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.

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.

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.

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.

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.

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.

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.

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.

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.

The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end-points.

Loss of muscle mass and insulin sensitivity are common phenotypic traits of immobilisation and increased inflammatory burden. The suppression of muscle protein synthesis is the primary driver of muscle mass loss in human immobilisation, and includes blunting of post-prandial increases in muscle protein synthesis. However, the mechanistic drivers of this suppression are unresolved. Immobilisation also induces limb insulin resistance in humans, which appears to be attributable to the reduction in muscle contraction per se. Again mechanistic insight is missing such that we do not know how muscle senses its "inactivity status" or whether the proposed drivers of muscle insulin resistance are simply arising as a consequence of immobilisation. A heightened inflammatory state is associated with major and rapid changes in muscle protein turnover and mass, and dampened insulin-stimulated glucose disposal and oxidation in both rodents and humans. A limited amount of research has attempted to elucidate molecular regulators of muscle mass loss and insulin resistance during increased inflammatory burden, but rarely concurrently. Nevertheless, there is evidence that Akt (protein kinase B) signalling and FOXO transcription factors form part of a common signalling pathway in this scenario, such that molecular cross-talk between atrophy and insulin signalling during heightened inflammation is believed to be possible. To conclude, whilst muscle mass loss and insulin resistance are common end-points of immobilisation and increased inflammatory burden, a lack of understanding of the mechanisms responsible for these traits exists such that a substantial gap in understanding of the pathophysiology in humans endures.

Socioeconomic Position and Health Outcomes Following Critical Illness: A Systematic Review.

OBJECTIVES: Systematically review evidence examining association between preadmission socioeconomic position and physical function, health-related quality of life and survival following critical illness. DATA SOURCES: Four electronic databases (MEDLINE, Embase, CINAHL, CENTRAL) and personal libraries were searched. Reference lists of eligible articles were cross-checked. STUDY SELECTION: Primary quantitative studies reporting association between socioeconomic position and physical function, health-related quality of life, or survival of adults admitted to the ICU were included. DATA EXTRACTION: Performed by two reviewers independently in duplicate using a prepiloted data extraction form. Quality appraisal was completed by two reviewers independently in duplicate using standardized algorithms and checklists. The Preferred Reporting Items for Systematic Reviews guidelines were followed. DATA SYNTHESIS: From 1,799 records, 10 studies were included, one examining association of socioeconomic position with health-related quality of life and five with survival. Four studies accounted for socioeconomic position in survival analyses. Patients with lower socioeconomic position were found to have higher ICU, in-hospital, 30-day, and long-term mortality and lower 6-month Short Form-12 Mental Component Summary scores. No articles examined socioeconomic position and performance-based physical function. Notable variability in methods of socioeconomic position assessment was observed. CONCLUSIONS: Lower socioeconomic position is associated with higher mortality and lower 6-month Short Form-12 Mental Component Summary scores following critical illness. Effect on performance-based physical function is unknown. We make recommendations for consistent socioeconomic position measurement in future ICU studies.

Body Composition and Acquired Functional Impairment in Survivors of Pediatric Critical Illness.

OBJECTIVES: To identify whether body mass and composition is associated with acquired functional impairment in PICU survivors. DESIGN: Retrospective dual-cohort study. SETTING: Single multidisciplinary PICU. PATIENTS: Two distinct PICU survivor cohorts: 432 unselected admissions from April 2015 to March 2016, and separately 92 patients with abdominal CT imaging at admission from January 2010 to December 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Admission body mass index and Functional Status Scale scores at admission, PICU discharge, and hospital discharge were obtained for all patients. Acquired functional impairment was defined as increase greater than or equal to 3 in Functional Status Scale from baseline. Patients were classified as having: "temporary acquired impairment" (acquired impairment at PICU discharge recovering by hospital discharge), "persistent acquired impairment" (acquired impairment at PICU discharge persisting to hospital discharge), and "no acquired impairment." CT scans were analyzed for skeletal muscle and fat area using National Institute of Health ImageJ software (Bethesda, MD). Multinomial logistic regression analyses were conducted to identify associations between body mass index, muscle and fat indices, and acquired functional impairment. High baseline body mass index was consistently predictive of persistent acquired impairment in both cohorts. In the second cohort, when body mass index was replaced with radiologic anthropometric measurements, greater skeletal muscle, and visceral adipose tissue indices were independently associated with persistent acquired impairment at hospital discharge (adjusted odds ratio, 1.29; 95% CI, 1.03-1.61; p = 0.024 and adjusted odds ratio, 1.13; 95% CI, 1.01-1.28; p = 0.042, respectively). However, this relationship was no longer significant in children with PICU stay greater than 2 days. CONCLUSIONS: In PICU survivors, baseline body mass and composition may play a role in the persistence of acquired functional impairment at hospital discharge. Characterization and quantification of skeletal muscle and fat deserves further study in larger cohorts of PICU children.

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.

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.

Sepsis Reduces Bone Strength Before Morphologic Changes Are Identifiable.

