Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired ...weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.
Stays in intensive care units are commonly accompanied by muscle weakness. This article reviews the basis for these changes and provides guidance on how to prevent, diagnose, and treat this ...condition.
Weakness acquired in the intensive care unit (ICU) is caused by many different pathophysiological mechanisms that are not mutually exclusive. This is not surprising, given the diverse diseases that precipitate critical illness, the drugs used during its management, and the consequences of protracted immobility. Nonetheless, conceptualization of this entity is valuable, since weakness in survivors of critical illness is common and is associated with long-standing consequences that dramatically affect recovery. Moreover, as survival rates among patients in the ICU increase, ICU-acquired weakness will have increasing relevance for care providers outside the ICU. This article provides an overview of the condition . . .
OBJECTIVES:To longitudinally evaluate the association of post-ICU muscle weakness and associated trajectories of weakness over time with 5-year survival.
DESIGN:Longitudinal prospective cohort study ...over 5 years of follow-up.
SETTING:Thirteen ICUs in four hospitals in Baltimore, MD.
PATIENTS:One hundred fifty-six acute respiratory distress syndrome survivors.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Strength was evaluated with standardized manual muscle testing using the Medical Research Council sum score (range, 0–60; higher is better), with post-ICU weakness defined as sum score less than 48. Muscle strength was assessed at hospital discharge and at 3, 6, 12, 24, 36, and 48 months after acute respiratory distress syndrome. At discharge, 38% of patients had muscle weakness. Every one point increase in sum score at discharge was associated with improved survival (hazard ratio 95% CI, 0.96 0.94–0.98), with similar findings longitudinally (0.95 0.93–0.98). Having weakness at discharge was associated with worse 5-year survival (1.75 1.01–3.03), but the association was attenuated (1.54 0.82–2.89) when evaluated longitudinally over follow-up. Persisting and resolving trajectories of muscle weakness, occurring in 50% of patients during follow-up, were associated with worse survival (3.01 1.12-8.04; and 3.14 1.40-7.03, respectively) compared to a trajectory of maintaining no muscle weakness.
CONCLUSIONS:At hospital discharge, greater than one third of acute respiratory distress syndrome survivors had muscle weakness. Greater strength at discharge and throughout follow-up was associated with improved 5-year survival. In patients with post-ICU weakness, both persisting and resolving trajectories were commonly experienced and associated with worse survival during follow-up.
Patients with chronic kidney disease experience substantial loss of muscle mass, weakness, and poor physical performance. As kidney disease progresses, skeletal muscle dysfunction forms a common ...pathway for mobility limitation, loss of functional independence, and vulnerability to disease complications. Screening for those at high risk for mobility disability by self-reported and objective measures of function is an essential first step in developing an interdisciplinary approach to treatment that includes rehabilitative therapies and counseling on physical activity. Exercise has beneficial effects on systemic inflammation, muscle, and physical performance in chronic kidney disease. Kidney health providers need to identify patient and care delivery barriers to exercise in order to effectively counsel patients on physical activity. A thorough medical evaluation and assessment of baseline function using self-reported and objective function assessment is essential to guide an effective individualized exercise prescription to prevent function decline in persons with kidney disease. This review focuses on the impact of kidney disease on skeletal muscle dysfunction in the context of the disablement process and reviews screening and treatment strategies that kidney health professionals can use in clinical practice to prevent functional decline and disability.
Coenzyme Q biosynthesis in health and disease Acosta, Manuel Jesús; Vazquez Fonseca, Luis; Desbats, Maria Andrea ...
Biochimica et biophysica acta,
August 2016, 2016-Aug, 2016-08-00, Letnik:
1857, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is ...also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant.
CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7.
Mutations in human COQ genes cause primary CoQ10 deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy.
The pathogenesis of CoQ10 deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ10 function are implicated.
CoQ10 deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ10 supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–6, 2016’, edited by Prof. Paolo Bernardi.
•Coenzyme Q is an essential component of the mitochondrial respiratory chain and an antioxidant.•Its biosynthesis requires a set of at least 12 proteins encoded by COQ genes.•These proteins form a complex localized to the inner mitochondrial membrane.•Mutations in COQ genes cause primary CoQ10 deficiency.•Many patients with CoQ10 deficiency respond to oral CoQ10 supplementation.
Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes.
To determine acute outcomes, 1-year ...mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge.
Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis.
A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio HR, 0.709 0.549-0.888; P = 0.009), live ICU (HR, 0.698 0.553-0.861; P = 0.008) and hospital discharge (HR, 0.680 0.514-0.871; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001).
After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).
