Prolonged immobility is harmful with rapid reductions in muscle mass, bone mineral density and impairment in other body systems evident within the first week of bed rest which is further exacerbated ...in individuals with critical illness. Our understanding of the aetiology and secondary consequences of prolonged immobilization in the critically ill is improving with recent and ongoing research to establish the cause, effect, and best treatment options. This review aims to describe the current literature on bed rest models for examining immobilization-induced changes in the musculoskeletal system and pathophysiology of immobilisation in critical illness including examination of intracellular signalling processes involved. Finally, the review examines the current barriers to early activity and mobilization and potential rehabilitation strategies, which are being, investigated which may reverse the effects of prolonged bed rest. Addressing the deleterious effects of immobilization is a major step in treatment and prevention of the public health issue, that is, critical illness survivorship.
OBJECTIVES:A rapid and early loss of skeletal muscle mass underlies the physical disability common amongst survivors of critical illness. However, skeletal muscle function depends not only on its ...quantity but its quality, which may be adversely affected. We set out to characterise the changes in macroscopic muscle echogenicity and fascial characteristics that occur early in critical illness, and to relate these to microscopic histologically defined myofibre necrosis and fascial pathology.
DESIGN AND SETTING:Prospective two center observational study.
PATIENTS:Thirty subjects comprising a subgroup of patients recruited to the Musculoskeletal Ultrasound in Critical IllnessLongitudinal Evaluation (MUSCLE) study.
MEASUREMENTS AND MAIN RESULTS:Comparisons were made between sequential Vastus Lateralis histological specimens and ultrasound assessment of Rectus Femoris echogenicity. Change in muscle echogenicity was greater in patients who developed muscle necrosis (n = 15) than in those who did not (8.2% 95% CI, –5.3 to 21.7 vs –15.0% 95% CI, –28.9 to –1.09; p = 0.016). The area under receiver operator curve for ultrasound echogenicity’s prediction of myofiber necrosis was 0.74 (95% CI, 0.565 to 0.919; p = 0.024) increasing to 0.85 (95% CI, 0.703 to –0.995; p = 0.003) with the removal of those with potential iatrogenic muscle damage. Fasciitis was observed in 18 of 30 biopsies (60%).
CONCLUSIONS:Myofiber necrosis and fascial inflammation can be detected noninvasively using ultrasound in the critically ill. Fasciitis precedes and frequently accompanies muscle necrosis. These findings may have functional implications for survivors of critical illness.
Increasing numbers of patients are both being admitted to intensive care and surviving critical illness. As mortality from critical illness decreases, survivorship has become a major public health ...issue. In survivors, return-to-work rates are low, and older patients and those with preceding poor functional state need an increased level of care, resulting in care facility and rehabilitation discharges. In a single-center randomized control trial of 104 patients, a multimodal intervention of physical and occupational therapy initiated at 1.5 versus 7.4 days postintubation resulted in a higher return to functional independence in the intervention group. Subsequent multicenter trials of physical rehabilitation are yet to reproduce such results. The PRaCTICaL (Pragmatic Randomised, Controlled Trial of Intensive Care Postdischarge Review Clinics in Improving Longer-term Outcomes from Critical Illness) study from the United Kingdom showed no difference in health-related quality of life at 12 months, and a 12-center Australian study of post-intensive care unit (ICU) rehabilitation did not demonstrate a recovery effect from exercise intervention. More recently, a single-center study of intensive rehabilitation from intensive care through to outpatient classes published a further negative result. 18 references
ObjectivesTo characterise the sketetal muscle metabolic phenotype during early critical illness.MethodsVastus 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 resultsFrom 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.ConclusionsDecreased 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.
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.
IMPORTANCE Survivors of critical illness demonstrate skeletal muscle wasting with associated functional
impairment. OBJECTIVE To perform a comprehensive prospective characterization of skeletal ...muscle wasting, defining the
pathogenic roles of altered protein synthesis and breakdown. DESIGN, SETTING, AND PARTICIPANTS Sixty-three critically ill patients (59% male; mean age: 54.7 years 95% CI, 50.0-59.6 years)
with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were
prospectively recruited within 24 hours following intensive care unit (ICU) admission from August
2009 to April 2011 at a university teaching and a community hospital in England. Patients were
recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to
spend more than 7 days in critical care, and to survive ICU stay. MAIN OUTCOMES AND MEASURES Muscle loss was determined through serial ultrasound measurement of the rectus femoris
cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was
quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was
performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways
were characterized. RESULTS There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% 95%
CI, −25.9% to 8.1%; P < .001). In the 28 patients assessed by
all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1%
to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5%
(95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced
multiorgan failure by day 7 (−15.7%; 95% CI, −27.7% to 11.4%) compared with single organ
failure (−3.0%; 95% CI, −5.3% to 2.1%) (P < .001), even
by day 3 (−8.7% 95% CI, −59.3% to 50.6% vs −1.8% 95% CI, −12.3% to
10.5%, respectively; P = .03). Myofiber necrosis occurred in 20 of 37
patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was
depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates
observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour)
(P = .57) and increased by day 7 (0.076% 95% CI, 0.032%-0.120%/hour;
P = .03) to rates associated with fed controls (0.065%/hour 95% CI,
0.049% to 0.080%/hour; P = .30), independent of nutritional load. Leg
protein breakdown remained elevated throughout the study (8.5 95% CI, 4.7 to 12.3 to 10.6 95% CI,
6.8 to 14.4 μmol of phenylalanine/min/ideal body weight × 100;
P = .40). The pattern of intracellular signaling supported increased
breakdown (n = 9, r = −0.83,
P = .005) and decreased synthesis (n = 9,
r = −0.69, P = .04). CONCLUSIONS AND RELEVANCE Among these critically ill patients, muscle wasting occurred early and rapidly during the first
week of critical illness and was more severe among those with multiorgan failure compared with
single organ failure. These findings may provide insights into skeletal muscle wasting in critical
illness.
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.
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.
figure legend Schematic diagram depicting how Akt and FOXO signalling may form part of a common signalling pathway influencing muscle protein breakdown, protein synthesis and the induction of insulin resistance under conditions of heightened inflammatory burden (see text for abbreviations).
Abstract
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.
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