The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial.

BACKGROUND: On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes. METHODS: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547. FINDINGS: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline. INTERPRETATION: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores. FUNDING: None.

A Comparison of High and Usual Protein Dosing in Critically Ill Patients With Obesity: A Post Hoc Analysis of an International, Pragmatic, Single-Blinded, Randomized Clinical Trial.

OBJECTIVES: Across guidelines, protein dosing for critically ill patients with obesity varies considerably. The objective of this analysis was to evaluate whether this population would benefit from higher doses of protein. DESIGN: A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial. SETTING: Eighty-five adult ICUs across 16 countries. PATIENTS: Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m 2 ( n = 425). INTERVENTIONS: In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d). MEASUREMENTS AND MAIN RESULTS: Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m 2 . After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58-1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, -5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups. CONCLUSIONS: In critically ill patients with obesity, higher protein doses did not improve clinical outcomes, including those with higher nutritional and frailty risk.

Dietary protein in the ICU in relation to health outcomes.

PURPOSE OF REVIEW: Critical care nutrition guidelines recommend provision of higher protein doses than recommended in health. These recommendations have been predominately based on lower quality evidence and physiological rationale that greater protein doses may attenuate the significant muscle loss observed in critically ill patients. This review discusses the mechanistic action of protein in the critically ill, details results from recent trials on health outcomes, discusses considerations for interpretation of trial results, and provides an overview of future directions. RECENT FINDINGS: Two recent large clinical trials have investigated different protein doses and the effect on clinical outcome. Important findings revealed potential harm in certain sub-groups of patients. This harm must be balanced with the potential for beneficial effects on muscle mass and physical function given that two recent systematic reviews with meta-analyses demonstrated attenuation of muscle loss with higher protein doses. Utilizing biological markers such as urea: creatinine ratio or urea levels may prove useful in monitoring harm from higher protein doses. SUMMARY: Future research should focus on prospectively investigating biological signatures of harm as well as taking into the consideration elements that will likely enhance the effectiveness of protein dose.

Association between urea trajectory and protein dose in critically ill adults: a secondary exploratory analysis of the effort protein trial (RE-EFFORT).

BACKGROUND: Delivering higher doses of protein to mechanically ventilated critically ill patients did not improve patient outcomes and may have caused harm. Longitudinal urea measurements could provide additional information about the treatment effect of higher protein doses. We hypothesised that higher urea values over time could explain the potential harmful treatment effects of higher doses of protein. METHODS: We conducted a reanalysis of a randomised controlled trial of higher protein doses in critical illness (EFFORT Protein). We applied Bayesian joint models to estimate the strength of association of urea with 30-day survival and understand the treatment effect of higher protein doses. RESULTS: Of the 1301 patients included in EFFORT Protein, 1277 were included in this analysis. There were 344 deaths at 30 days post-randomisation. By day 6, median urea was 2.1 mmol/L higher in the high protein group (95% CI 1.1-3.2), increasing to 3.0 mmol/L (95% CI 1.3-4.7) by day 12. A twofold rise in urea was associated with an increased risk of death at 30 days (hazard ratio 1.34, 95% credible interval 1.21-1.48), following adjustment of baseline characteristics including age, illness severity, renal replacement therapy, and presence of AKI. This association persisted over the duration of 30-day follow-up and in models adjusting for evolution of organ failure over time. CONCLUSIONS: The increased risk of death in patients randomised to a higher protein dose in the EFFORT Protein trial was estimated to be mediated by increased urea cycle activity, of which serum urea is a biological signature. Serum urea should be taken into consideration when initiating and continuing protein delivery in critically ill patients. CLINICALTRIALS: gov Identifier: NCT03160547 (2017-05-17).

The effect of high protein dosing in critically ill patients: an exploratory, secondary Bayesian analyses of the EFFORT Protein trial.

