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Management of COPD: surgical options.

Dyspnoea on exertion and exercise intolerance are the hallmarks of chronic obstructive pulmonary disease (COPD); the primary causes appear to be respectively, increased airway resistance with reduced maximal ventilatory capacity and peripheral skeletal muscle dysfunction with early onset of anaerobic metabolism. Patients with end-stage COPD usually show little or no benefit from conventional medical treatment. Physical training is capable of ameliorating exercise tolerance, but improvement is usually modest in the advanced disease state. Two surgical options are generally accepted for carefully selected patients with emphysema: resection of large bullae, when identified, and lung transplantation. Transplantation, the only effective cure for advanced COPD, is of limited use primarily because of age, comorbidity, limited availability of organs and cost. A different approach for severe emphysema, lung volume reduction surgery (LVRS), has been increasingly utilized during the past several years. In carefully selected emphysematous patients, LVRS improves lung volumes and mechanics, and reduces exertional dyspnoea. Unfortunately, surgical mortality still remains high and some patients show no measurable improvement after surgery. There is an urgent need for data on long-term effects of LVRS; the results of large, randomized trials will soon be forthcoming. The aim of this brief review is to summarize the available knowledge on the effects of LVRS, the criteria for patient selection, short- versus long-term effects and, finally, to propose future directions in this field.

Dyspnea↗

Alterations in contractility and intracellular Ca2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure.

To determine if chronic heart failure (CHF) leads to functional or structural alterations of skeletal muscle, we compared intracellular Ca2+ signaling, contractility, and the rate of fatigue development, together with electron microscopy (EM), in skeletal muscle preparations from rats with myocardial infarction-induced CHF versus sham-operated control rats. Bundles of 100 to 200 cells were dissected from the extensor digitorum longus (EDL) muscle of control (n = 13) and CHF (n = 19) rats and were either loaded with aequorin or fixed for EM. Muscles from CHF rats exhibited depressed tension development compared with control muscles during twitches (1.4 +/- 0.2 versus 2.8 +/- 0.7 g/mm2, P < .05) and maximal tetani (5.3 +/- 1.4 versus 10.7 +/- 2.4 g/mm2, P < .05). Depressed tension in CHF was accompanied by reduced quantitative [Ca2+]i release during twitches (0.7 +/- 0.1 versus 0.4 +/- 0.1 microM, P < .05) and during maximal tetani (1.8 +/- 0.3 versus 0.9 +/- 0.2 microM, P < .05). Skeletal muscle from CHF rats also demonstrated prolonged intracellular Ca2+ transients during twitches and tetani and accelerated fatigue development. EM revealed a lack of cellular atrophy in the CHF rats. In conclusion, EDL skeletal muscle from rats with CHF had intrinsic abnormalities in excitation-contraction coupling unrelated to cellular atrophy. These findings indicate that CHF is a condition accompanied by EDL skeletal muscle dysfunction.

Aequorin↗

Effects of dietary curcumin or N-acetylcysteine on NF-kappaB activity and contractile performance in ambulatory and unloaded murine soleus.

BACKGROUND: Unloading of skeletal muscle causes atrophy and loss of contractile function. In part, this response is believed to be mediated by the transcription factor nuclear factor-kappa B (NF-kappaB). Both curcumin, a component of the spice turmeric, and N-acetylcysteine (NAC), an antioxidant, inhibit activation of NF-kappaB by inflammatory stimuli, albeit by different mechanisms. In the present study, we tested the hypothesis that dietary curcumin or NAC supplementation would inhibit unloading-induced NF-kappaB activity in skeletal muscle and thereby protect muscles against loss of mass and function caused by prolonged unloading. METHODS: We used hindlimb suspension to unload the hindlimb muscles of adult mice. Animals had free access to drinking water or drinking water supplemented with 1% NAC and to standard laboratory diet or diet supplemented with 1% curcumin. For 11 days, half the animals in each dietary group were suspended by the tail (unloaded) and half were allowed to ambulate freely. RESULTS: Unloading caused a 51-53% loss of soleus muscle weight and cross-sectional area relative to freely-ambulating controls. Unloading also decreased total force and force per cross-sectional area developed by soleus. Curcumin supplementation decreased NF-kappaB activity measured in peripheral tissues of ambulatory mice by gel shift analysis. In unloaded animals, curcumin supplementation did not inhibit NF-kappaB activity or blunt the loss of muscle mass in soleus. In contrast, NAC prevented the increase in NF-kappaB activity induced by unloading but did not prevent losses of muscle mass or function. CONCLUSION: In conclusion, neither dietary curcumin nor dietary NAC prevents unloading-induced skeletal muscle dysfunction and atrophy, although dietary NAC does prevent unloading induced NF-kappaB activation.

