Comparison of energy intake in critical illness survivors, general medical patients, and healthy volunteers: A descriptive cohort study.

BACKGROUND: Intensive care unit (ICU) survivors have reduced oral intake; it is unknown whether intake and associated barriers are unique to this group. OBJECTIVE: To quantify energy intake and potential barriers in ICU survivors compared with general medical (GM) patients and healthy volunteers. DESIGN: A descriptive cohort study in ICU survivors, GM patients, and healthy volunteers. Following an overnight fast, participants consumed a 200 ml test-meal (213 kcal) and 180 min later an ad libitum meal to measure energy intake (primary outcome). Secondary outcomes; taste recognition, nutrition-impacting symptoms, malnutrition, and quality of life (QoL). Data are mean ± SD, median (interquartile range [IQR]) or number [percentage]). RESULTS: Twelve ICU survivors (57 ± 17 years, BMI: 30 ± 6), eight GM patients (69 ± 19 years, BMI: 30 ± 6), and 25 healthy volunteers (58 ± 27 years, BMI: 25 ± 4) were included. Recruitment ceased early because of slow recruitment and SARS-CoV-2. Energy intake was lower in both patient groups than in health (ICU: 289 [288, 809], GM: 426 [336, 592], health: 815 [654, 1165] kcal). Loss of appetite was most common (ICU: 78%, GM: 67%). For ICU survivors, GM patients and healthy volunteers, respectively, severe malnutrition prevalence; 40%, 14%, and 0%; taste identification; 8.5 [7.0, 11.0], 8.5 [7.0, 9.5], and 8.0 [6.0, 11.0]; and QoL; 60 [40-65], 50 [31-55], and 90 [81-95] out of 100. CONCLUSIONS: Energy intake at a buffet meal is lower in hospital patients than in healthy volunteers but similar between ICU survivors and GM patients. Appetite loss potentially contributes to reduced energy intake.

Observed differences in nutrition management at two time points spanning a decade in critically ill trauma patients with and without head injury.

BACKGROUND: Nutritional needs of trauma patients admitted to the intensive care unit may differ from general critically ill patients, but most current evidence is based on large clinical trials recruiting mixed populations. OBJECTIVE: The aim of the study was to investigate nutrition practices at two time points that span a decade in trauma patients with and without head injury. METHODS: This observational study recruited adult trauma patients receiving mechanical ventilation and artificial nutrition from a single-centre intensive care unit between February 2005 to December 2006 (cohort 1), and December 2018 to September 2020 (cohort 2). Patients were categorised into head injury and non-head injury subgroups. Data regarding energy and protein prescription and delivery were collected. Data are presented as median [interquartile range]. Wilcoxon rank-sum test assessed the differences between cohorts and subgroups, with a P value ≤ 0.05. The protocol was registered with the Australian and New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001816246). RESULTS: Cohort 1 included 109 patients, and 112 patients were included in cohort 2 (age: 46 ± 19 vs 50 ± 19 y; 80 vs 79% M). Overall, nutrition practice did not differ between head-injured and non-head-injured subgroups (all P > 0.05). Energy prescription and delivery decreased from time point one to time point two, regardless of subgroup (Prescription: 9824 [8820-10 581] vs 8318 [7694-9071] kJ; Delivery: 6138 [5130-7188] vs 4715 [3059-5996] kJ; all P < 0.05). Protein prescription did not change from time point one to time point two. Although protein delivery remained constant from time point one to time point two in the head injury group, protein delivery reduced in the non-head injury subgroup (70 [56-82] vs 45 [26-64] g/d, P < 0.05). CONCLUSION: In this single-centre study, energy prescription and delivery in critically ill trauma patients reduced from time point one to time point two. Protein prescription did not change, but protein delivery reduced from time point one to time point two in non-head injury patients. Reasons for these differing trajectories require exploration. STUDY REGISTRATION: Trial registered at www.anzctr.org.au. TRIAL ID: ACTRN12618001816246.

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol.

INTRODUCTION: The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE. METHODS AND ANALYSIS: REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial. ETHICS AND DISSEMINATION: All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to - Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION NUMBER: NCT03374800.