We present areas of uncertainty concerning intensive care unit-acquired weakness (ICUAW) and identify areas for future research. Age, pre-ICU functional and cognitive state, concurrent illness, ...frailty, and health trajectories impact outcomes and should be assessed to stratify patients. In the ICU, early assessment of limb and diaphragm muscle strength and function using nonvolitional tests may be useful, but comparison with established methods of global and specific muscle strength and physical function and determination of their reliability and normal values would be important to advance these techniques. Serial measurements of limb and respiratory muscle strength, and systematic screening for dysphagia, would be helpful to clarify if and how weakness of these muscle groups is independently associated with outcome. ICUAW, delirium, and sedatives and analgesics may interact with each other, amplifying the effects of each individual factor. Reduced mobility in patients with hypoactive delirium needs investigations into dysfunction of central and peripheral nervous system motor pathways. Interventional nutritional studies should include muscle mass, strength, and physical function as outcomes, and prioritize elucidation of mechanisms. At follow-up, ICU survivors may suffer from prolonged muscle weakness and wasting and other physical impairments, as well as fatigue without demonstrable weakness on examination. Further studies should evaluate the prevalence and severity of fatigue in ICU survivors and define its association with psychiatric disorders, pain, cognitive impairment, and axonal loss. Finally, methodological issues, including accounting for baseline status, handling of missing data, and inclusion of patient-centered outcome measures should be addressed in future studies.
Both limb muscle weakness and respiratory muscle weakness are exceedingly common in critically ill patients. Respiratory muscle weakness prolongs ventilator dependence, predisposing to nosocomial ...complications and death. Limb muscle weakness persists for months after discharge from intensive care and results in poor long-term functional status and quality of life. Major mechanisms of muscle injury include critical illness polymyoneuropathy, sepsis, pharmacologic exposures, metabolic derangements, and excessive muscle loading and unloading. The diaphragm may become weak because of excessive unloading (leading to atrophy) or because of excessive loading (either concentric or eccentric) owing to insufficient ventilator assistance.
Sarcopenia and muscle weakness are responsible for considerable health care expenditure but little is known about these costs in the UK. To address this, we estimated the excess economic burden for ...individuals with muscle weakness regarding the provision of health and social care among 442 men and women (aged 71–80 years) who participated in the Hertfordshire Cohort Study (UK). Muscle weakness, characterised by low grip strength, was defined according to the Foundation for the National Institutes of Health criteria (men < 26 kg, women < 16 kg). Costs associated with primary care consultations and visits, outpatient and inpatient secondary care, medications, and formal (paid) as well as informal care for each participant were calculated. Mean total costs per person and their corresponding components were compared between groups with and without muscle weakness. Prevalence of muscle weakness in the sample was 11%. Mean total annual costs for participants with muscle weakness were £4592 (CI £2962–£6221), with informal care, inpatient secondary care and primary care accounting for the majority of total costs (38%, 23% and 19%, respectively). For participants without muscle weakness, total annual costs were £1885 (CI £1542–£2228) and their three highest cost categories were informal care (26%), primary care (23%) and formal care (20%). Total excess costs associated with muscle weakness were £2707 per person per year, with informal care costs accounting for 46% of this difference. This results in an estimated annual excess cost in the UK of £2.5 billion.
Objectives
To compare the relative predictive power of handgrip and leg extension strength in predicting slow walking.
Design
Report of correlative analysis from two epidemiological cohort studies.
...Setting
Foundation of the National Institutes of Health Sarcopenia Project.
Participants
Men and women aged 67 to 93 (N = 6,766).
Measurements
Leg strength, handgrip strength, and gait speed were measured. Strength cutpoints associated with slow gait speed were developed using classification and regression tree analyses and compared using ordinary least squares regression models.
Results
The cutpoints of lower extremity strength associated with slow gait speed were 154.6 N‐m in men and 89.9 N‐m in women for isometric leg extension strength and 94.5 N‐m in men and 62.3 N‐m in women for isokinetic leg extension strength. Weakness defined according to handgrip strength (odds ratios (OR) = 1.99 to 4.33, c‐statistics = 0.53 to 0.67) or leg strength (ORs = 2.52 to 5.77; c‐statistics = 0.61 to 0.66) was strongly related to odds of slow gait speed. Lower extremity strength contributed 1% to 16% of the variance and handgrip strength contributed 3% to 17% of the variance in the prediction of gait speed depending on sex and mode of strength assessment.
Conclusion
Muscle weakness of the leg extensors and forearm flexors is related to slow gait speed. Leg extension strength is only a slightly better predictor of slow gait speed. Thus, handgrip and leg extension strength appear to be suitable for screening for muscle weakness in older adults.
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