BACKGROUND: The EFFORT Protein trial assessed the effect of high vs usual dosing of protein in adult ICU patients with organ failure. This study provides a probabilistic interpretation and evaluates heterogeneity in treatment effects (HTE). METHODS: We analysed 60-day all-cause mortality and time to discharge alive from hospital using Bayesian models with weakly informative priors. HTE on mortality was assessed according to disease severity (Sequential Organ Failure Assessment [SOFA] score), acute kidney injury, and serum creatinine values at baseline. RESULTS: The absolute difference in mortality was 2.5% points (95% credible interval -6.9 to 12.4), with a 72% posterior probability of harm associated with high protein treatment. For time to discharge alive from hospital, the hazard ratio was 0.91 (95% credible interval 0.80 to 1.04) with a 92% probability of harm for the high-dose protein group compared with the usual-dose protein group. There were 97% and 95% probabilities of positive interactions between the high protein intervention and serum creatinine and SOFA score at randomisation, respectively. Specifically, there was a potentially relatively higher mortality of high protein doses with higher baseline serum creatinine or SOFA scores. CONCLUSIONS: We found moderate to high probabilities of harm with high protein doses compared with usual protein in ICU patients for the primary and secondary outcomes. We found suggestions of heterogeneity in treatment effects with worse outcomes in participants randomised to high protein doses with renal dysfunction or acute kidney injury and greater illness severity at baseline.

How to avoid harm with feeding critically ill patients: a synthesis of viewpoints of a basic scientist, dietitian and intensivist.

The optimal feeding strategy in critically ill patients is a matter of debate, with current guidelines recommending different strategies regarding energy and protein targets. Several recent trials have added to the debate and question our previous understanding of the provision of nutrition during critical illness. This narrative review aims to provide a summary of interpretation of recent evidence from the view of basic scientist, critical care dietitian and intensivist, resulting in joined suggestions for both clinical practice and future research. In the most recent randomised controlled trial (RCT), patients receiving 6 versus 25 kcal/kg/day by any route achieved readiness for ICU discharge earlier and had fewer GI complications. A second showed that high protein dosage may be harmful in patients with baseline acute kidney injury and more severe illness. Lastly, a prospective observational study using propensity score matched analysis suggested that early full feeding, especially enteral, compared to delayed feeding is associated with a higher 28-day mortality. Viewpoints from all three professionals point to the agreement that early full feeding is likely harmful, whereas important questions regarding the mechanisms of harm as well as on timing and optimal dose of nutrition for individual patients remain unanswered and warrant future studies. For now, we suggest giving low dose of energy and protein during the first few days in the ICU and apply individualised approach based on assumed metabolic state according to the trajectory of illness thereafter. At the same time, we encourage research to develop better tools to monitor metabolism and the nutritional needs for the individual patient accurately and continuously.

Personalized nutrition therapy in critical care: 10 expert recommendations.

Personalization of ICU nutrition is essential to future of critical care. Recommendations from American/European guidelines and practice suggestions incorporating recent literature are presented. Low-dose enteral nutrition (EN) or parenteral nutrition (PN) can be started within 48 h of admission. While EN is preferred route of delivery, new data highlight PN can be given safely without increased risk; thus, when early EN is not feasible, provision of isocaloric PN is effective and results in similar outcomes. Indirect calorimetry (IC) measurement of energy expenditure (EE) is recommended by both European/American guidelines after stabilization post-ICU admission. Below-measured EE (~ 70%) targets should be used during early phase and increased to match EE later in stay. Low-dose protein delivery can be used early (~ D1-2) (< 0.8 g/kg/d) and progressed to ≥ 1.2 g/kg/d as patients stabilize, with consideration of avoiding higher protein in unstable patients and in acute kidney injury not on CRRT. Intermittent-feeding schedules hold promise for further research. Clinicians must be aware of delivered energy/protein and what percentage of targets delivered nutrition represents. Computerized nutrition monitoring systems/platforms have become widely available. In patients at risk of micronutrient/vitamin losses (i.e., CRRT), evaluation of micronutrient levels should be considered post-ICU days 5-7 with repletion of deficiencies where indicated. In future, we hope use of muscle monitors such as ultrasound, CT scan, and/or BIA will be utilized to assess nutrition risk and monitor response to nutrition. Use of specialized anabolic nutrients such as HMB, creatine, and leucine to improve strength/muscle mass is promising in other populations and deserves future study. In post-ICU setting, continued use of IC measurement and other muscle measures should be considered to guide nutrition. Research on using rehabilitation interventions such as cardiopulmonary exercise testing (CPET) to guide post-ICU exercise/rehabilitation prescription and using anabolic agents such as testosterone/oxandrolone to promote post-ICU recovery is needed.