Journal Article↗

Performance enhancement in chronic obstructive pulmonary disease.

BACKGROUND: Exercise limitation is a hallmark of chronic obstructive pulmonary disease (COPD) and is integral to the associated impaired health status of these patients. The poor exercise tolerance is multifactorial in origin, relating to airflow obstruction, disadvantageous lung mechanics, reduced oxygen delivery and skeletal muscle dysfunction. A number of interventions have been studied to determine whether they can impact on exercise performance. The most evidence-based of these is exercise training, which along with other approaches, both previously investigated and putative, are discussed in this review.

Exercise Therapy↗

Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in nonhypoxemic COPD patients.

STUDY OBJECTIVES: The slow oxygen uptake (VO(2)) kinetics observed in COPD patients is a manifestation of skeletal muscle dysfunction of multifactorial origin. We determined whether oxygen supplementation during exercise makes the dynamic VO(2) response faster and reduces transient lactate increase. DESIGN: Ten patients with severe COPD (ie, mean [+/- SD] FEV(1), 31 +/- 10% predicted) and 7 healthy subjects of similar age performed four repetitions of the transition between rest and 10 min of moderate-intensity, constant-work rate exercise while breathing air or 40% oxygen in random order. Minute ventilation (VE), gas exchange, and heart rate (HR) were recorded breath-by-breath, and arterialized venous pH, PCO(2), and lactate levels were measured serially. RESULTS: Compared to healthy subjects, the time constants (tau) for VO(2), HR, carbon dioxide output (VCO(2)), and VE kinetic responses were significantly slower in COPD patients than in healthy subjects (70 +/- 8 vs 44 +/- 3 s, 98 +/- 14 vs 44 +/- 8 s, 86 +/- 8 vs 61 +/- 4 s, and 81 +/- 7 vs 62 +/- 4 s, respectively; p < 0.05). Hyperoxia decreased end-exercise E in the COPD group but not the healthy group. Hyperoxia did not increase the speed of VO(2) kinetics but significantly slowed VCO(2) and E response dynamics in both groups. Only small increases in lactate occurred with exercise, and this increase did not correlate with the tau for VO(2). CONCLUSION: In nonhypoxemic COPD patients performing moderate exercise, the lower ventilatory requirement induced by oxygen supplementation is not related to improved muscle function but likely stems from direct chemoreceptor inhibition.

Aged↗

Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease.

An imbalance between oxidants and antioxidants is considered to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is considerable evidence that an increased oxidative burden occurs in the lungs of patients with this disorder, and this may be involved in many of the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases, and enhancing lung inflammation through activation of redox-sensitive transcription factors. COPD is now recognized to have multiple systemic consequences, such as weight loss and skeletal muscle dysfunction. Moreover, it is appreciated that oxidative stress extends beyond the lung and may, through similar oxidative stress mechanisms as those in the lung, contribute to several of the systemic manifestations in COPD.

Airway Obstruction↗

[Clinical and muscular evaluation in patients with subclinical hypothyroidism].

