttvaeeuuooonpmm iirrrssycccaaeeuondgm ‑iifffttscvae3uonpDm illttscaeeeuoonnnpmm iiIttssaaennpCUm iilfrrtzaaeoonddm illtttaaEEeRuongNm iiiiljrrtzyaeeunhnmmm iiiilrtsaSTeeeonnddUmm :iiIrrrtsyccaaaeuondgN ,iilrrttzcaeeeuonnddmm ‑iilllfrrttcaeooonhhdg ‑iiltssseeeeuoonddm iiirttsaaonndm ‑iiiilrrrsskcccaaauhhgdg ittsaenp iirttyuuoonnnbm l‑iiiiillllllfrrrttycccaeuon ittsaenp iilrrrttttssssaaeeuonnn ‑iiiillrrrtsxyccaeuohnpp iillllttsycaaenp iiilrttt“””ssvaeeeounnnd iiil|rttt”saeeoouunnndp llrrttssvaaeeeeeeuuhdw u T G E A S in Im E n re .T n ep t i n se t Average score 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 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 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 Comparative study of different nutritional assessment tools to identify the best tool that differentiates the response to caloric and protein intake Effects of permissive underfeeding (calories) with and without high‑ dose protein supplementation in critically ill obese on (mortality and) physical function 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 Best feeding strategy for sepsis patients with respect to calories and proteins 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) Effects of continuous versus intermittent (infuse 20–30 min, off 90 min, repeat q 2 h) feeding on (mortality and) physical function What bedside assessment of muscle mass can accurately identify low muscle mass, be used to monitor nutrition success, and predict for function recovery? 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 RCT evaluating the effects of prokinetic use on the recovery of critically ill patients with persistent intolerance to EN Effects of high vs low energy dose with standardized active and passive mobilization during the acute phase of critical illness 1.93 on (mortality and) recovery (physical function, ICU length of stay) of severely ill patients (treated with mechanical ventila‑ tion and vasoactive drug during the acute phase) Effects of stepwise increases in caloric provision during the first week on the complication rate and physical function 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 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 Effects of permissive underfeeding (calories) with high‑ dose protein supplementation in critically ill diabetic patients on (mortality and) physical function Nutrition and physical activity guided by muscle mass assessment on (mortality and) long‑term physical function 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) Use of resolvins and/or protectins in critically ill patients. The main outcomes are mortality and physical function The effect of GLP‑1 and its agonists in hyperglycemic critically ill patients on mortality on mortality, organ function, and functional status The effect of insulin glargine in hyperglycemic critically ill patients on mortality, organ function, and functional status suggested candidate topics, then rated each one using a grading system (0–4). Potential studies were ranked on the basis of average score. The following received the highest priory scores. To study the effects of high compared to low protein dose combined with standardized active and passive mobilization during the acute phase of critical illness on mortality and recovery of severely ill patients. To study the effects of high compared to low protein dose combined with standardized active and passive mobilization during the post-acute phase of critical illness on mortality and recovery of severely ill patients. To determine which patient groups benefit from specific nutritional interventions and which do not or experience harm. Such determination requires development and/or validation of clinical and laboratory nutritional assessment tools, with validation being best done in RCTs. To examine the effects of permissive underfeeding (caloric restriction) with and without high-dose protein supplementation in critically ill obese on mortality and physical function. To study the effects of continuous versus intermittent EN on mechanistic markers in a phase II trial to inform a phase III RCT with mortality and physical function being the main outcomes. To study the effects of high compared to low energy dose with standardized active and passive mobilization post-acute phase of critical illness on mortality and recovery of severely ill patients. To determine which bedside assessment of muscle mass can accurately identify low muscle mass, be used to monitor nutrition success, and predict functional recovery. To perform 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. To evaluate the effects of prokinetic use on the recovery of critically ill patients with persistent intolerance to EN. To study the effects of high vs low energy dose with standardized active and passive mobilization during the acute phase of critical illness on mortality and recovery of severely ill patients. In conclusion, recent trials have answered important questions but also highlighted or revealed several uncertainties in many aspects of critical care nutrition and metabolism. We ranked the top 10 studies for the next 10  years, with the prospect that different nutritional interventions targeted to the appropriate patient population will be examined for their effect on facilitating recovery and improving survival in adequately powered and properly designed studies, probably in conjunction with mobilization. Undoubtedly, the next 10 years are likely to be an exciting era for nutrition and metabolism. Electronic supplementary material The online version of this article (doi:10.1007/s00134‑017‑4711‑6) contains supplementary material, which is available to authorized users. Author details 1 Intensive Care Department, MC 1425, College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU‑HS), King Abdullah Inter ‑ national Medical Research Center (KAIMRC), P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. 2 Laboratory and Clinical Department of Intensive Care Medicine, Catholic University Leuven, Leuven, Belgium. 3 Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia. 4 Department of Criti‑ cal Care Medicine, Queen’s University, Kingston, ON, Canada. 5 Anesthesiol‑ ogy and Intensive Care Medicine, Intensive Care Unit, Pasteur 2 Hospital, University Hospital of Nice, Nice, France. 6 Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA. 7 Division of General and Gastrointestinal Surgery, Hospital Nutrition Services, Oregon Health and Science University, Portland, OR, USA. 8 Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA. 9 Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. 10 Université de Nantes, Nantes, France. 11 CHU de Nantes, Service de Médecine Intensive Réanimation, Nantes, France. 12 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. 13 Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan, Ede, The Netherlands. 14 Nutrition and Dietetics, Department of Internal Medicine, and Department of Intensive Care Medicine, VU University Medical Center, Amsterdam, The Netherlands. 15 Department of Nutrition and Dietetics, School of Sports and Nutrition, Amsterdam University of Applied Sciences, Amsterdam, The Netherlands. 1. 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Yaseen M. Arabi, Michael P. Casaer, Marianne Chapman, Daren K. Heyland, Carole Ichai, Paul E. Marik, Robert G. Martindale, Stephen A. McClave, Jean-Charles Preiser, Jean Reignier, Todd W. Rice, Greet Van den Berghe, Arthur R. H. van Zanten, Peter J. M. Weijs. The intensive care medicine research agenda in nutrition and metabolism, Intensive Care Medicine, 2017, 1239-1256, DOI: 10.1007/s00134-017-4711-6