Study protocol for TARGET protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomised, cross-sectional, double cross-over, clinical trial.

Background: It is unknown whether increasing dietary protein to 1.2-2.0 g/kg/day as recommended in international guidelines compared to current practice improves outcomes in intensive care unit (ICU) patients. The TARGET Protein trial will evaluate this. Objective: To describe the study protocol for the TARGET Protein trial. Design setting and participants: TARGET Protein is a cluster randomised, cross-sectional, double cross-over, pragmatic clinical trial undertaken in eight ICUs in Australia and New Zealand. Each ICU will be randomised to use one of two trial enteral formulae for three months before crossing over to the other formula, which is then repeated, with enrolment continuing at each ICU for 12 months. All patients aged ≥16 years in their index ICU admission commencing enteral nutrition will be eligible for inclusion. Eligible patients will receive the trial enteral formula to which their ICU is allocated. The two trial enteral formulae are isocaloric with a difference in protein dose: intervention 100g/1000 ml and comparator 63g/1000 ml. Staggered recruitment commenced in May 2022. Main outcomes measures: The primary outcome is days free of the index hospital and alive at day 90. Secondary outcomes include days free of the index hospital at day 90 in survivors, alive at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. Conclusion: TARGET Protein aims to determine whether augmented enteral protein delivery reduces days free of the index hospital and alive at day 90. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831).

Muscle size, strength, and physical function in response to augmented calorie delivery: A TARGET sub-study.

PURPOSE: Augmented calories may attenuate muscle loss experienced in critical illness. This exploratory sub-study assessed the effect of augmented calorie delivery on muscle mass, strength, and function. MATERIALS AND METHODS: Patients in The Augmented versus Routine approach to Giving Energy Trial (TARGET) randomised to 1.5 kcal/ml or 1.0 kcal/ml enteral formulae at a single-centre were included. Ultrasound-derived muscle layer thickness (MLT) at quadriceps, forearm and mid-upper arm, and handgrip strength, were measured weekly from baseline to hospital discharge, and 3- and 6-months. Physical function was assessed at 3- and 6-months using the 'get up and go' and 6-min walk tests. Data are mean ± SD. RESULTS: Eighty patients were recruited (1.5 kcal: n = 38, 58 ± 14y, 60%M, APACHE II 20 ± 7; 1.0 kcal: n = 42, 54 ± 18y, 66%M, APACHE II 22 ± 10). The 1.5 kcal/ml group received more calories with no difference in quadriceps MLT at any timepoint including ICU discharge (primary outcome) (2.90 ± 1.27 vs 2.39 ± 1.06 cm; P = 0.141). Relationships were similar for all MLT measures, handgrip strength, and 6-min walk test. Patients in the 1.5 kcal/ml group had improved 'get up and go' test at 3-months (6.66 ± 1.33 vs. 9.11 ± 2.94 s; P = 0.014). CONCLUSION: Augmented calorie delivery may not attenuate muscle loss or recovery of strength or function 6-months post-ICU, but this requires exploration in a larger trial.

Higher versus lower enteral calorie delivery and gastrointestinal dysfunction in critical illness: A systematic review and meta-analysis.

BACKGROUND AND AIMS: In critical illness, enteral nutrition (EN) is frequently limited by gastrointestinal (GI) dysfunction. The aim of this systematic review and meta-analysis was to determine relationships between enteral calorie delivery and GI dysfunction in critically ill adults. METHODS: MEDLINE, EMCARE, EMBASE, and CINAHL databases were searched from 1 January 2000 to 11 August 2021 to identify parallel group randomised controlled trials of an EN intervention that resulted in a significant difference in calorie delivery between groups and reported at least one outcome relating to GI dysfunction. Study groups were categorised as 'higher' or 'lower' calorie delivery and data were extracted on study interventions, GI dysfunction and clinical outcomes. Extracted data were aggregated using a random effects model and presented as risk ratio with 95% confidence intervals. A P-value <0.05 was considered significant. The risk of publication bias was assessed graphically using a funnel plot. RESULTS: From 13 studies involving 6824 patients the mean calorie delivery in the higher calorie group was 1673 ± 468 kcal/day compared to 1121 ± 312 kcal/day in the lower calorie group. The higher calorie group had an increased risk of a large (any volume ≥300 ml) gastric residual volume (GRV) (RR 1.40; 95% CI 1.09, 1.80; P = 0.009) and prokinetic administration (RR 1.18; 95% CI 1.11, 1.27; P < 0.00001). There were no between group differences in the presence of vomiting/regurgitation (RR 0.93; 95% CI 0.58, 1.49; P = 0.76), diarrhoea (RR 1.12; 95% CI 0.93, 1.35; P = 0.22) or abdominal distension (RR 0.71; 95% CI 0.49, 1.04; P = 0.08). There was no evidence of publication bias. CONCLUSION: Higher calorie delivery is associated with increased rates of GRV≥300 ml and prokinetic administration, but not vomiting/regurgitation, diarrhoea or abdominal distension. OTHER: No funding was received for the conduct of this systematic review and meta-analysis. The protocol was prospectively registered with PROSPERO (CRD42021268876).