HMB and leucine supplementation during critical illness and recovery.

PURPOSE OF REVIEW: Skeletal muscle wasting is a serious consequence of critical illness, which may impact on long term physical and functional disability. To date, no intervention has been proven to reduce skeletal muscle wasting. Leucine and it's metabolite ß-hydroxy-ß-methylbutyrate (HMB) have been proposed as interventions. This review details the mechanism of action of both leucine and HMB, discusses the most recent research for both leucine and HMB and lastly discusses considerations for future research. RECENT FINDINGS: Only one study of leucine in critical illness has recently been published. This was a feasibility study where the physiological and muscle related outcomes were not reported to be feasible. Three studies on HMB have been reported recently with no effect seen on either muscle mass or strength. The main limitation in our understanding of the potential use of leucine or HMB on skeletal muscle wasting is the lack of mechanistic studies available in this population. SUMMARY: Mechanistic studies should be a priority before embarking on further randomized controlled trials related to this topic.

Nutrition in postacute rehabilitation of COVID-19 survivors.

PURPOSE OF REVIEW: Patients hospitalised with COVID-19 are at high nutrition risk and a significant number are likely to require ongoing nutrition rehabilitation. Here, we summarise guideline recommendations for nutritional rehabilitation in postacute COVID-19 infection, outline the rationale for nutrition rehabilitation for survivors of postacute COVID-19 in patients admitted to both the hospital ward and intensive care unit and discuss current evidence for interventions. RECENT FINDINGS: Several guidelines exist outlining recommendations for nutrition care in hospital, critical care and the community setting. All have common themes pertaining to the importance of nutrition screening, nutrition assessment, appropriate choice of intervention and continuity of care across settings. While a plethora of data exists highlighting the high nutrition risk and prevalence of malnutrition in this population, minimal interventional studies have been published. SUMMARY: Patients hospitalised with COVID-19 are at high nutrition risk. Future studies should focus on nutrition interventions for the rehabilitation period and determine whether nutrition needs differ between COVID-19 and non-COVID-19 survivors.

Relationship Between Skeletal Muscle Area and Density and Clinical Outcome in Adults Receiving Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate the prevalence of low skeletal muscle index (area normalized for height) and density, their trajectory of change, and to determine associations with clinical outcome in adults with severe respiratory failure requiring venovenous extracorporeal membrane oxygenation. DESIGN: Prospective observational study. PATIENTS: Adults receiving venovenous extracorporeal membrane oxygenation for a minimum of 72 hours and a maximum of 6 months between September 2010 and June 2017, who had a CT scan which included the third lumbar vertebra. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Skeletal muscle index and density was determined using Slice-O-Matic V5.0 (TomoVision, Montreal, QC, Canada). Low skeletal muscle index and density were defined using published criteria. Regression models were used to assess for associations between muscle index and density and clinical outcome. Two-hundred fifteen patients, median (interquartile range) age 46 years (35.0-57.0 yr) were included. Forty-five patients (21.1%) had low skeletal muscle index, and 48 (22.3%) had low skeletal muscle density on commencement of venovenous extracorporeal membrane oxygenation. Low skeletal muscle index was more prevalent in males (28.8% vs 11.6%; χ2 = 9.4; p = 0.002) and was associated with a longer duration of venovenous extracorporeal membrane oxygenation (B = 5.0; 95% CI, 0.2-9.9; p = 0.042). Higher skeletal muscle density was independently associated with ICU survival (odds ratio 1.6 per 10 Hounsfield units; 95% CI, 1.1-2.5; p = 0.025). No relationship was observed between skeletal muscle index nor density and physical function. Adequacy of energy and protein did not influence change in skeletal muscle index or density. CONCLUSIONS: Low skeletal muscle index at the commencement of venovenous extracorporeal membrane oxygenation was associated with a longer duration of venovenous extracorporeal membrane oxygenation, whereas preserved skeletal muscle density was associated with improved survival.