Some symptoms and signs of hypothyroidism, as well as some laboratory abnormalities, may be present in subclinical hypothyroidism (SH). This study evaluates the prevalence of signs and symptoms of hypothyroidism and skeletal muscle dysfunction in 57 patients with SH compared to 37 euthyroid controls. The participants received a clinical score based on signs and symptoms of hypothyroidism. The muscle strength was estimated by manual testing and chair dynamometer and inspiratory force by manuvacuometer. Thyroid hormones and muscle enzymes were measured. The SH group presented with higher score (p< 0.01), complained about myalgia and weakness more frequently (p< 0.05), and showed strength disability in scapular and pelvic girdles (p< 0.05). The median free T4 serum levels were lower in SH (p< 0.001). These findings suggest that signs and symptoms of thyroid dysfunction may be related to lower levels of FT4 in SH and should be taken into account in the decision of beginning LT4 therapy.

Adolescent↗

Cytokines in the pathogenesis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality. The term is heterogenous and encompasses a number of distinct but often overlapping phenotypes including chronic bronchitis, small airways obstruction, emphysema and in some individuals, a systemic component. Although there have been significant advances in understanding the pathophysiology of COPD, understanding of the role of the inflammation in the pathogenesis of the condition remains in its infancy. Indeed, cytokines that are known to orchestrate the inflammatory response in asthma and other inflammatory diseases are only beginning to be reported in COPD. In this review, we highlight the potential role of cytokines in the development of mucus hypersecretion observed in chronic bronchitis and the morphological changes observed in the small airways and airspaces contributing to the development of airflow limitation and respiratory failure respectively. We report evidence that exacerbations are linked to increased expression of pro-inflammatory cytokines and that the wasting and skeletal muscle dysfunction observed in some patients is most probably related to the presence of a systemic inflammatory response. In addition transgenic and gene therapy technology has been used to explore the temporal and co-ordinated role of cytokines in the development of COPD animal models. Enhanced understanding of the events involved in the pathogenesis of COPD will lead to the development of therapy with potential to modify the observed progressive decline in lung function and impact on the development of the illness.

Animals↗

The importance of exercise training in predialysis patients with chronic kidney disease.

Patients with chronic renal failure show a decline in maximal exercise capacity and muscle strength as renal function decreases. Renal anemia, skeletal muscle dysfunction, tiredness and increasing inactivity are the major causes of this deterioration in predialysis patients. Exercise training improves maximal exercise capacity, muscle strength and endurance in young, middle-aged and elderly predialysis patients. It has a positive effect on muscle catabolism and counteracts weight loss and malnutrition. Moreover, exercise training has positive effects on functional capacity and health-related quality of life. However, early referral to a nephrologist and multiprofessional teamwork in the care of predialysis patients is essential in order to implement comprehensive predialysis care and exercise training successfully.

Animals↗

Hypokalaemia.

OBJECTIVE: To review the metabolism and function of potassium and causes and management of hypokalaemia. DATA SOURCES: A review of studies reported from 1966 to 1998 and identified through a MEDLINE search of the English-language literature of hypokalaemia. SUMMARY OF REVIEW: Potassium is predominantly an intracellular ion that contributes to approximately 50% of the intracellular fluid osmolality and is largely responsible for the resting membrane potential. The latter accounts for its influence on the excitability of muscle and nervous tissue. Hypokalaemia is defined as a serum potassium of less than 3.5 mmol/L or plasma potassium less than 3.0 mmol/L and may be asymptomatic. Clinical features associated with hypokalaemia include abnormalities of cardiovascular, neurological and metabolic function and may be treated with oral potassium salts, although tachycardia and muscle weakness are the two life threatening disorders which may require rapid intravenous correction. The potassium salts of chloride, phosphate and acetate are often used, although the choice is often guided by the presence of an associated hypochloraemic alkalosis, non-anion gap acidosis or hypophosphataemia, indicating treatment with potassium chloride, potassium acetate, or potassium phosphate, respectively. The infusion rates of intravenous therapy depends upon the salt used. Potassium chloride is usually infused at a rate up to 40 mmol/h, whereas potassium acetate and potassium monohydrogen or dihydrogen phosphate are usually infused up to 5 mmol/h and 2 mmol/h respectively. CONCLUSIONS: Hypokalaemia can be asymptomatic or it may cause cardiovascular, neurological or skeletal muscle dysfunction. If intravenous potassium therapy is required, then correction with potassium chloride, acetate, or phosphate salts are usually guided by the presence of a metabolic acidosis, alkalosis or hypophosphataemia.