Methodological Rigor and Transparency in Clinical Practice Guidelines for Nutrition Care in Critically Ill Adults: A Systematic Review Using the AGREE II and AGREE-REX Tools.

Background: To evaluate the methodological quality of (1) clinical practice guidelines (CPGs) that inform nutrition care in critically ill adults using the AGREE II tool and (2) CPG recommendations for determining energy expenditure using the AGREE-REX tool. Methods: CPGs by a professional society or academic group, intended to guide nutrition care in critically ill adults, that used a systematic literature search and rated the evidence were included. Four databases and grey literature were searched from January 2011 to 19 January 2022. Five investigators assessed the methodological quality of CPGs and recommendations specific to energy expenditure determination. Scaled domain scores were calculated for AGREE II and a scaled total score for AGREE-REX. Data are presented as medians (interquartile range). Results: Eleven CPGs were included. Highest scoring domains for AGREE II were clarity of presentation (82% [76-87%]) and scope and purpose (78% [66-83%]). Lowest scoring domains were applicability (37% [32-42%]) and stakeholder involvement (46% [33-51%]). Eight (73%) CPGs provided recommendations relating to energy expenditure determination; scores were low overall (37% [36-40%]) and across individual domains. Conclusions: Nutrition CPGs for critically ill patients are developed using systematic methods but lack engagement with key stakeholders and guidance to support application. The quality of energy expenditure determination recommendations is low.

Muscle Protein Synthesis after Protein Administration in Critical Illness.

Rationale: Dietary protein may attenuate the muscle atrophy experienced by patients in the ICU, yet protein handling is poorly understood. Objectives: To quantify protein digestion and amino acid absorption and fasting and postprandial myofibrillar protein synthesis during critical illness. Methods: Fifteen mechanically ventilated adults (12 male; aged 50 ± 17 yr; body mass index, 27 ± 5 kg⋅m-2) and 10 healthy control subjects (6 male; 54 ± 23 yr; body mass index, 27 ± 4 kg⋅m-2) received a primed intravenous L-[ring-2H5]-phenylalanine, L-[3,5-2H2]-tyrosine, and L-[1-13C]-leucine infusion over 9.5 hours and a duodenal bolus of intrinsically labeled (L-[1-13C]-phenylalanine and L-[1-13C]-leucine) intact milk protein (20 g protein) over 60 minutes. Arterial blood and muscle samples were taken at baseline (fasting) and for 6 hours following duodenal protein administration. Data are mean ± SD, analyzed with two-way repeated measures ANOVA and independent samples t test. Measurements and Main Results: Fasting myofibrillar protein synthesis rates did not differ between ICU patients and healthy control subjects (0.023 ± 0.013% h-1 vs. 0.034 ± 0.016% h-1; P = 0.077). After protein administration, plasma amino acid availability did not differ between groups (ICU patients, 54.2 ± 9.1%, vs. healthy control subjects, 61.8 ± 13.1%; P = 0.12), and myofibrillar protein synthesis rates increased in both groups (0.028 ± 0.010% h-1 vs. 0.043 ± 0.018% h-1; main time effect P = 0.046; P-interaction = 0.584) with lower rates in ICU patients than in healthy control subjects (main group effect P = 0.001). Incorporation of protein-derived phenylalanine into myofibrillar protein was ∼60% lower in ICU patients (0.007 ± 0.007 mol percent excess vs. 0.017 ± 0.009 mol percent excess; P = 0.007). Conclusions: The capacity for critically ill patients to use ingested protein for muscle protein synthesis is markedly blunted despite relatively normal protein digestion and amino acid absorption.