ß-hydroxy-ß-methylbutyrate supplementation in older persons - an update.

PURPOSE OF REVIEW: The interest in the use of beta-hydroxy-beta-methylbutyrate (HMB) as an intervention to prevent and treat sarcopenia has increased over recent years. The purpose of this review is to explore recent evidence pertaining to the mechanism of action of HMB and how this may influence changes in lean mass and strength in older persons who are both hospitalized and living in the community. RECENT FINDINGS: No new studies have been published over the last 2 years investigating the effect of HMB in older persons who are hospitalized, aside from one posthoc analysis of a randomized controlled trial exploring the effect of a high protein oral nutrition supplement containing HMB on handgrip strength and nutritional status. Three studies recruiting community-dwelling older adults have been published, but results are influenced by suboptimal methodological quality. SUMMARY: Recent data suggest the need for high-quality studies investigating the effectiveness of HMB to improve outcomes related to sarcopenia in both hospitalized and community-dwelling older persons.

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine.

BACKGROUND: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. METHODS: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. RESULTS: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. CONCLUSIONS: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Meeting nutritional targets of critically ill patients by combined enteral and parenteral nutrition: review and rationale for the EFFORTcombo trial.

While medical nutrition therapy is an essential part of the care for critically ill patients, uncertainty exists about the right form, dosage, timing and route in relation to the phases of critical illness. As enteral nutrition (EN) is often withheld or interrupted during the intensive care unit (ICU) stay, combined EN and parenteral nutrition (PN) may represent an effective and safe option to achieve energy and protein goals as recommended by international guidelines. We hypothesise that critically ill patients at high nutritional risk may benefit from such a combined approach during their stay on the ICU. Therefore, we aim to test if an early combination of EN and high-protein PN (EN+PN) is effective in reaching energy and protein goals in patients at high nutritional risk, while avoiding overfeeding. This approach will be tested in the here-presented EFFORTcombo trial. Nutritionally high-risk ICU patients will be randomised to either high (≥2·2 g/kg per d) or low protein (≤1·2 g/kg per d). In the high protein group, the patients will receive EN+PN; in the low protein group, patients will be given EN alone. EN will be started in accordance with international guidelines in both groups. Efforts will be made to reach nutrition goals within 48-96 h. The efficacy of the proposed nutritional strategy will be tested as an innovative approach by functional outcomes at ICU and hospital discharge, as well as at a 6-month follow-up.

Designing nutrition-based interventional trials for the future: addressing the known knowns.

The consistent decline in critical illness mortality has a significant effect on trial design, whereby either an improbable effect sizes or large number of patients are required.The signal-to-noise ratio is of particular interest for the critically ill. When considering the potential signal, interventions need to match outcomes in regard to biological plausibility. Provision of nutrition is a complex decision with many underappreciated aspects of noise. However, a fundamental interaction is often not accounted for time.Working as a community to evolve trial design will be our challenge for nutrition interventions in the critically ill for the future.

Nutrition and Exercise Rehabilitation in Obesity hypoventilation syndrome (NERO): a pilot randomised controlled trial.

