A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed.

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure managed on intensive care units were randomised (Ketogenic n = 14, Control n = 15) into a two-centre pilot open-label trial of ketogenic versus standard enteral feeding. The primary endpoints were assessment of feasibility and safety, recruitment and retention rates and achievement of ketosis and glucose control. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis in all patients in the intervention group, with a refusal rate of 4.1% and 82.8% retention. Patients who received ketogenic feeding had fewer hypoglycaemic events (0.0% vs. 1.6%), required less exogenous international units of insulin (0 (Interquartile range 0-16) vs.78 (Interquartile range 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Ketogenic feeding was feasible and may be an intervention for addressing bioenergetic failure in critically ill patients. Clinical Trials.gov registration: NCT04101071.

Critical care and pandemic preparedness and response.

Critical care was established partially in response to a polio epidemic in the 1950s. In the intervening 70 yr, several epidemics and pandemics have placed critical care and allied services under extreme pressure. Pandemics cause wholesale changes to accepted standards of practice, require reallocation and retargeting of resources and goals of care. In addition to clinical acumen, mounting an effective critical care response to a pandemic requires local, national, and international coordination in a diverse array of fields from research collaboration and governance to organisation of critical care networks and applied biomedical ethics in the eventuality of triage situations. This review provides an introduction to an array of topics that pertain to different states of pandemic acuity: interpandemic preparedness, alert, surge activity, recovery and relapse through the literature and experience of recent pandemics including COVID-19, H1N1, Ebola, and SARS.

Muscle Ultrasound Changes and Physical Function of Critically Ill Children: A Comparison of Rectus Femoris Cross-Sectional Area and Quadriceps Thickness Measurements.

Quadriceps thickness (QT) and rectus femoris cross-sectional area (RFCSA) are both used to evaluate muscle changes in critically ill children. However, their correlation and association with physical function has not been compared. OBJECTIVES: To compare QT with RFCSA changes, and their association with physical function in critically ill children. DESIGN SETTING AND PARTICIPANTS: Secondary analysis of a prospective cohort study of children 0-18 years old admitted to a tertiary mixed PICU between January 2015 and October 2018 with PICU stay greater than 48 hours and greater than or equal to one organ dysfunction. MAIN OUTCOMES AND MEASURES: Ultrasound QT and RFCSA were measured at PICU admission, PICU discharge, hospital discharge, and 6 months post-discharge. QT and RFCSA changes from baseline were compared with each other and with change in motor function, physical ability, and physical health-related quality of life (HRQOL). RESULTS: Two hundred thirty-seven images from 66 subjects were analyzed. RFCSA change was not significantly different from QT change at PICU (-8.07% [interquartile range (IQR), -17.11% to 4.80%] vs -4.55% [IQR, -14.32% to 4.35%]; p = 0.927) or hospital discharge (-5.62% [IQR, -15.00% to 9.42%] vs -8.81% [IQR, -18.67% to 2.39%]; p = 0.238) but was significantly greater than QT change at 6 months (32.7% [IQR, 5.74-109.76%] vs 9.66% [IQR, -8.17% to 25.70%]; p < 0.001). Motor function change at PICU discharge was significantly associated with RFCSA change (adjusted ß coefficient, 0.02 [95% CI, 0.01-0.03]; p = 0.013) but not QT change (adjusted ß coefficient, -0.01 [95% CI, -0.02 to 0.01]; p = 0.415). Similar results were observed for physical HRQOL changes at hospital discharge (adjusted ß coefficient for RFCSA change, 0.51 [95% CI, 0.10-0.92]; p = 0.017 and adjusted ß coefficient for QT change, -0.21 [-0.76 to 0.35]; p = 0.458). Physical ability was not significantly associated with RFCSA or QT changes at 6 months post-discharge. CONCLUSIONS AND RELEVANCE: Ultrasound derived RFCSA is associated with PICU motor function and hospital discharge physical HRQOL changes, unlike QT, and may be more useful for in-hospital muscle monitoring in critically ill children.

Characterising biological mechanisms underlying ethnicity-associated outcomes in COVID-19 through biomarker trajectories: a multicentre registry analysis.

