Decline In Respiratory Function Research Articles

Outpatient management of chronic obstructive pulmonary disease.

The outpatient management of chronic obstructive pulmonary disease (COPD) is designed to limit the decline in respiratory function over time, to relieve the symptoms and improve the patient's functional status, and to manage complications when they arise. Factors that predispose to airway inflammation, including cigarette smoking and respiratory infections, are prevented by behavioral modification programs, measures such as exercise and nutrition to improve general health, and regular vaccination. Symptoms are relieved by bronchodilator and anti-inflammatory therapy, based upon the specific needs of the patient. Hypoxemia and acute infections are treated with oxygen administration and the use of antibiotics when necessary. The management of acute exacerbations of COPD is addressed elsewhere in this symposium (ie, choice of antibiotics is not discussed here). Also, certain aspects of management, such as surgical procedures, chest physical therapy, and other aspects of pulmonary rehabilitation, are also subjects of subsequent articles in this series. Although none of these modalities, except for smoking cessation and oxygen administration, have been shown to alter the course of COPD, the careful choice of the therapeutic measures discussed here can lead to significant relief of symptoms in the patient with chronic airway obstruction.

Outpatient Management of Chronic Obstructive Pulmonary Disease

The outpatient management of chronic obstructive pulmonary disease (COPD) is designed to limit the decline in respiratory function over time, to relieve the symptoms and improve the patient’s functional status, and to manage complications when they arise. Factors that predispose to airway inflammation, including cigarette smoking and respiratory infections, are prevented by behavioral modification programs, measures such as exercise and nutrition to improve general health, and regular vaccination. Symptoms are relieved by bronchodilator and antiinflammatory therapy, based upon the specific needs of the patient. Hypoxemia and acute infections are treated with oxygen administration and the use of antibiotics when necessary. The management of acute exacerbations of COPD is addressed elsewhere in this symposium (ie, choice of antibiotics is not discussed here). Also, certain aspects of management, such as surgical procedures, chest physical therapy, and other aspects of pulmonary rehabilitation, are also subjects of subsequent articles in this series. Although none of these modalities, except for smoking cessation and oxygen administration, have been shown to alter the course of COPD, the careful choice of the therapeutic measures discussed here can lead to significant relief of symptoms in the patient with chronic airway obstruction.

Course and prognosis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) continues to increase in incidence as the population of developed countries ages. Much time has been devoted to studying the natural course of this disorder and to searching for risk factors for a decline in respiratory function. The major risk factor for a decline in 1-second forced expiratory volume (FEV1) is cigarette smoking, and smoking cessation is a major part of its prevention. Other risk factors for development of COPD include passive exposure to cigarette smoke, age, and genetic factors including airway hyperreactivity, eosinophilia, and a history of atopy. This discussion presents a review of the current literature regarding the natural course and prognosis of COPD. The approach to patients with end-stage disease and the use of advance directives is considered.

Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function.

Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled, and the activities of the respiratory enzymes are concomitantly decreased in various human tissues upon aging. An immediate consequence of such gradual impairment of the respiratory function is the increase in the production of the reactive oxygen species (ROS) and free radicals in the mitochondria through the increased electron leak of the electron transport chain. Moreover, the intracellular levels of antioxidants and free radical scavenging enzymes are gradually altered. These two compounding factors lead to an age-dependent increase in the fraction of the ROS and free radical that may escape the defense mechanism and cause oxidative damage to various biomolecules in tissue cells. A growing body of evidence has established that the levels of ROS and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues. The mitochondrial DNA (mtDNA), although not protected by histones or DNA-binding proteins, is susceptible to oxidative damage by the ever-increasing levels of ROS and free radicals in the mitochondrial matrix. In the past few years, oxidative modification (formation of 8-hydroxy-2'-deoxyguanosine) and large-scale deletion and point mutation of mtDNA have been found to increase exponentially with age in various human tissues. The respiratory enzymes containing the mutant mtDNA-encoded defective protein subunits inevitably exhibit impaired respiratory function and thereby increase electron leak and ROS production, which in turn elevates the oxidative stress and oxidative damage of the mitochondria. This vicious cycle operates in different tissue cells at different rates and thereby leads to the differential accumulation of mutation and oxidative damage to mtDNA in human aging. This may also play some role in the pathogenesis of degenerative diseases and the age-dependent progression of the clinical course of mitochondrial diseases.