Gastrointestinal dysfunction during enteral nutrition delivery in intensive care unit (ICU) patients: Risk factors, natural history, and clinical implications. A post-hoc analysis of The Augmented versus Routine approach to Giving Energy Trial (TARGET).

BACKGROUND: Slow gastric emptying occurs frequently during critical illness and is roughly quantified at bedside by large gastric residual volumes (GRVs). A previously published trial (The Augmented versus Routine approach to Giving Energy Trial; TARGET) reported larger GRVs with energy-dense (1.5 kcal/mL) compared with standard (1.0 kcal/mL) enteral nutrition (EN), warranting further exploration. OBJECTIVE: To assess the incidence, risk factors, duration, and timing of large GRVs (≥250 mL) and its relation to clinical outcomes in mechanically ventilated adults. METHODS: A post-hoc analysis of TARGET data in patients with ≥1 GRV recorded. Data are n (%) or median [IQR]. RESULTS: Of 3876 included patients, 1777 (46%) had ≥1 GRV ≥250 mL, which was more common in males (50 compared with 39%; P < 0.001) and in patients receiving energy-dense compared with standard EN (52 compared with 40%; RR = 1.27 (95% CI: 1.19, 1.36); P < 0.001) in whom it also lasted longer (1 [0-2] compared with 0 [0-1] d; P < 0.001), with no difference in time of onset after EN initiation (day 1 [0-2] compared with 1 [0-2]; P = 0.970). Patients with GRV ≥250 mL were more likely to have the following: vasopressor administration (88 compared with 76%; RR = 1.15 [1.12, 1.19]; P < 0.001), positive blood cultures (16 compared with 8%; RR = 1.92 [1.60, 2.31]; P < 0.001), intravenous antimicrobials (88 compared with 81%; RR = 1.09 [1.06, 1.12]; P < 0.001), and prolonged intensive care unit (ICU) stay (ICU-free days to day 28; 12.9 [0.0-21.0] compared with 20.0 [3.9-24.0]; P < 0.001), hospital stay (hospital-free days to day 28: 0.0 [0.0-12.0] compared with 7.0 [0.0-17.6] d; P < 0.001), ventilatory support (ventilator-free days to day 28: 16.0 [0.0-23.0] compared with 22.0 [8.0-25.0]; P < 0.001), and a higher 90-d mortality (29 compared with 23%; adjusted: RR = 1.17 [1.05, 1.30]; P = 0.003). CONCLUSION: Large GRVs were more common in males and those receiving energy-dense formulae, occurred early and were short-lived, and were associated with a number of negative clinical sequelae, including increased mortality, even when adjusted for illness severity. This trial was registered at clinicaltrials.gov as NCT02306746.

The use of smartphone-derived location data to evaluate participation following critical illness: A pilot observational cohort study.

BACKGROUND: Disability is common following critical illness, impacting the quality of life of survivors, and is difficult to measure. 'Participation' can be quantified as involvement in life outside of their home requiring movement from their home to other locations. Participation restriction is a key element of disability, and following critical illness, participation may be diminished. It may be possible to quantify this change using pre-existing smartphone data. OBJECTIVES: The feasibility of extracting location data from smartphones of survivors of intensive care unit (ICU) admission and assessing participation, using location-based outcomes, during recovery from critical illness was evaluated. METHODS: Fifty consecutively admitted, consenting adult survivors of non-elective admission to ICU of greater than 48-h duration were recruited to a prospective observational cohort study where they were followed up at 3 and 6 months following discharge. The feasibility of extracting location data from survivors' smartphones and creating location-derived outcomes assessing participation was investigated over three 28-d study periods: pre-ICU admission and at 3 and 6 months following discharge. The following were calculated: time spent at home; the number of destinations visited; linear distance travelled; and two 'activity spaces', a minimum convex polygon and standard deviation ellipse. RESULTS: Results are median [interquartile range] or n (%). The number of successful extractions was 9/50 (18%), 12/39 (31%), and 13/33 (39%); the percentage of time spent at home was 61 [56-68]%, 77 [66-87]%, and 67 [58-77]% (P = 0.16); the number of destinations visited was 34 [18-64], 38 [22-63], and 65 [46-88] (P = 0.02); linear distance travelled was 367 [56-788], 251 [114-323], and 747 [326-933] km over 28 d (P = 0.02), pre-ICU admission and at 3 and 6 months following ICU discharge, respectively. Activity spaces were successfully created. CONCLUSION: Limited smartphone ownership, missing data, and time-consuming data extraction limit current implementation of mass extraction of location data from patients' smartphones to aid prognostication or measure outcomes. The number of journeys taken and the linear distance travelled increased between 3 and 6 months, suggesting participation may improve over time.