OBJECTIVES: Survivors of critical illness have an increased prevalence of bone fractures. However, early changes in bone strength, and their relationship to structural changes, have not been described. We aimed to characterize early changes in bone functional properties in critical illness and their relationship to changes in bone structure, using a sepsis rodent model. DESIGN: Experimental study. SETTING: Animal research laboratory. SUBJECTS: Adult Sprague-Dawley rats. INTERVENTIONS: Forty Sprague-Dawley rats were randomized to cecal ligation and puncture or sham surgery. Twenty rodents (10 cecal ligation and puncture, 10 sham) were killed at 24 hours, and 20 more at 96 hours. MEASUREMENTS AND MAIN RESULTS: Femoral bones were harvested for strength testing, microCT imaging, histologic analysis, and multifrequency scanning probe microscopy. Fracture loads at the femoral neck were significantly reduced for cecal ligation and puncture-exposed rodents at 24 hours (83.39 ± 10.1 vs 103.1 ± 17.6 N; p = 0.014) and 96 hours (81.60 ± 14.2 vs 95.66 ± 14.3 N; p = 0.047). Using multifrequency scanning probe microscopy, collagen elastic modulus was lower in cecal ligation and puncture-exposed rats at 24 hours (1.37 ± 0.2 vs 6.13 ± 0.3 GPa; p = 0.001) and 96 hours (5.57 ± 0.5 vs 6.13 ± 0.3 GPa; p = 0.006). Bone mineral elastic modulus was similar at 24 hours but reduced in cecal ligation and puncture-exposed rodents at 96 hours (75.34 ± 13.2 vs 134.4 ± 8.2 GPa; p < 0.001). There were no bone architectural or bone mineral density differences by microCT. Similarly, histologic analysis demonstrated no difference in collagen and elastin staining, and C-X-C chemokine receptor type 4, nuclear factor kappa beta, and tartrate-resistant acid phosphatase immunostaining. CONCLUSIONS: In a rodent sepsis model, trabecular bone strength is functionally reduced within 24 hours and is associated with a reduction in collagen and mineral elastic modulus. This is likely to be the result of altered biomechanical properties, rather than increased bone mineral turnover. These data offer both mechanistic insights and may potentially guide development of therapeutic interventions.

An Exploratory Study of Long-Term Outcome Measures in Critical Illness Survivors: Construct Validity of Physical Activity, Frailty, and Health-Related Quality of Life Measures.

OBJECTIVE: Functional capacity is commonly impaired after critical illness. We sought to clarify the relationship between objective measures of physical activity, self-reported measures of health-related quality of life, and clinician reported global functioning capacity (frailty) in such patients, as well as the impact of prior chronic disease status on these functional outcomes. DESIGN: Prospective outcome study of critical illness survivors. SETTING: Community-based follow-up. PATIENTS: Participants of the Musculoskeletal Ultrasound Study in Critical Care: Longitudinal Evaluation Study (NCT01106300), invasively ventilated for more than 48 hours and on the ICU greater than 7 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Physical activity levels (health-related quality of life [36-item short-form health survey] and daily step counts [accelerometry]) were compared to norm-based or healthy control scores, respectively. Controls for frailty (Clinical Frailty Score) were non-morbid, age- and gender-matched to survivors. Ninety-one patients were recruited on ICU admission: 41 were contacted for post-discharge assessment, and data were collected from 30 (14 female; mean age, 55.3 yr [95% CI, 48.3-62.3]; mean post-discharge, 576 d [95% CI, 539-614]). Patients' mean daily step count (5,803; 95% CI, 4,792-6,813) was lower than that in controls (11,735; 95% CI, 10,928-12,542; p < 0.001), and lower in those with preexisting chronic disease than without (2,989 [95% CI, 776-5,201] vs 7,737 [95% CI, 4,907-10,567]; p = 0.013). Physical activity measures (accelerometry, health-related quality of life, and frailty) demonstrated good construct validity across all three tools. Step variability (from SD) was highly correlated with daily steps (r = 0.67; p < 0.01) demonstrating a potential boundary constraint. CONCLUSIONS: Subjective and objective measures of physical activity are all informative in ICU survivors. They are all reduced 18 months post-discharge in ICU survivors, and worse in those with pre-admission chronic disease states. Investigating interventions to improve functional capacity in ICU survivors will require stratification based on the presence of premorbidity.

Functional Outcomes and Physical Impairments in Pediatric Critical Care Survivors: A Scoping Review.

OBJECTIVE: Although more children are surviving critical illness, little is known about long-term physical impairment. This scoping review aims to critically appraise existing literature on functional outcome measurement tools, prevalence, and risk factors for physical impairments in pediatric critical care survivors. DATA SOURCES: PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature, using a combination of MeSH terms and keywords (critical illness, intensive care, and functional outcomes/status). STUDY SELECTION: All human studies reporting functional outcomes in children 0-18 years old admitted to the PICU. Non-English language, adult and preterm infant studies were excluded. DATA SYNTHESIS: Three global assessment tools and eight multidimensional measures were used to measure functional outcome in pediatric survivors of critical illness. Rates of acquired functional impairment in a general pediatric intensive care cohort ranged from 10% to 36% at discharge and 10% to 13% after more than 2 years. Risk factors for acquired functional impairment include illness severity, the presence of organ dysfunction, length of ICU stay, and younger age. There is some evidence that physical impairment may be more severe and persistent than psychosocial components. CONCLUSIONS: Functional impairment may be persistent in pediatric survivors of critical care. Unfortunately, studies varied largely in measurement timing and tools used. The lack of differentiation between impairment in different functional domains limited the generalizability of data. Further studies using a combination of standardized measures at various time points of the disease process can help establish more comprehensive rates of physical impairment.