Journal Article↗

Muscle dysfunction during exercise of a single skeletal muscle in rats with congestive heart failure is not associated with reduced muscle blood supply.

AIM: Inadequate muscle blood flow is a possible explanation for reduced fatigue resistance in patients with congestive heart failure (CHF). METHODS: In rats with post-infarction CHF we electrically stimulated the soleus muscle (SOL) in situ with intact blood supply. Contractile properties, blood flow, high-energy phosphates and metabolites were measured during 30 min of intermittent stimulation, and in addition capillarization of SOL was recorded. RESULTS: During stimulation, SOL contracted more slowly in rats with CHF compared with sham-operated rats. However, the blood flow in SOL was unaltered and capillary density was maintained in CHF rats. Further, the content of ATP, ADP, AMP, NAD, CrP, P(i) and lactate in SOL was not different between the groups. CONCLUSION: The cause of contractile dysfunction in a single exercising skeletal muscle in rats with CHF cannot be explained simply by reduced blood supply. In addition, absence of changes in high-energy phosphates and metabolites indicate that the oxidative metabolism of SOL is intact in rats with CHF.

Animals↗

Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat.

Septic patients have low plasma ascorbate concentrations and compromised microvascular perfusion. The purpose of the present experiments was to determine whether ascorbate improves capillary function in volume-resuscitated sepsis. Cecal ligation and perforation (CLP) was performed on male Sprague-Dawley rats. The concentration of ascorbate in plasma and urine, mean arterial blood pressure, and density of continuously perfused capillaries in the extensor digitorum longus muscle were measured 24 h after surgery. CLP caused a 50% decrease (from 56 +/- 4 to 29 +/- 2 microM) in plasma ascorbate concentration, 1,000% increase (from 46 +/- 13 to 450 +/- 93 microM) in urine ascorbate concentration, 20% decrease (from 115 +/- 2 to 91 +/- 2 mmHg) in mean arterial pressure, and 30% decrease (from 24 +/- 1 to 17 +/- 1 capillaries/mm) in the density of perfused capillaries, compared with time-matched controls. A bolus of intravenous ascorbate (7.6 mg/100 g body wt) administered immediately after the CLP procedure increased plasma ascorbate concentration and restored both blood pressure and density of perfused capillaries to control levels. In vitro experiments showed that ascorbate (100 microM) inhibited replication of bacteria and prevented hydrogen peroxide injury to cultured microvascular endothelial cells. These results indicate that ascorbate is lost in the urine during sepsis and that a bolus of ascorbate can prevent microvascular dysfunction in the skeletal muscle of septic animals. Our study supports the view that ascorbate may be beneficial for patients with septic syndrome.

Animals↗

Microvascular dysfunction in postischemic skeletal muscle.

In recent years, considerable research efforts have been directed at elucidating the mechanisms underlying the pathophysiologic alterations associated with reperfusion (reoxygenation) of ischemic (hypoxic) skeletal muscle. This intensive effort has led to the accumulation of a large body of evidence supporting the concept that reactive oxygen metabolites, generated at the onset of reperfusion, initiate the formation and release of proinflammatory agents, which subsequently attract and activate granulocytes. The activated neutrophils adhere to the microvascular endothelium, extravasate, and release cytotoxic oxidants and hydrolytic enzymes. As a consequence of these pathologic events, vascular permeability and transcapillary fluid filtration are increased and the no-reflow phenomenon (ie, some capillaries fail to reperfuse upon reinstitution of blood flow) becomes apparent. These microvascular alterations may be of considerable functional importance since the marked accumulation of fluid in the interstitial spaces, coupled with the incomplete and maldistributed blood flow, increases the functional diffusion path length for nutrients. Thus cellular nutrition is limited during reperfusion, which in turn impairs the functional recovery of postischemic muscles. Moreover, the infiltrating neutrophils are able to direct a focussed attack on myocytes, thereby exacerbating contractile dysfunction and tissue injury during reperfusion. These observations indicate that alterations in the microcirculation play a critical role in the genesis of ischemia/reperfusion injury in skeletal muscle. This review summarizes the evidence we have accumulated in support of the view that reactive oxygen metabolites and neutrophils contribute to production of postischemic microvascular dysfunction and describes the experimental models we have used to examine the mechanisms involved in the pathogenesis of ischemia and reperfusion.