Assessment of physiological barriers to nutrition following critical illness.

BACKGROUND & AIMS: Nutrition may be important for recovery from critical illness. Gastrointestinal dysfunction is a key barrier to nutrition delivery in the Intensive Care Unit (ICU) and metabolic rate is elevated exacerbating nutritional deficits. Whether these factors persist following ICU discharge is unknown. We assessed whether delayed gastric emptying (GE) and impaired glucose absorption persist post-ICU discharge. METHODS: A prospective observational study was conducted in mechanically ventilated adults at 3 time-points: in ICU (V1); on the post-ICU ward (V2); and 3-months after ICU discharge (V3); and compared to age-matched healthy volunteers. On each visit, all participants received a test-meal containing 100 ml of 1 kcal/ml liquid nutrient, labelled with 0.1 g 13C-octanoic acid and 3 g 3-O-Methyl-glucose (3-OMG), and breath and blood samples were collected over 240min to quantify GE (gastric emptying coefficient (GEC)), and glucose absorption (3-OMG concentration; area under the curve (AUC)). Data are mean ± standard error of the mean (SEM) and differences shown with 95% confidence intervals (95%CI). RESULTS: Twenty-six critically ill patients completed V1 (M:F 20:6; 62.0 ± 2.9 y; BMI 29.8 ± 1.2 kg/m2; APACHE II 19.7 ± 1.9), 15 completed V2 and eight completed V3; and were compared to 10 healthy volunteers (M:F 6:4; 60.5 ± 7.5 y; BMI 26.0 ± 1.0 kg/m2). GE was significantly slower on V1 compared to health (GEC difference: -0.96 (95%CI -1.61, -0.31); and compared to V2 (-0.73 (-1.16, -0.31) and V3 (-1.03 (-1.47, -0.59). GE at V2 and V3 were not different to that in health (V2: -0.23 (-0.61, 0.14); V3: 0.10 (-0.27, 0.46)). GEC: V1: 2.64 ± 0.19; V2: 3.37 ± 0.12; V3: 3.67 ± 0.10; health: 3.60 ± 0.13. Glucose absorption (3-OMG AUC0-240) was impaired on V1 compared to V2 (-37.9 (-64.2, -11.6)), and faster on V3 than in health (21.8 (0.14, 43.4) but absorption at V2 and V3 did not differ from health. Intestinal glucose absorption: V1: 63.8 ± 10.4; V2: 101.7 ± 7.0; V3: 111.9 ± 9.7; health: 90.7 ± 3.8. CONCLUSION: This study suggests that delayed GE and impaired intestinal glucose absorption recovers rapidly post-ICU. This requires further confirmation in a larger population. The REINSTATE trial was prospectively registered at www.anzctr.org.au. TRIAL ID: ACTRN12618000370202.

Mixed-mode versus paper surveys for patient-reported outcomes after critical illness: A randomised controlled trial.