Oxygen consumption and biosynthetic function in perfused liver from rats at different stages of development.

Changes in mitochondrial function were studied in perfused liver from rats aged 24-365 days. Oxygen consumption together with the rates of gluconeogenesis, urea synthesis and ketogenesis were determined. Basal mitochondrial respiration as well as the ability of the liver to synthesize glucose, urea and ketone bodies declined from 24- to 365-day-old rats. On the other hand, on transition from 24 to 60 days the liver oxidation rate of hexanoate, sorbitol and glycerol is enhanced, but not of ketone bodies or palmitate. Our results show that the transition from weaning to middle age is accompanied by defined changes in hepatic substrate oxidation. From the observed time course of the decrease in basal and substrate-stimulated oxygen consumption, it is concluded that in rat liver cells a decline in respiratory chain function, long-chain fatty acid and ketone body metabolism, gluconeogenesis and ureogenesis occurs at a relatively early life stage.

Six year longitudinal study of respiratory function in dairy farmers in the Doubs province.

A previous study, carried out in 1986 in France, showed the prevalence of respiratory symptoms and of respiratory function impairment to be higher in dairy farmers than in a control group of nonexposed subjects living in a rural zone. In order to confirm the harmful effect of dairy farming, the two groups were re-studied 6 yrs later at the same period of the year. One hundred and ninety-four (77.6%) farmers and 155 (62%) control subjects were available for re-examination. Non-re-evaluated subjects were comparable to re-evaluated subjects for age, sex, smoking and respiratory symptoms and function at initial evaluation. Dairy farmers consistently had more respiratory symptoms and lower levels of respiratory function than did control subjects. In the study populations as a whole, the mean annual decline in vital capacity (VC) and forced expiratory volume in one second (FEV1) was slightly, but nonsignificantly, higher in farmers than in control subjects: in mL x yr(-1) (SD), -43.1 (68.2) versus -37.9 (60.2) for VC and -32.8 (56.7) versus -30 (47.2) for FEV1. There was a positive interaction between farming and age (i.e. duration of exposure in this cohort) on respiratory function decline, and in male subjects aged > or = 45 yrs, dairy farming was associated with an accelerated loss in VC (p<0.05) and FEV1 (p<0.05) after controlling for age, smoking, height and geographic location in a multiple linear regression model. Initial values of respiratory function, age and pack-years smoked (only for VC) were the other variables found to be significant determinants of decline in lung function. In conclusion, this study mainly suggests that dairy farming is associated to a very moderate accelerated loss in respiratory function that increases with duration of exposure and is significant in older male subjects.

Steroid myopathy in cancer patients.

We prospectively evaluated 15 adult cancer patients being treated with adrenocorticosteroids (steroids) to determine the frequency and time course of "steroid myopathy." Nine (60%) developed clinically detectable proximal muscle weakness that, in six, was severe enough to interfere with activities of daily living. Proximal muscle weakness developed within 15 days in eight of nine patients and was significantly related to the cumulative dose of steroid. Eight of nine patients with proximal muscle weakness, and two of six without such weakness, experienced a significant decline in respiratory function, leading to symptomatic dyspnea in four patients of the former group. In three patients who could be followed for more than 3 months off steroids, there was either improvement or resolution of the weakness and, when present, of the respiratory impairment. Steroid myopathy is a common complication among cancer patients receiving steroids. It can often affect respiratory function even when proximal limb muscles remain strong. Clinical recognition is important since steroid myopathy can lead to increased morbidity and may be reversible with reduction or discontinuation of steroids.