BACKGROUND: Respiratory management of obesity hypoventilation syndrome (OHS) focusses on the control of sleep-disordered breathing rather than the treatment of obesity. Currently, there are no data from randomised trials of weight loss targeted rehabilitation programmes for patients with OHS. INTERVENTION: A 3-month multimodal hybrid inpatient-outpatient motivation, exercise and nutrition rehabilitation programme, in addition to non invasive ventilation (NIV), would result in greater per cent weight loss compared with standard care. METHODS: A single-centre pilot randomised controlled trial allocated patients to either standard care or standard care plus rehabilitation. Primary outcome was per cent weight loss at 12 months with secondary exploratory outcomes of weight loss, exercise capacity and health-related quality of life (HRQOL) at the end of the rehabilitation programme to assess the intervention effect. RESULTS: Thirty-seven patients (11 male, 59.8±12.7 years) with a body mass index of 51.1±7.7 kg/m2 were randomised. At 12 months, there was no between-group difference in per cent weight loss (mean difference -5.9% (95% CI -14.4% to 2.7%; p=0.17)). At 3 months, there was a greater per cent weight loss (mean difference -5% (95% CI -8.3% to -1.4%; p=0.007)), increased exercise capacity (6 min walk test 60 m (95% CI 29.5 to 214.5) vs 20 m (95% CI 11.5 to 81.3); p=0.036) and HRQL (mean difference SF-36 general health score (10 (95% CI 5 to 21.3) vs 0 (95% CI -5 to 10); p=0.02)) in the rehabilitation group. CONCLUSION: In patients with OHS, a 3-month comprehensive rehabilitation programme, in addition to NIV, resulted in improved weight loss, exercise capacity and QOL at the end of the rehabilitation period, but these effects were not demonstrated at 12 months, in part, due to the limited retention of patients at 12 months. TRIAL REGISTRATION NUMBER: Pre-results; NCT01483716.

Metabolic phenotype of skeletal muscle in early critical illness.

OBJECTIVES: To characterise the sketetal muscle metabolic phenotype during early critical illness. METHODS: Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). MEASUREMENTS AND MAIN RESULTS: From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (-27.4CN (95% CI -123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (-1859CN (IQR -5557-1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (-4.8 mmol/kg dw (IQR -8.0-1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR -0.09-2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5-1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR -0.44-3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4-39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR -7-100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered. CONCLUSIONS: Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. TRIAL REGISTRATION NUMBER: NCT01106300.

Emerging outcome measures for nutrition trials in the critically ill.

PURPOSE OF REVIEW: Mortality has long been the gold-standard outcome measure for intensive care clinical trials. However, as the critical care community begins to understand and accept that survivorship is associated with functional disability and a health and socioeconomic burden, the clinical and research focus has begun to shift towards long-term physical function RECENT FINDINGS: To use mortality as a primary outcome measure, one would either have to choose an improbable effect (e.g. a difference of 5-10% in mortality as a result of a single intervention) or recruit a larger number of patients, the latter being unfeasible for most critical care trials.Outcome measures will need to match interventions. As an example, amino acids, or intermittent feeding, can stimulate muscle protein synthesis, and so prevention of muscle wasting may seem an appropriate outcome measure when assessing the effectiveness of these interventions. Testing the effectiveness of these interventions requires the development of novel outcome measures that are targeted and acceptable to patients. We describe advancements in dual-energy X-ray absorptiometry scanning, bio-impedence analysis, MRI and muscle ultrasound in this patient group that are beginning to address this development need. SUMMARY: New approaches to outcome assessment are beginning to appear in post-ICU research, which promise to improve our understanding of nutrition and exercise interventions on skeletal muscle structure, composition and function, without causing undue suffering to the patient.

Can the critically ill patient generate sufficient energy to facilitate exercise in the ICU?