OBJECTIVE: The aim of the study was to determine the response rate to a mixed-mode survey using email compared with that to a paper survey in survivors of critical illness. DESIGN: This is a prospective randomised controlled trial. SETTING: The study was conducted at a single-centre quaternary intensive care unit (ICU) in Adelaide, Australia. PARTICIPANTS: Study participants were patients admitted to the ICU for ≥48 h and discharged from the hospital. INTERVENTIONS: The participants were randomised to receive a survey by paper (via mail) or via online (via email, or if a non-email user, via a letter with a website address). Patients who did not respond to the initial survey received a reminder paper survey after 14 days. The survey included quality of life (EuroQol-5D-5L), anxiety and depression (Hospital Anxiety and Depression Scale), and post-traumatic symptom (Impact of Event Scale-Revised) assessment. MAIN OUTCOME MEASURES: Survey response rate, extent of survey completion, clinical outcomes at different time points after discharge, and survey cost analysis were the main outcome measures. Outcomes were stratified based on follow-up time after ICU discharge (3, 6, and 12 months). RESULTS: A total of 239 patients were randomised. The response rate was similar between the groups (mixed-mode: 78% [92/118 patients] vs. paper: 80% [97/121 patients], p = 0.751) and did not differ between time points of follow-up. Incomplete surveys were more prevalent in the paper group (10% vs 18%). The median EuroQol-5D-5L index value was 0.83 [0.71-0.92]. Depressive symptoms were reported by 25% of patients (46/187), anxiety symptoms were reported by 27% (50/187), and probable post-traumatic stress disorder was reported by 14% (25/184). Patient outcomes did not differ between the groups or time points of follow-up. The cost per reply was AU$ 16.60 (mixed-mode) vs AU$ 19.78 (paper). CONCLUSION: The response rate of a mixed-mode survey is similar to that of a paper survey and may provide modest cost savings.

Effects of Standard vs Energy-Dense Formulae on Gastric Retention, Energy Delivery, and Glycemia in Critically Ill Patients.

BACKGROUND: Energy-dense formulae are often provided to critically ill patients with enteral feed intolerance with the aim of increasing energy delivery, yet the effect on gastric emptying is unknown. The rate of gastric emptying of a standard compared with an energy-dense formula was quantified in critically ill patients. METHODS: Mechanically ventilated adults were randomized to receive radiolabeled intragastric infusions of 200 mL standard (1 kcal/mL) or 100 mL energy-dense (2 kcal/mL) enteral formulae on consecutive days in this noninferiority, blinded, crossover trial. The primary outcome was scintigraphic measurement of gastric retention (percentage at 120 minutes). Other measures included area under the curve (AUC) for gastric retention and intestinal energy delivery (calculated from gastric retention of formulae over time), blood glucose (peak and AUC), and intestinal glucose absorption (using 3-O-methyl-D-gluco-pyranose [3-OMG] concentrations). Comparisons were undertaken using paired mixed-effects models. Data presented are mean ± SE. RESULTS: Eighteen patients were studied (male/female, 14:4; age, 55.2 ± 5.3 years). Gastric retention at 120 minutes was greater with the energy-dense formula (standard, 17.0 ± 5.9 vs energy-dense, 32.5 ± 7.1; difference, 12.7% [90% confidence interval, 0.8%-30.1%]). Energy delivery (AUC120 , 13,038 ± 1119 vs 9763 ± 1346 kcal/120 minutes; P = 0.057), glucose control (peak glucose, 10.1 ± 0.3 vs 9.7 ± 0.3 mmol/L, P = 0.362; and glucose AUC120 8.7 ± 0.3 vs 8.5 ± 0.3 mmol/L.120 minutes, P = 0.661), and absorption (3-OMG AUC120 , 38.5 ± 4.0 vs 35.7 ± 4.0 mmol/L.120 minutes; P = .508) were not improved with the energy-dense formula. CONCLUSION: In critical illness, administration of an energy-dense formula does not reduce gastric retention, increase energy delivery to the small intestine, or improve glucose absorption or glucose control; instead, there is a signal for delayed gastric emptying.

Gut dysfunction in the ICU: diagnosis and management.