BACKGROUND: Differences in routinely collected biomarkers between ethnic groups could reflect dysregulated host responses to disease and to treatments, and be associated with excess morbidity and mortality in COVID-19. METHODS: A multicentre registry analysis from patients aged ≥16 yr with SARS-CoV-2 infection and emergency admission to Barts Health NHS Trust hospitals during January 1, 2020 to May 13, 2020 (wave 1) and September 1, 2020 to February 17, 2021 (wave 2) was subjected to unsupervised longitudinal clustering techniques to identify distinct phenotypic patient clusters based on trajectories of routine blood results over the first 15 days of hospital admission. Distribution of trajectory clusters across ethnic categories was determined, and associations between ethnicity, trajectory clusters, and 30-day survival were assessed using multivariable Cox proportional hazards modelling. Secondary outcomes were ICU admission, survival to hospital discharge, and long-term survival to 640 days. RESULTS: We included 3237 patients with hospital length of stay ≥7 days. In patients who died, there was greater representation of Black and Asian ethnicity in trajectory clusters for C-reactive protein and urea-to-creatinine ratio associated with increased risk of death. Inclusion of trajectory clusters in survival analyses attenuated or abrogated the higher risk of death in Asian and Black patients. Inclusion of C-reactive protein went from hazard ratio (HR) 1.36 [0.95-1.94] to HR 0.97 [0.59-1.59] (wave 1), and from HR 1.42 [1.15-1.75]) to HR 1.04 [0.78-1.39] (wave 2) in Asian patients. Trajectory clusters associated with reduced 30-day survival were similarly associated with worse secondary outcomes. CONCLUSIONS: Clinical biochemical monitoring of COVID-19 and progression and treatment response in SARS-CoV-2 infection should be interpreted in the context of ethnic background.

Responsiveness of Critically Ill Adults With Multimorbidity to Rehabilitation Interventions: A Patient-Level Meta-Analysis Using Individual Pooled Data From Four Randomized Trials.

OBJECTIVE: To explore if patient characteristics (pre-existing comorbidity, age, sex, and illness severity) modify the effect of physical rehabilitation (intervention vs control) for the coprimary outcomes health-related quality of life (HRQoL) and objective physical performance using pooled individual patient data from randomized controlled trials (RCTs). DATA SOURCES: Data of individual patients from four critical care physical rehabilitation RCTs. STUDY SELECTION: Eligible trials were identified from a published systematic review. DATA EXTRACTION: Data sharing agreements were executed permitting transfer of anonymized data of individual patients from four trials to form one large, combined dataset. The pooled trial data were analyzed with linear mixed models fitted with fixed effects for treatment group, time, and trial. DATA SYNTHESIS: Four trials contributed data resulting in a combined total of 810 patients (intervention n = 403, control n = 407). After receiving trial rehabilitation interventions, patients with two or more comorbidities had HRQoL scores that were significantly higher and exceeded the minimal important difference at 3 and 6 months compared with the similarly comorbid control group (based on the Physical Component Summary score (Wald test p = 0.041). Patients with one or no comorbidities who received intervention had no HRQoL outcome differences at 3 and 6 months when compared with similarly comorbid control patients. No patient characteristic modified the physical performance outcome in patients who received physical rehabilitation. CONCLUSIONS: The identification of a target group with two or more comorbidities who derived benefits from the trial interventions is an important finding and provides direction for future investigations into the effect of rehabilitation. The multimorbid post-ICU population may be a select population for future prospective investigations into the effect of physical rehabilitation.

Safety and Feasibility Assessment of Repetitive Vascular Occlusion Stimulus (RVOS) Application to Multi-Organ Failure Critically Ill Patients: A Pilot Randomised Controlled Trial.