Animals↗

Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle dysfunction.

Ageing is associated with skeletal muscle atrophy, a deficit in force generation, an increased susceptibility to contraction-induced injury, and a permanent force deficit following severe injury. Muscles of young mice adapt rapidly following exercise by an increase in the production of heat shock proteins (HSPs), whereas muscles of old mice show a severely diminished response. We hypothesized that overexpression of HSP70 in muscle throughout life would reduce age-related changes in function. The maximum tetanic force of extensor digitorum longus (EDL) muscles of adult and old wild-type (WT) and HSP70 overexpressor transgenic mice was determined. EDL muscles were subjected to damaging lengthening contractions and the ability to generate force was assessed for up to 28 days following the contractions. Overexpression of HSP70 in muscles of old transgenic mice prevented the specific force deficit observed in muscles of old WT mice. The complete recovery of muscles of old HSP70 transgenic mice by 14 days following the contraction protocol was in contrast to the 44% force deficit, which remained in muscles of old WT mice at 28 days following the protocol. These data indicate that a diminished production of HSP70 in muscles of old mammals has a major effect on age-related functional deficits.

Aging↗

Thyroid status and endothelium-dependent vasodilation in skeletal muscle.

Cardiovascular dysfunction is characteristic of both hypo- and hyperthyroidism. Endothelium-dependent dilation of conductance vessels is impaired in hypothyroidism but augmented in hyperthyroidism. We hypothesized that these alterations in dilation extend into the resistance vasculature of skeletal muscle. To test this hypothesis, rats were made hypothyroid with propylthiouracil (Hypo; n = 13) or hyperthyroid with triiodothyronine (Hyper; n = 9) over 3-4 mo. Compared with euthyroid controls (Eut; n = 14), Hypo rats were characterized by reduced skeletal muscle oxidative capacity and blunted growth; Hyper rats exhibited increased muscle oxidative capacity and left ventricular hypertrophy (P < 0.05 for all effects). Vasodilation to the endothelium-dependent agent acetylcholine ( approximately 2 x 10(-4) M) in skeletal muscle was determined in situ. Conductance in certain muscles increased from control [e.g., soleus: 0.98 +/- 0.15 (Eut), 0.79 +/- 0.14 (Hypo), and 1.06 +/- 0.24 ml.min(-1).100 g(-1).mmHg(-1) (Hyper); not significant among groups] to acetylcholine [1.91 +/- 0.21 (Eut), 2.28 +/- 0.26 (Hypo), and 2.15 +/- 0.33 ml.min(-1).100 g(-1).mmHg(-1) (Hyper); P < 0.05 vs. control values for all groups] but did not differ among groups. Expression of mRNA for the endothelial isoform of nitric oxide synthase in resistance vessels isolated from various muscles was similarly unchanged with alterations in thyroid status [e.g., soleus 1A arterioles: 33.15 +/- 0.58 (Eut), 32.73 +/- 0.27 (Hypo), and 32.80 +/- 0.54 (Hyper) cycles at threshold; not significant]. These data suggest that endothelium-dependent dilation of resistance vasculature in skeletal muscle is unchanged in both hypo- and hyperthyroidism. These data also emphasize the importance of examining resistance vasculature to improve understanding of effects of chronic disease on integrated cardiovascular function.

Acetylcholine↗

Neutrophil-mediated microvascular dysfunction in postischemic canine skeletal muscle. Role of granulocyte adherence.