PURPOSE OF REVIEW: Progress has been made in our understanding of gut dysfunction in critical illness. This review will outline new findings and give perspectives based on previous knowledge and concurrent advances in nutrition. RECENT FINDINGS: The relationship between gut dysfunction and poor outcomes in critical illness has received considerable interest. It remains uncertain whether gut dysfunction is merely a marker of illness severity or if it is directly responsible for prolonged critical illness and increased mortality. This relationship is difficult to ascertain given there is no agreed method for identification and quantification; biomarkers such as intestinal fatty acid binding protein and citrulline show promise but require further study. Recent studies have investigated strategies to deliver enteral nutrition targets with impacts on gut function, including high calorie or protein formulae, intermittent regimes and novel prokinetics. SUMMARY: Gut dysfunction is associated with poor outcomes, but it remains uncertain whether strategies to improve gut function will influence survival and recovery.

Use of a High-Protein Enteral Nutrition Formula to Increase Protein Delivery to Critically Ill Patients: A Randomized, Blinded, Parallel-Group, Feasibility Trial.

BACKGROUND: International guidelines recommend critically ill adults receive more protein than most receive. We aimed to establish the feasibility of a trial to evaluate whether feeding protein to international recommendations would improve outcomes, in which 1 group received protein doses representative of international guideline recommendations (high protein) and the other received doses similar to usual practice. METHODS: We conducted a prospective, randomized, blinded, parallel-group, feasibility trial across 6 intensive care units. Critically ill, mechanically ventilated adults expected to receive enteral nutrition (EN) for ≥2 days were randomized to receive EN containing 63 or 100 g/L protein for ≤28 days. Data are mean (SD) or median (interquartile range). RESULTS: The recruitment rate was 0.35 (0.13) patients per day, with 120 patients randomized and data available for 116 (n = 58 per group). Protein delivery was greater in the high-protein group (1.52 [0.52] vs 0.99 [0.27] grams of protein per kilogram of ideal body weight per day; difference, 0.53 [95% CI, 0.38-0.69] g/kg/d protein), with no difference in energy delivery (difference, -26 [95% CI, -190 to 137] kcal/kg/d). There were no between-group differences in the duration of feeding (8.7 [7.3] vs 8.1 [6.3] days), and blinding of the intervention was confirmed. There were no differences in clinical outcomes, including 90-day mortality (14/55 [26%] vs 15/56 [27%]; risk difference, -1.3% [95% CI, -17.7% to 15.0%]). CONCLUSION: Conducting a multicenter blinded trial is feasible to compare protein delivery at international guideline-recommended levels with doses similar to usual care during critical illness.

Acceleration of Gastric Emptying by Insulin-Induced Hypoglycemia is Dependent on the Degree of Hypoglycemia.

CONTEXT: Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized "non-severe" hypoglycemia into level 1 (<3.9 mmol/L) and 2 (<3 mmol/L) hypoglycemia. Gastric emptying of carbohydrate is a major determinant of postprandial glycemia but its role in hypoglycemia counter-regulation remains underappreciated. "Marked" hypoglycemia (~2.6 mmol/L) accelerates gastric emptying and increases carbohydrate absorption in health and type 1 diabetes, but the impact of "mild" hypoglycemia (3.0-3.9 mmol/L) is unknown. OBJECTIVE: To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L ("marked") and 3.6 mmol/L ("mild"), on gastric emptying in health. DESIGN, SETTING, AND SUBJECTS: Fourteen healthy male participants (mean age: 32.9 ±â€…8.3 years; body mass index: 24.5 ±â€…3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. RESULTS: Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. CONCLUSION: In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

Early anthropometry, strength, and function in survivors of critical illness.

BACKGROUND: Critically ill patients experience acute muscle wasting and long-term functional impairments, yet this has been inadequately categorised early in recovery. OBJECTIVE: This observational study aimed to evaluate anthropometry, strength, and muscle function after intensive care unit discharge. METHODS: Adult patients able to complete study measures after prolonged intensive care unit stay (≥5 d) were eligible. Demographic and clinical data were collected, and bodyweight, height, triceps skinfold, trunk length, handgrip strength, 6-minute walk test, whole-body dual-energy x-ray absorptiometry, and mid-thigh, knee, and above-ankle circumferences were measured. Body cell mass was calculated from these data. Data are presented as mean (standard deviation) or median [interquartile range]. RESULTS: Fourteen patients (50% male; 57 [10.5] years) were assessed 11.1 (6.9) d after intensive care unit discharge. Patients lost 4.76 (6.66) kg in the intensive care unit. Triceps skinfold thickness (17.00 [8.65] mm) and handgrip strength (12.60 [8.57] kg) were lower than normative data. No patient could commence the 6-minute walk test. Dual-energy x-ray absorptiometry-derived muscle mass correlated with handgrip strength (R = 0.57; 95% confidence interval = 0.06-0.85; p = 0.03), but body cell mass did not. CONCLUSIONS: Anthropometry and strength in intensive care unit survivors are below normal. Muscle mass derived from dual-energy x-ray absorptiometry correlates with handgrip strength but body cell mass does not.