Muscle wasting is implicated in the pathogenesis of intensive care unit acquired weakness (ICU-AW), affecting 40% of patients and causing long-term physical disability. A repetitive vascular occlusion stimulus (RVOS) limits muscle atrophy in healthy and orthopaedic subjects, thus, we explored its application to ICU patients. Adult multi-organ failure patients received standard care +/- twice daily RVOS {4 cycles of 5 min tourniquet inflation to 50 mmHg supra-systolic blood pressure, and 5 min complete deflation} for 10 days. Serious adverse events (SAEs), tolerability, feasibility, acceptability, and exploratory outcomes of the rectus femoris cross-sectional area (RFCSA), echogenicity, clinical outcomes, and blood biomarkers were assessed. Only 12 of the intended 32 participants were recruited. RVOS sessions (76.1%) were delivered to five participants and two could not tolerate it. No SAEs occurred; 75% of participants and 82% of clinical staff strongly agreed or agreed that RVOS is an acceptable treatment. RFCSA fell significantly and echogenicity increased in controls (n = 5) and intervention subjects (n = 4). The intervention group was associated with less frequent acute kidney injury (AKI), a greater decrease in the total sequential organ failure assessment score (SOFA) score, and increased insulin-like growth factor-1 (IGF-1), and reduced syndecan-1, interleukin-4 (IL-4) and Tumor necrosis factor receptor type II (TNF-RII) levels. RVOS application appears safe and acceptable, but protocol modifications are required to improve tolerability and recruitment. There were signals of possible clinical benefit relating to RVOS application.

Nutritional priorities in patients with severe COVID-19.

PURPOSE OF REVIEW: The COVID-19 pandemic has altered the profile of critical care services internationally, as professionals around the globe have struggled to rise to the unprecedented challenge faced, both in terms of individual patient management and the sheer volume of patients that require treatment and management in intensive care. This review article sets out key priorities in nutritional interventions during the patient journey, both in the acute and recovery phases. RECENT FINDINGS: The current review covers the care of the acutely unwell patient, and the evidence base for nutritional interventions in the COVID-19 population. One of the biggest differences in caring for critically ill patients with acute respiratory failure from COVID-19 is often the time prior to intubation. This represents specific nutritional challenges, as does nursing patients in the prone position or in the setting of limited resources. This article goes on to discuss nutritional support for COVID-19 sufferers as they transition through hospital wards and into the community. SUMMARY: Nutritional support of patients with severe COVID-19 is essential. Given the longer duration of their critical illness, combined with hypermetabolism and energy expenditure, patients with COVID-19 are at increased risk for malnutrition during and after their hospital stay.

A narrative review of skeletal muscle atrophy in critically ill children: pathogenesis and chronic sequelae.

Muscle wasting is now recognized as a growing, debilitating problem in critically ill adults, resulting in long-term deficits in function and an impaired quality of life. Ultrasonography has demonstrated decreases in skeletal muscle size during pediatric critical illness, although variations exist. However, muscle protein turnover patterns during pediatric critical illness are unclear. Understanding muscle protein turnover during critical illness is important in guiding interventions to reduce muscle wasting. The aim of this review was to explore the possible protein synthesis and breakdown patterns in pediatric critical illness. Muscle protein turnover studies in critically ill children are lacking, with the exception of those with burn injuries. Children with burn injuries demonstrate an elevation in both muscle protein breakdown (MPB) and synthesis during critical illness. Extrapolations from animal models and whole-body protein turnover studies in children suggest that children may be more dependent on anabolic factors (e.g., nutrition and growth factors), and may experience greater muscle degradation in response to insults than adults. Yet, children, particularly the younger ones, are more responsive to anabolic agents, suggesting modifiable muscle wasting during critical illness. There is a lack of evidence for muscle wasting in critically ill children and its correlation with outcomes, possibly due to current available methods to study muscle protein turnover in children-most of which are invasive or tedious. In summary, children may experience muscle wasting during critical illness, which may be more reversible by the appropriate anabolic agents than adults. Age appears an important determinant of skeletal muscle turnover. Less invasive methods to study muscle protein turnover and associations with long-term outcome would strengthen the evidence for muscle wasting in critically ill children.

Acute kidney injury in COVID-19: multicentre prospective analysis of registry data.