Effects of physical activity and age on mitochondrial function.

It has been proposed that ageing results from the accumulation of mitochondrial DNA mutations with age which interfere with respiratory chain ATP production. Insufficient ATP production impairs cell function, and tissue dysfunction ensues, leading to morbidity, decline and eventually death. Supporting this theory, mitochondrial DNA mutations accumulate with age and respiratory chain function declines dramatically in human skeletal muscle. However, the extent of decline in respiratory chain function is greater (50%) than anticipated from the low levels of mitochondrial DNA mutations (< 1%) observed in aged muscle. We hypothesized that an age-related reduction in physical activity could be an important factor in this decline and thus studied the influence of chronological age on muscle mitochondria in subjects matched for levels of physical activity. In this carefully selected group, there was little correlation between oxidative metabolism and age. However, several parameters of respiratory chain function did correlate with markers of physical activity (activity score and handgrip strength). Our results suggest that reduced physical activity is a major contribution to the decline in mitochondrial oxidations during ageing. Physical activity ameliorates and may even mask mitochondrial 'ageing' in muscle.

Liver transplantation for hepatic cirrhosis in cystic fibrosis.

About 10% of children with CF develop hepatic cirrhosis and progressive portal hypertension. As the portal hypertension worsens these children are likely to develop serious variceal bleeding and other complications including malnutrition and a decline in respiratory function. Indices of lung function may fall as much as 50% in a year and chest infections may require frequent admissions to hospital. The respiratory symptoms are often attributed to CF related lung disease and affected children may therefore be considered unsuitable for liver transplantation. We propose a simple scoring system which can help to select patients who should be referred for assessment of liver transplantation. After careful assessment and preparation children with lung function indices as low as 30% predicted can have a successful outcome after liver transplantation. With good graft function portal hypertension is relieved and absorption, nutrition and respiratory function all improve. The improved quality of life of these children is remarkable.

Epidemiology and Treatment of Chronic Bronchitis and Its Exacerbations

Epidemiology and Treatment of Chronic Bronchitis and Its Exacerbations

The universality of bioenergetic disease and amelioration with redox therapy

Overt mitochondrial diseases associated with mitochondrial DNA mutations are characterized by a decline in mitochondrial respiratory function. Similarly, a progressive decline in mitochondrial respiratory function associated with mitochondrial DNA mutations is clearly evidenced in aged human subjects. This communication is concerned with the development of a rat model for the study of bioenergy decline associated with the ageing process and overt mitochondrial diseases. The model involves the treatment of young rats with AZT to induce skeletal and cardiac myopathies. It has shown that there is a decline in soleus muscle function in vivo and that this decline is mirrored in the capacity of heart sub-mitochondral particles to maintain bioenergy function. Coenzyme Q 10 and several analogs were administered with AZT as potential therapeutics for the re-energization of affected tissues. Coenzyme Q 10 and especially decyl Q were found to be therapeutically beneficial by both in vivo improvement in soleus muscle function and in vitro cardiac mitochondrial membrane potential capacity. Sub-mitochondrial particles were also prepared from heart mitochondria of young and aged rats. The particles prepared from the aged rats were found to have a decreased ability to maintain membrane potential as compared to those derived from the young rats.

Pulmonary Function at Diagnosis of Amyotrophic Lateral Sclerosis: Rate of Deterioration

The purpose of this study was to determine the degree of respiratory muscle impairment in patients with newly diagnosed amyotrophic lateral sclerosis (ALS) and the subsequent rate of decline of respiratory function. Thirty-one of 36 patients had respiratory muscle weakness at presentation, although only 7 complained of any respiratory symptoms. Vital capacity (percent predicted) was significantly lower in the symptomatic group (55.9 +/- 20.3) compared with the asymptomatic group (76.4 +/- 21.0). Respiratory muscle impairment as measured by vital capacity (percent predicted) was related to stage of disease at presentation. Rate of decline of respiratory muscle strength as measured by VC (-3.5 percent/month), negative inspiratory pressure (NIF) (+2.9 cm H2O/month), and positive expiratory pressure (PEP) (-3.4 cm H2O/month) tended to be linear with a great deal of interpatient variability. It is concluded that early measurement of respiratory muscle strength in ALS with subsequent follow-up studies may be useful in determining overall prognosis and in decision making.

Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: Effect of ageing

The analysis of human skeletal muscle mitochondria revealed a progressive decline in mitochondrial respiratory chain function with age. The activities affected to the greatest extent were those of complexes I and IV which were decreased by 59% and 47% respectively between the ages of 20–30 years and 60–90 years of age. Quantitation of the 5 kb ‘common’ deletion of mtDNA using PCR revealed a progressive accumulation with age, from approximately 1 in 100 000 at 21 years to 1 in 10 000 at 56 years and 1 in 5000 at 78 years of age. The low absolute levels of this mutation are unlikely to contribute significantly to the observed mitochondrial dysfunction.

Mitochondria and ageing.

This work reviews the role of mitochondria in the ageing process and summarizes pathomorphological biochemical and molecular genetic data. The pathophysiological mechanisms underlying the phenomenon of ageing are only partly understood. There is, however, increasing evidence that mitochondria are essentially involved. In various tissues of various species a decline in the respiratory chain capacity is seen with ageing. Enzyme histochemistry of cytochrome c oxidase (complex IV of the respiratory chain) has revealed an age-related increase of randomly distributed defective fibres/cells in the skeletal and heart muscle the random pattern probably indicating cellular heterogeneity of the ageing process. Observed deletions of mitochondrial DNA during ageing may represent one causative factor. Similar to primary mitochondrial myopathies point mutations and depletion of the mtDNA are probably also involved. There is some evidence that damage of the mitochondrial genome and of other mitochondrial structures might be due to increased oxygen radical production during ageing. The role of nuclear influences on the degeneration of mitochondrial function remains, however, also to be determined. Nevertheless, the decline of respiratory chain function with ageing represents an important factor for the decline of functional organ reserve capacity in senescence.

Bronchiolitis Obliterans after Autologous Bone Marrow Transplantation

Two patients are reported who underwent autologous bone marrow transplantation for lymphoma and developed rapidly progressive respiratory insufficiency at posttransplant (PT) days 90 and 273. Clinical examination revealed persistent cough, exertional dyspnea, inspiratory rales, and expiratory wheezing. Results of pulmonary function studies were consistent with rapidly progressive severe respiratory disease in both patients. Despite aggressive immunosuppressive therapy, both patients had a progressive decline in respiratory function and died of respiratory insufficiency at PT days 400 and 446, respectively. Each patient had histologic evidence of bronchiolitis obliterans (BrOb). These cases demonstrate that life-threatening obliterative bronchiolitis is not limited to patients undergoing allogeneic bone marrow transplantation, but can also follow autologous transplant. Awareness that this group is also at risk for BrOb and severe respiratory compromise may lead to early diagnosis and treatment.

Bronchoalveolar lavage fluid obtained from smokers exhibits increased monocyte chemokinetic activity