Blinded, Double-Dummy, Parallel-Group, Phase 2a Randomized Clinical Trial to Evaluate the Efficacy and Safety of a Highly Selective 5-Hydroxytryptamine Type 4 Receptor Agonist in Critically Ill Patients With Enteral Feeding Intolerance.

BACKGROUND: Delayed gastric emptying is the leading cause of enteral feeding intolerance (EFI) in critical illness. This phase 2a study compared TAK-954, a selective agonist of 5-hydroxytryptamine type 4 receptors, with metoclopramide in critically ill patients with EFI (NCT01953081). METHODS: A blinded, double-dummy trial was conducted in mechanically ventilated patients with EFI (>200 mL gastric residual volume within 24 hours before randomization). Patients were randomized to receive either 0.5 mg intravenous TAK-954 over 1 hour then 0.9% saline injection 4 times/d (sham metoclopramide) or the active comparator 10 mg intravenous metoclopramide 4 times/d and a 1-hour 0.9% saline infusion. After initial dosing, participants received a radiolabeled meal of liquid nutrient (Ensure; 106 kcal), and gastric emptying was measured (scintigraphy). Adverse events (AEs) were recorded from the time of consent through to day 5; serious AEs were collected to day 30. RESULTS: Thirteen patients (TAK-954, n = 7; metoclopramide, n = 6) participated. Five patients in the TAK-954 group and 4 in the metoclopramide group experienced AEs (2 and 3, respectively, were serious). All AEs except 1 (diarrhea in the metoclopramide group) were considered unrelated to study drug. Following treatment, a greater proportion of patients receiving TAK-954 had normal gastric retention (<13% retention at 180 minutes) than those receiving metoclopramide (6/7 vs 3/6 patients, respectively). CONCLUSION: A single dose of 0.5 mg intravenous TAK-954 appears to have at least similar efficacy in accelerating gastric emptying to multiple doses of 10 mg metoclopramide and was not associated with increased AEs.

Protein delivery in mechanically ventilated adults in Australia and New Zealand: current practice.

Objective: To quantify current protein prescription and delivery in critically ill adults in Australia and New Zealand and compare it with international guidelines. Design: Prospective, multicentre, observational study. Setting: Five intensive care units (ICUs) across Australia and New Zealand. Participants: Mechanically ventilated adults who were anticipated to receive enteral nutrition for ≥ 24 hours. Main outcome measures: Baseline demographic and nutrition data in ICU, including assessment of requirements, prescription and delivery of enteral nutrition, parenteral nutrition and protein supplementation, were collected. The primary outcome was enteral nutrition protein delivery (g/kg ideal body weight [IBW] per day). Data are reported as mean ± standard deviation or n (%). Results: 120 patients were studied (sex, 60% male; mean age, 59 ± 16 years; mean admission APACHE II score, 20 ± 8). Enteral nutrition was delivered on 88%, parenteral nutrition on 6.8%, and protein supplements on 0.3% of 1156 study days. For the 73% (88/120) of patients who had a nutritional assessment, the mean estimated protein requirements were 99 ± 22 g/day (1.46 ± 0.55 g/kg IBW per day). The mean daily protein delivery was 54 ± 23 g (0.85 ± 0.35 g/kg IBW per day) from enteral nutrition and 56 ± 23 g (0.88 ± 0.35 g/kg IBW per day) from all sources (enteral nutrition, parenteral nutrition, protein supplements). Protein delivery was ≥ 1.2 g/kg IBW per day on 29% of the total study days per patient. Conclusions: Protein delivery as a part of current usual care to critically ill adults in Australia and New Zealand remains below that recommended in international guidelines.