BACKGROUND: Acute kidney injury (AKI) is a common and important complication of coronavirus disease 2019 (COVID-19). Further characterization is required to reduce both short- and long-term adverse outcomes. METHODS: We examined registry data including adults with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection admitted to five London Hospitals from 1 January to 14 May 2020. Prior end-stage kidney disease was excluded. Early AKI was defined by Kidney Disease: Improving Global Outcomes creatinine criteria within 7 days of admission. Independent associations of AKI and survival were examined in multivariable analysis. Results are given as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals. RESULTS: Among 1855 admissions, 455 patients (24.5%) developed early AKI: 200 (44.0%) Stage 1, 90 (19.8%) Stage 2 and 165 (36.3%) Stage 3 (74 receiving renal replacement therapy). The strongest risk factor for AKI was high C-reactive protein [OR 3.35 (2.53-4.47), P < 0.001]. Death within 30 days occurred in 242 (53.2%) with AKI compared with 255 (18.2%) without. In multivariable analysis, increasing severity of AKI was incrementally associated with higher mortality: Stage 3 [HR 3.93 (3.04-5.08), P < 0.001]. In 333 patients with AKI surviving to Day 7, 134 (40.2%) recovered, 47 (14.1%) recovered then relapsed and 152 (45.6%) had persistent AKI at Day 7; an additional 105 (8.2%) patients developed AKI after Day 7. Persistent AKI was strongly associated with adjusted mortality at 90 days [OR 7.57 (4.50-12.89), P < 0.001]. CONCLUSIONS: AKI affected one in four hospital in-patients with COVID-19 and significantly increased mortality. Timing and recovery of COVID-19 AKI is a key determinant of outcome.

Ethnicity and acute hospital admissions: Multi-center analysis of routine hospital data.

Background: The effects of ethnic and social inequalities on patient outcomes in acute healthcare remain poorly understood. Methods: Prospectively-defined analysis of registry data from four acute NHS hospitals in east London including all patients ≥ 18 years with a first emergency admission between 1st January 2013 and 31st December 2018. We calculated adjusted one-year mortality risk using logistic regression. Results are presented as n (%), median (IQR), and odds ratios (OR) with 95% confidence intervals. Findings: We included 203,182 patients. 43,101 (21%) patients described themselves as Asian, 21,388 (10.5%) Black, 2,982 (1.4%) Mixed, 13,946 (6.8%) Other ethnicity, and 100,065 (49%) White. We excluded 21,700 (10.7%) patients with undisclosed ethnicity. 16,054 (7.9%) patients died within one year. Non-white patients were younger (Asian: 43 [31-62] years; Black: 48 [33-63] years; Mixed 36 [26-52] years) than White patients (55 [35-75] years), with a higher incidence of comorbid disease. In each age-group, non-white patients were more likely to be admitted to hospital. This effect was greatest in the ≥ 80 years age-group (32% non-white admitted to hospital versus 23% non-white in community population). Deprivation was associated with increased mortality in all ethnic groups (OR 1.41 [1.33-1.50]; p < 0.001). However, when adjusted for age, Asian (0.69 [0.66-0.73], p < 0.0001) and Black patients (0.79 [0.74-0.85]; p < 0.0001) experienced a lower mortality risk than White patients. Interpretation: Ethnic and social disparities are associated with important differences in acute health outcomes. However, these differences are masked by statistical adjustment because patients from ethnic minorities present at a younger age. Funding: None.

Talking to multi-morbid patients about critical illness: an evolving conversation.

Conversations around critical illness outcomes and benefits from intensive care unit (ICU) treatment have begun to shift away from binary discussions on living versus dying. Increasingly, the reality of survival with functional impairment versus survival with a late death is being recognised as relevant to patients. Most ICU admissions are associated with new functional and cognitive disabilities that are significant and long lasting. When discussing outcomes, clinicians rightly focus on patients' wishes and the quality of life (QoL) that they would find acceptable. However, patients' views may encompass differing views on acceptable QoL post-critical illness, not necessarily reflected in standard conversations. Maintaining independence is a greater priority to patients than simple survival. QoL post-critical illness determines judgments on the benefits of ICU support but translating this into clinical practice risks potential conflation of health outcomes and QoL. This article discusses the concept of response shift and the implication for trade-offs between number/length of invasive treatments and change in physical function or death. Conversations need to delineate how health outcomes (e.g. tracheostomy, muscle wasting, etc.) may affect individual outcomes most relevant to the patient and hence impact overall QoL. The research strategy taken to explore decision-making for critically ill patients might benefit from gathering qualitative data, as a complement to quantitative data. Patients, families and doctors are motivated by far wider considerations, and a consultation process should relate to more than the simple likelihood of mortality in a shared decision-making context.