Alveolar macrophages, which are cells derived from blood monocytes, accumulate within the lower respiratory tract of cigarette smokers. One mechanism to account for this accumulation of alveolar macrophages may be an increase in the migration of blood monocytes into the lungs of smokers. To evaluate this hypothesis, bronchoalveolar lavage fluid (BALF) was obtained from 15 smokers and 16 nonsmokers. The smokers' BALF possessed a significantly increased capacity to attract normal blood monocytes when evaluated using a blind-well chamber technique (26.2 +/- 7.6 vs 14.8 +/- 6.9 cells/high-power field, P less than 0.01). Checkerboard analysis of the activity revealed that it was predominantly chemokinetic. Partial characterization of the activity in smokers' BALF revealed that it was lipid soluble but only partially sensitive to trypsin and heat. The chemokinetic activity correlated with alveolar macrophage numbers in the BALF (r = 0.4391, P = 0.009). Furthermore, both the chemokinetic activity and alveolar macrophage number correlated with alterations of respiratory function (forced expiratory volume in 1 s, diffusing capacity for carbon monoxide, and forced expiratory flow at 75% of the vital capacity). These results suggest that the increase in alveolar macrophage number present in the BALF of cigarette smokers may be due, at least in part, to an increased amount of chemokinetic factor(s) in the smokers' BALF, and these factor(s) may participate in the decline of respiratory function associated with cigarette smoking, probably by recruiting monocytes into lung.

Decline in Respiratory Function and Experience with Long-Term Assisted Ventilation in Advanced Duchenne's Muscular Dystrophy

We present 17 patients with advanced DMD who required long-term assisted ventilation. Eleven patients used part-time assisted ventilation. Five of the patients received BV and/or M-IPPV or N-IPPV between two and nine years before requiring full-time T-IPPV, while six others initially used part-time T-IPPV. One patient used all three modes before requiring full-time T-IPPV. Mean (+/- SD) FVC and rebreathe PCO2 at the outset of assisted ventilation were 0.62 +/- 0.20 L and 47.4 +/- 7.5 mm Hg, respectively. Clinical features were divided between symptoms suggesting respiratory muscle fatigue and sleep-related disordered breathing. We found that, while useful in early respiratory insufficiency, BV is associated with recurrent aspiration. In our experience, N-IPPV offers the safest and most convenient form of noninvasive ventilation. When the VC has decreased to about 300 ml, most patients will require full-time ventilation; T-IPPV is advised to provide airway access to suction secretions.

1581 EARLY EFFECTS OF A NEPHROTOXIC CEPHALOSPORIN ON RENAL CORTICAL AND MITOCHONDRIAL CALCIUM (CA) CONTENT AND MITOCHONDRIAL FUNCTION

Cephaloglycin (CG) is one of several nephrotoxic drugs in the cephalosporin family of antibiotics. The mechanism of injury produced by these drugs is uncertain. Since CA has been implicated in the damage sustained by the kidney following a variety of insults, the effects of CG on CA accumulation in the cortex (CTX) and cortical mitochondria (MITO) and the relationship of mitochondrial oxygen consumption to tissue CA content were studied. The CA content of whole renal CTX and renal cortical MITO was measured two hours after a toxic dose of CG (200mg/kg IV) in control (CTRL) and experimental (EXPT) rabbits. Mitochondrial oxygen consumption supported by succinate in the presence of ADP or CA was measured from the same preparations. Data are expressed as nanomoles/mg protein and as means±SD, n=6-10, *p<.05 or better compared to CTRL.CG leads to early accumulation of CA in the renal CTX and cortical MITO. There is a parallel decline in mitochondrial respiratory function. These results suggest that CA may play an important role in the proximal tubular necrosis and mitochondrial dysfunction caused by CG.

Evaluation of pulmonary function in muscular dystrophy patients requiring spinal surgery.

Scoliosis associated with muscular dystrophy frequently necessitates surgical stabilization of the spine. The timing of surgery usually is based on the degree of spinal angulation. Pulmonary function, which deteriorates with age in children with muscular dystrophy, should also be an important consideration in this timing. In a retrospective study of 48 patients who underwent spinal stabilization, preoperative respiratory function tests were correlated with postoperative respiratory complications. The percentage of predicted vital capacity provided the best indicator of outcome and values of less than 30% were associated with major respiratory complications. Spinal fixation failed to arrest the decline in respiratory function in these patients, but it seemed to slow the rate of deterioration compared with preoperative changes. Evaluation of pulmonary function should play a major role in the timing of surgical intervention in muscular dystrophy.