PURPOSE OF REVIEW: Trials of physical rehabilitation post critical illness have yet to deliver improved health-related quality of life in critical illness survivors. Muscle mass and strength are lost rapidly in critical illness and a proportion of patients continue to do so resulting in increased mortality and functional disability. Addressing this issue is therefore fundamental for recovery from critical illness. RECENT FINDINGS: Altered mitochondrial function occurs in the critically ill and is likely to result in decreased adenosine tri-phosphate (ATP) production. Muscle contraction is a process that requires ATP. The metabolic demands of exercise are poorly understood in the ICU setting. Recent research has highlighted that there is significant heterogeneity in energy requirements between critically ill individuals undertaking the same functional activities, such as sit-to-stand. Nutrition in the critically ill is currently thought of in terms of carbohydrates, fat and protein. It may be that we need to consider nutrition in a more contextual manner such as energy generation or management of protein homeostasis. SUMMARY: Current nutritional support practices in critically ill patients do not lead to improvements in physical and functional outcomes, and it may be that alternative methods of delivery or substrates are needed.

Continuous or intermittent feeding: pros and cons.

PURPOSE OF REVIEW: There has been a recent shift in the focus of providing nutrition support to critically ill adults towards enhancing recovery and promoting survivorship. With this has come an evaluation of our current approaches to nutrition support, which includes whether continuous feeding is optimal, particularly for reducing muscle wasting, but also for managing blood glucose levels and feeding intolerance and at the organizational level. This review will discuss the pros and cons of using intermittent and continuous feeding relating to several aspects of the management of critically ill adults. RECENT FINDINGS: Few studies have investigated the effect of intermittent feeding over continuous feeding. Overall, intermittent feeding has not been shown to increase glucose variability or gastrointestinal intolerance, two of the reasons continuous feeding is the preferred method. A current study investigating the effect of intermittent vs. continuous feeding is awaited to provide insight into the effect of muscle wasting. SUMMARY: Although there are limited studies investigating the safety and efficacy of an intermittent rather than continuous feeding regimen in critically ill adults, there are several theoretical advantages. Further studies should investigate these and in the meantime, feeding regimens should be devised based on individual patient factors.

suPAR as a marker of infection in acute kidney injury - a prospective observational study.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) has emerged as a new sepsis biomarker. It is not known whether suPAR has a role in critically ill patients with severe acute kidney injury (AKI). METHODS: Our main aims were to describe serial serum suPAR concentrations in patients with severe AKI, to investigate a potential association between suPAR and C-reactive protein (CRP), and to compare suPAR and CRP as diagnostic markers of infection in patients with AKI. Between April 2013 - April 2014, we recruited adult patients (≥18 years) with AKI KDIGO stage 2/3 admitted to a multidisciplinary Intensive Care Unit (ICU) in a University Hospital in UK. Serial serum suPAR and CRP concentrations were measured for 6 days. We compared the characteristics and serial suPAR and CRP concentrations of patients with and without an infection using Chi-squared, Fisher's exact, t-test and Mann-Whitney tests as appropriate, and calculated the area under the receiver operating characteristics curve (AUC). RESULTS: Data of 55 patients with AKI stage 2/3 were analysed (62% male; mean age 60.5) of whom 43 patients received continuous renal replacement therapy. suPAR was not detectable in effluent fluid. There was no significant correlation between daily suPAR and CRP concentrations. In patients with an infection, suPAR results were significantly higher than in those without an infection across all time points; there was no significant difference in CRP levels between both groups. After exclusion of patients with an infection before or on day of admission to ICU, the AUC of suPAR for predicting an infection later was 0.62 (95% CI 0.43-0.80) compared to 0.50 (95% CI 0.29-0.71) for CRP. CONCLUSIONS: In critically ill patients with AKI stage 2/3, suPAR is a better marker of infection than CRP. TRIAL REGISTRATION: The study was retrospectively registered on the ISRCTN registry on 25 November 2012 ( ISRCTN88354940 ).