Skeletal Muscle Changes, Function, and Health-Related Quality of Life in Survivors of Pediatric Critical Illness.

OBJECTIVES: To describe functional and skeletal muscle changes observed during pediatric critical illness and recovery and their association with health-related quality of life. DESIGN: Prospective cohort study. SETTING: Single multidisciplinary PICU. PATIENTS: Children with greater than or equal to 1 organ dysfunction, expected PICU stay greater than or equal to 48 hours, expected survival to discharge, and without progressive neuromuscular disease or malignancies were followed from admission to approximately 6.7 months postdischarge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional status was measured using the Functional Status Scale score and Pediatric Evaluation of Disability Inventory-Computer Adaptive Test. Patient and parental health-related quality of life were measured using the Pediatric Quality of Life Inventory and Short Form-36 questionnaires, respectively. Quadriceps muscle size, echogenicity, and fat thickness were measured using ultrasonography during PICU stay, at hospital discharge, and follow-up. Factors affecting change in muscle were explored. Associations between functional, muscle, and health-related quality of life changes were compared using regression analysis. Seventy-three survivors were recruited, of which 44 completed follow-ups. Functional impairment persisted in four of 44 (9.1%) at 6.7 months (interquartile range, 6-7.7 mo) after discharge. Muscle size decreased during PICU stay and was associated with inadequate energy intake (adjusted ß, 0.15; 95% CI, 0.02-0.28; p = 0.030). No change in echogenicity or fat thickness was observed. Muscle growth postdischarge correlated with mobility function scores (adjusted ß, 0.05; 95% CI, 0.01-0.09; p = 0.046). Improvements in mobility scores were associated with improved physical health-related quality of life at follow-up (adjusted ß, 1.02; 95% CI, 0.23-1.81; p = 0.013). Child physical health-related quality of life at hospital discharge was associated with parental physical health-related quality of life (adjusted ß, 0.09; 95% CI, 0.01-0.17; p = 0.027). CONCLUSIONS: Muscle decreased in critically ill children, which was associated with energy inadequacy and impaired muscle growth postdischarge. Muscle changes correlated with change in mobility, which was associated with child health-related quality of life. Mobility, child health-related quality of life, and parental health-related quality of life appeared to be interlinked.

A Cross-Sectional Study of the Clinical Metrics of Functional Status Tools in Pediatric Critical Illness.

OBJECTIVES: To determine the clinical metrics of functional assessments in pediatric critical illness survivors. DESIGN: Cross-sectional observational study. SETTING: PICU follow-up clinic. PATIENTS: Forty-four PICU survivors 6-12 months post PICU stay, and 52 healthy controls 0-18 years old. INTERVENTIONS: Nil. MEASUREMENTS AND MAIN RESULTS: Function was assessed using the Pediatric Quality of Life Inventory 4.0 generic scales and infant scales, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test, and the Functional Status Scale. Muscle strength was assessed by hand grip strength in children greater than or equal to 6 years. Clinical metrics assessed included floor and ceiling effects, known-group, and convergent validity. Floor and ceiling effects were present if the participants achieving the worst or best scores exceeded 15%, respectively. Known-group validity was assessed by comparing scores between those with and without complex chronic conditions and abnormal versus good baseline function. Convergent validity was assessed using partial correlation between two tools. Functional Status Scale and Pediatric Quality of Life Inventory physical domain scores showed significant ceiling effects in PICU survivors (69.2% and 15.4%, respectively, achieved the highest possible score). Functional scores were not significantly different between children with or without complex chronic conditions or children with good versus abnormal baseline function. In healthy children, Pediatric Quality of Life Inventory physical correlated moderately with hand grip strength (partial r = 0.66; p < 0.001), whereas Pediatric Quality of Life Inventory psychosocial correlated moderately with Pediatric Evaluation of Disability Inventory-Computer Adaptive Test social/cognitive score (partial r = 0.53; p < 0.001). In PICU survivors, only Pediatric Quality of Life Inventory physical and Pediatric Evaluation of Disability Inventory-Computer Adaptive Test mobility scores were correlated (partial r = 0.55; p < 0.001). CONCLUSIONS: PICU functional assessment tools have varying clinical metrics. Considering ceiling effects, Pediatric Evaluation of Disability Inventory-Computer Adaptive Test may be more suitable in survivors than Functional Status Scale. Differences in scores between children with or without complex chronic conditions, and with or without baseline functional impairment, were not observed. Functional assessments likely require a combination of tools to measure the spectrum of pediatric critical illness and recovery.