Recent studies implicate a role for granulocytes in the genesis of the microvascular and parenchymal cell dysfunction, which occurs upon reperfusion of ischemic tissues. Although the molecular mechanisms underlying this neutrophil-mediated injury are not completely understood, it is clear that an essential first step in granulocyte migration from the vascular lumen to the interstitial space is adherence to vascular endothelium. The purpose of this study was to determine whether prevention of neutrophil adherence with monoclonal antibody IB4 directed against the neutrophil CD11/CD18 glycoprotein adherence complex or neutrophil depletion with a specific polyclonal antineutrophil serum would attenuate the microvascular dysfunction seen in postischemic skeletal muscle. Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient for total plasma proteins (sigma) in isolated canine gracilis muscle subjected to ischemia/reperfusion, ischemia/reperfusion plus antineutrophil serum, or ischemia/reperfusion plus IB4. Estimates of sigma averaged 0.83 +/- 0.04 in nonischemic, control gracilis muscles, while ischemia/reperfusion was associated with a marked increase in vascular permeability (decrease in sigma to 0.54 +/- 0.04) and vascular resistance (increased by 135 +/- 41% over the control value). Prevention of neutrophil adherence or neutrophil depletion prevented this increase in vascular permeability (sigma = 0.80 +/- 0.03 and 1.01 +/- 0.06, respectively) and resistance (decrease of 16.51 +/- 8.0% and increase of 2.4 +/- 4.6% over control values, respectively). The results of this study suggest that neutrophils play a critical role in the genesis of microvascular dysfunction in postischemic skeletal muscle. Furthermore, neutrophil adherence to vascular endothelium appears to be a prerequisite for the production of this injury.

Animals↗

The effects of burn trauma on adenosine 3':5' cyclic monophosphate, inositol trisphosphate, and contraction in mouse gastrocnemius muscle.

This study examines the nature of skeletal muscle weakness (dysfunction) that is exhibited by patients who have incurred large-size body surface area burns (greater than 30%). It uses the mouse model of scald-burn injury in which groups of mice with varying burn sizes (i.e., 20%, 30%, and 50%) and time-matched controls were evaluated on postburn day 21. The primary purpose of this work was to evaluate secondary messenger cascades in gastrocnemius muscle relative to increasing burn size. Muscles that were distantly located to the actual site of burn injury were used for twitch analyses to measure active tension. The second messengers, adenosine 3':5' cyclic monophosphate (cAMP), inositol, 1,4,5-trisphosphate (IP3) and Ca2+, were measured with radioisotopes. The results of this study indicate that perturbations in the cAMP-IP3 cascade may be responsible for increasing myoplasmic Ca2+, which leads to dysfunction. The long-term goal of this work is to aid in the alleviation of chronic skeletal muscle dysfunction that leads to sustained debilitation and prolonged rehabilitation in patients with burns.

Animals↗

Importance of intrinsic calf vasodilator capacity in determining distribution of skeletal muscle perfusion during supine bicycle exercise in patients with left ventricular dysfunction.

BACKGROUND: Distribution of skeletal muscle perfusion during exercise is an important factor in determining exercise capacity and is markedly impaired in patients with cardiac disease. This study examined the importance of intrinsic calf vasodilator capacity in determining distribution of skeletal muscle perfusion during supine bicycle exercise in patients with left ventricular dysfunction. METHODS: We studied 19 patients with left ventricular dysfunction (left ventricular ejection fraction <45%) after myocardial infarction. All the patients underwent cardiopulmonary exercise testing with measurements of central hemodynamics, leg blood flow (LBF), and the percentage of cardiac output distributed to both legs (%LBF). Calf reactive hyperemic flow (RH) was measured by venous occlusive plethysmography at supine rest. RESULTS: LBF at peak exercise was closely related to peak cardiac output and RH. Furthermore, %LBF at peak exercise had modest correlation with peak cardiac output and good correlation with RH. Although peak cardiac output and RH were independent determinants of LBF at peak exercise by multiple regression analysis, RH had higher correlation with %LBF at peak exercise than peak cardiac output. Despite marked changes in other hemodynamic variables, nonleg blood flow during exercise was constantly maintained at a level identical to resting value. CONCLUSIONS: Calf vasodilator capacity, which was the major determinant of distribution of skeletal muscle perfusion during exercise, may have contributed to maintaining perfusion of important nonexercising regions during exercise in patients with left ventricular dysfunction.

Adult↗