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.
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.
Non-invasive respiratory support (NIRS) has increasingly been used in the management of COVID-19-associated acute respiratory failure, but questions remain about the utility, safety, and outcome ...benefit of NIRS strategies. We identified two randomised controlled trials and 83 observational studies, compromising 13 931 patients, that examined the effects of NIRS modalities-high-flow nasal oxygen, continuous positive airway pressure, and bilevel positive airway pressure-on patients with COVID-19. Of 5120 patients who were candidates for full treatment escalation, 1880 (37%) progressed to invasive mechanical ventilation and 3658 of 4669 (78%) survived to study end. Survival was 30% among the 1050 patients for whom NIRS was the stated ceiling of treatment. The two randomised controlled trials indicate superiority of non-invasive ventilation over high-flow nasal oxygen in reducing the need for intubation. Reported complication rates were low. Overall, the studies indicate that NIRS in patients with COVID-19 is safe, improves resource utilisation, and might be associated with better outcomes. To guide clinical decision making, prospective, randomised studies are needed to address timing of intervention, optimal use of NIRS modalities-alone or in combination-and validation of tools such as oxygenation indices, response to a trial of NIRS, and inflammatory markers as predictors of treatment success.
Metabolic basis to Sherpa altitude adaptation Horscroft, James A.; Kotwica, Aleksandra O.; Laner, Verena ...
Proceedings of the National Academy of Sciences - PNAS,
06/2017, Volume:
114, Issue:
24
Journal Article
Peer reviewed
Open access
The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison ...to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.
By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and ...candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.
Atrial Fibrillation After Cardiac Surgery (AFACS) occurs in about one in three patients following Coronary Artery Bypass Grafting (CABG). It is associated with increased short- and long-term ...morbidity, mortality and costs. To reduce AFACS incidence, efforts are often made to maintain serum potassium in the high-normal range (≥ 4.5mEq/L). However, there is no evidence that this strategy is efficacious. Furthermore, the approach is costly, often unpleasant for patients, and risks causing harm. We describe the protocol of a planned randomized non-inferiority trial to investigate the impact of intervening to maintain serum potassium ≥ 3.6 mEq/L vs ≥ 4.5 mEq/L on incidence of new-onset AFACS after isolated elective CABG.
Patients undergoing isolated CABG at sites in the UK and Germany will be recruited, randomized 1:1 and stratified by site to protocols maintaining serum potassium at either ≥ 3.6 mEq/L or ≥ 4.5 mEq/L. Participants will not be blind to treatment allocation. The primary endpoint is AFACS, defined as an episode of atrial fibrillation, flutter or tachycardia lasting ≥ 30 seconds until hour 120 after surgery, which is both clinically detected and electrocardiographically confirmed. Assuming a 35% incidence of AFACS in the 'tight control group', and allowing for a 10% loss to follow-up, 1684 participants are required to provide 90% certainty that the upper limit of a one-sided 97.5% confidence interval (CI) will exclude a > 10% difference in favour of tight potassium control. Secondary endpoints include mortality, use of hospital resources and incidence of dysrhythmias not meeting the primary endpoint (detected using continuous heart rhythm monitoring).
The Tight K Trial will assess whether a protocol to maintain serum potassium ≥ 3.6 mEq/L is non inferior to maintaining serum potassium ≥ 4.5 mEq/L in preventing new-onset AFACS after isolated CABG.
ClinicalTrials.gov Identifier: NCT04053816. Registered on 13 August 2019. Last update 7 January 2021.
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.
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.
Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients?
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.
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.
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.
ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov.
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