Ethnicity and outcomes in patients hospitalised with COVID-19 infection in East London: an observational cohort study.

OBJECTIVE: To describe outcomes within different ethnic groups of a cohort of hospitalised patients with confirmed COVID-19 infection. To quantify and describe the impact of a number of prognostic factors, including frailty and inflammatory markers. SETTING: Five acute National Health Service Hospitals in east London. DESIGN: Prospectively defined observational study using registry data. PARTICIPANTS: 1737 patients aged 16 years or over admitted to hospital with confirmed COVID-19 infection between 1 January and 13 May 2020. MAIN OUTCOME MEASURES: The primary outcome was 30-day mortality from time of first hospital admission with COVID-19 diagnosis during or prior to admission. Secondary outcomes were 90-day mortality, intensive care unit (ICU) admission, ICU and hospital length of stay and type and duration of organ support. Multivariable survival analyses were adjusted for potential confounders. RESULTS: 1737 were included in our analysis of whom 511 had died by day 30 (29%). 538 (31%) were from Asian, 340 (20%) black and 707 (40%) white backgrounds. Compared with white patients, those from minority ethnic backgrounds were younger, with differing comorbidity profiles and less frailty. Asian and black patients were more likely to be admitted to ICU and to receive invasive ventilation (OR 1.54, (95% CI 1.06 to 2.23); p=0.023 and OR 1.80 (95% CI 1.20 to 2.71); p=0.005, respectively). After adjustment for age and sex, patients from Asian (HR 1.49 (95% CI 1.19 to 1.86); p<0.001) and black (HR 1.30 (95% CI 1.02 to 1.65); p=0.036) backgrounds were more likely to die. These findings persisted across a range of risk factor-adjusted analyses accounting for major comorbidities, obesity, smoking, frailty and ABO blood group. CONCLUSIONS: Patients from Asian and black backgrounds had higher mortality from COVID-19 infection despite controlling for all previously identified confounders and frailty. Higher rates of invasive ventilation indicate greater acute disease severity. Our analyses suggest that patients of Asian and black backgrounds suffered disproportionate rates of premature death from COVID-19.

Prognostic association of routinely measured biomarkers in patients admitted to critical care: a systematic review.

PURPOSE: To examine reported prognostic associations of routine blood measurements in the intensive care unit. MATERIALS AND METHODS: We searched PubMed, EMBASE through 28th May 2020 to identify all studies in adult critical care investigating associations between parameters measured routinely in whole blood, plasma or serum, and length of stay or mortality. Registration: PROSPERO; CRD42019122058. RESULTS: A total of 128 studies, reporting 28 different putative prognostic biomarkers, met eligibility criteria. Those most frequently examined were red cell distribution width, neutrophil-to-lymphocyte ratio, C-reactive protein, and platelet count. A higher red cell distribution width, a lower platelet count, and a higher neutrophil-to-lymphocyte ratio were consistently associated with both increased mortality and length of stay. A lower level of albumin was consistently associated with greater mortality. C-reactive protein was inconsistent. Most studies (n = 110) used regression modelling with wide variation in variable selection and covariate-adjustment; none externally validated the proposed predictive models. CONCLUSIONS: Simple regression models have so far proved inadequate for the complexity of data available from routine blood sampling in critical care. Adoption of a direct causal framework may help better assess mechanistic processes, aid design of future studies, and guide clinical decision making using routine data.

Implications for post critical illness trial design: sub-phenotyping trajectories of functional recovery among sepsis survivors.

