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, −20.9% to −4.8%]; 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 compared with single organ failure by day 7 (−15.7% [95% CI, −19.1% to −12.4%] vs −3.0% [95% CI, −10.5% to 4.6%], P < .001), even by day 3 (−8.7% [95% CI, −13.7% to −3.6%] vs −1.8% [95% CI, −7.3% to 3.8%], 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

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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.

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IntroductionAcute skeletal muscle wasting is a major contributor to post critical illness physical impairment. However, the bone response remains uncharacterized. We prospectively investigated the early changes in bone mineral density (BMD) and fracture risk in critical illness.MethodsPatients were prospectively recruited ≤24 hours following intensive care unit (ICU) admission to a university teaching or a community hospital (August 2009 to April 2011). All were aged >18 years and expected to be intubated for >48 hours, spend >7 days in critical care and survive ICU admission. Forty-six patients were studied (55.3% male), with a mean age of 54.4 years (95% confidence interval (CI): 49.1 to 59.6) and an APACHE II score of 23.9 (95% CI: 22.4 to 25.5). Calcaneal dual X-ray absorptiometry (DXA) assessment of BMD was performed on day 1 and 10. Increase in fracture risk was calculated from the change in T-score.ResultsBMD did not change between day 1 and 10 in the cohort overall (0.434 (95% CI: 0.405 to 0.463) versus 0.425 g/cm2 (95% CI: 0.399 to 0.450), P = 0.58). Multivariable logistical regression revealed admission corrected calcium (odds ratio (OR): 1.980 (95% CI: 1.089 to 3.609), P = 0.026) and admission PaO2-to-FiO2 ratio (OR: 0.916 (95% CI: 0.833 to 0.998), P = 0.044) to be associated with >2% loss of BMD. Patients with acute respiratory distress syndrome had a greater loss in BMD than those without (−2.81% (95% CI: −5.73 to 0.118%), n = 34 versus 2.40% (95% CI: 0.204 to 4.586%), n = 12, P = 0.029). In the 34 patients with acute respiratory distress syndrome, fracture risk increased by 19.4% (95% CI: 13.9 to 25.0%).ConclusionsPatients with acute respiratory distress syndrome demonstrated early and rapid bone demineralisation with associated increase in fracture risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0892-y) contains supplementary material, which is available to authorized users.

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Neutrophilic inflammation plays an important role in inflammatory lung diseases but therapeutic targeting of neutrophil (PMN) persistence is lacking. PMN lifespan and function is regulated by hypoxia, a characteristic feature of inflamed tissues, via the HIF/VHL/ hydroxylase pathway, specifically hypoxia inducible factor-1α (HIF-1α) and prolyl hydroxylase-3 (PHD3). Targeting HIF-1α in myeloid cells impaired immune function, but PHD3 regulated PMN lifespan without affecting function. Given that PHD3 preferentially regulates HIF-2α, we investigated the role of HIF-2α in PMNmediated inflammation.Peripheral blood PMNs isolated from healthy volunteers and mice expressed HIF-2α and expression was enhanced by heat-killed bacteria. Using PMNs isolated from patients with active inflammatory arthritis (IA) we demonstrated significant upregulation of HIF2A mRNA (IA 92.9±30.3 vs. control 4.3±0.9 AU relative to ACTB, P<0.05) and protein (IA 0.26±0.05 vs. control 0.01±0.01 OD relative to P38, P<0.01) in circulating inflammatory PMNs. PMNs recruited to the airways of patients with COPD also displayed strong HIF-2α staining. The consequences of HIF-2α upregulation were examined using human PMNs from patients with gain-of-function mutations in the HIF2A gene. Neutrophils isolated from these patients had reduced rates of constitutive apoptosis. Recapitulation of the human HIF2A mutations in the orthologous HIF2A gene, epas1a, in zebrafish delayed resolution of inflammation in a tail injury model (24 hrs post injury, epas1a 12.7±1.4 vs. ctrl 5.2±0.5 PMNs, p<0.001) with an associated reduction in PMN apoptosis (epas1a 1.0% vs. ctrl 1.6%, p<0.05). Mice with myeloidspecific deletion of Hif2a had normal PMN survival in response to hypoxia and the cells showed no functional defect in vitro. Importantly, in a PMN-mediated acute lung injury model, myeloid-specific deficiency of HIF-2α markedly enhanced resolution of inflammation (BAL PMN count 48 hours following nebulised LPS, WT 2.13×10 6 ±0.08 vs. KO 1.39×10 6 ±0.24, p<0.05) and reduced lung injury (BAL IgM at 48 hours, WT 211±22.8 vs. KO 74.7±27.2 ng/ ml), implicating HIF-2α in PMN persistence in inflamed lung tissue.These data support a critical and selective role for HIF-2α in the resolution of inflammation through the maintenance of PMN survival, and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.