BACKGROUND: Patients who survive critical illness suffer from a significant physical disability. The impact of rehabilitation strategies on health-related quality of life is inconsistent, with population heterogeneity cited as one potential confounder. This secondary analysis aimed to (1) examine trajectories of functional recovery in critically ill patients to delineate sub-phenotypes and (2) to assess differences between these cohorts in both clinical characteristics and clinimetric properties of physical function assessment tools. METHODS: Two hundred ninety-one adult sepsis survivors were followed-up for 24 months by telephone interviews. Physical function was assessed using the Physical Component Score (PCS) of the Short Form-36 Questionnaire (SF-36) and Activities of Daily Living and the Extra Short Musculoskeletal Function Assessment (XSFMA-F/B). Longitudinal trajectories were clustered by factor analysis. Logistical regression analyses were applied to patient characteristics potentially determining cluster allocation. Responsiveness, floor and ceiling effects and concurrent validity were assessed within clusters. RESULTS: One hundred fifty-nine patients completed 24 months of follow-up, presenting overall low PCS scores. Two distinct sub-cohorts were identified, exhibiting complete recovery or persistent impairment. A third sub-cohort could not be classified into either trajectory. Age, education level and number of co-morbidities were independent determinants of poor recovery (AUROC 0.743 ((95%CI 0.659-0.826), p < 0.001). Those with complete recovery trajectories demonstrated high levels of ceiling effects in physical function (PF) (15%), role physical (RP) (45%) and body pain (BP) (57%) domains of the SF-36. Those with persistent impairment demonstrated high levels of floor effects in the same domains: PF (21%), RP (71%) and BP (12%). The PF domain demonstrated high responsiveness between ICU discharge and at 6 months and was predictive of a persistent impairment trajectory (AUROC 0.859 (95%CI 0.804-0.914), p < 0.001). CONCLUSIONS: Within sepsis survivors, two distinct recovery trajectories of physical recovery were demonstrated. Older patients with more co-morbidities and lower educational achievements were more likely to have a persistent physical impairment trajectory. In regard to trajectory prediction, the PF score of the SF-36 was more responsive than the PCS and could be considered for primary outcomes. Future trials should consider adaptive trial designs that can deal with non-responders or sub-cohort specific outcome measures more effectively.

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.

Effect of Intermittent or Continuous Feed on Muscle Wasting in Critical Illness: A Phase 2 Clinical Trial.

BACKGROUND: Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. RESEARCH QUESTION: Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? STUDY DESIGN AND METHODS: In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. RESULTS: Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 µM [44-98 µM]; P = .547) and trial day 10 (239 µM [33-444 µM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups. INTERPRETATION: Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov.

Repetitive vascular occlusion stimulus (RVOS) versus standard care to prevent muscle wasting in critically ill patients (ROSProx):a study protocol for a pilot randomised controlled trial.

BACKGROUND: Forty per cent of critically ill patients are affected by intensive care unit-acquired weakness (ICU-AW), to which skeletal muscle wasting makes a substantial contribution. This can impair outcomes in hospital, and can cause long-term physical disability after hospital discharge. No effective mitigating strategies have yet been identified. Application of a repetitive vascular occlusion stimulus (RVOS) a limb pressure cuff inducing brief repeated cycles of ischaemia and reperfusion, can limit disuse muscle atrophy in both healthy controls and bed-bound patients recovering from knee surgery. We wish to determine whether RVOS might be effective in mitigating against muscle wasting in the ICU. Given that RVOS can also improve vascular function in healthy controls, we also wish to assess such effects in the critically ill. We here describe a pilot study to assess whether RVOS application is safe, tolerable, feasible and acceptable for ICU patients. METHODS: This is a randomised interventional feasibility trial. Thirty-two ventilated adult ICU patients with multiorgan failure will be recruited within 48 h of admission and randomised to either the intervention arm or the control arm. Intervention participants will receive RVOS twice daily (except only once on day 1) for up to 10 days or until ICU discharge. Serious adverse events and tolerability (pain score) will be recorded; feasibility of trial procedures will be assessed against pre-specified criteria and acceptability by semi-structured interview. Together with vascular function, muscle mass and quality will be assessed using ultrasound and measures of physical function at baseline, on days 6 and 11 of study enrolment, and at ICU and hospital discharge. Blood and urine biomarkers of muscle metabolism, vascular function, inflammation and DNA damage/repair mechanism will also be analysed. The Health questionnaire will be completed 3 months after hospital discharge. DISCUSSION: If this study demonstrates feasibility, the derived data will be used to inform the design (and sample size) of an appropriately-powered prospective trial to clarify whether RVOS can help preserve muscle mass/improve vascular function in critically ill patients. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN44340629. Registered on 26 October 2017.