Dysfunction of small airways following pulmonary injury due to nitrogen dioxide.

Serial physiologic studies were performed to characterize both the immediate and delayed effects of a single occupational exposure to nitrogen dioxide in a nonsmoker. During the initial acute stage of pulmonary edema, the abnormal static pressure-volume curve and decreased static compliance corresponded to a reduction in pulmonary volume. During the delayed acute stage, elastic recoil and properties of resistance to flow were normal, but dynamic compliance was reduced and dependent on respiratory frequency, and oxygen transport was abnormal during exercise, which is consistent with dysfunction of the small airways.     

A human model of the pathophysiology of chronic obstructive pulmonary disease

This short review summarizes a series of studies on the effects of expiratory flow limitation (EFL) at approximately 1 L/s during incremental exercise to maximal workload (Wmax) in normal subjects on exercise performance, respiratory muscle dynamics and control, and CO(2) elimination. Each subject served as his or her own control by performing the same protocol without EFL. Additionally, an index of cardiac output was measured before and after imposing EFL while the subjects exercised at Wmax, Wmax was reduced to 65% of control by severe dyspnoea. EFL forced a decrease in the shortening velocity of expiratory muscles, resulting in increased expiratory pressures which accounted for 66% of the variance in Borg scale ratings of dyspnoea. In spite of an increase in the shortening velocity of inspiratory muscles, inspiratory pressures and power increased, because EFL exercise induced hypercapnia, which increased the chemical drive to breathe. This was in part due to an increased alveolar dead space presumably resulting from a reduction in pulmonary capillary blood volume secondary to the high expiratory pressures. A vicious circle was established in which expiratory muscle pressures induced hypercapnia, which resulted in an even stronger expiratory muscle contraction. The imposition of EFL reduced cardiac output by 10% and decreased arterial O(2) saturation, reducing energy supplies to working locomotor and respiratory muscles. This model reproduces the most important clinical features of COPD, and these arise from ventilatory pump dysfunction rather than from the lung. It also leads to hypotheses that can be tested in patients with COPD.     

Ventilatory markers during exercise for congestive heart failure

The exaggerated ventilatory response in patients with heart failure is clearly multifactorial and complex beyond a mere reduction in pulmonary blood flow. Pulmonary dysfunction, including ventilation-perfusion mismatching, decreased lung compliance, restriction, airway obstruction, decreased diffusion capacity, and decreases in respiratory muscle strength and endurance, contributes to an inefficient breathing pattern and increased work of breathing. This is further compounded by the limited ability of the failing heart to meet the metabolic demands of the respiratory muscles, leading to underperfusion and ischemia.Although VO2max has important implications with regard to functional capacity, exercise test personnel must be knowledgeable concerning the clinical physiology of ventilation during exercise in the patient with heart failure. Ventilatory markers, as Arena and coworkers have demonstrated, are most indicative of disease severity and enhance the prognostic value of the test results.     

Lung function tests in connective tissue diseases associated with Raynaud's phenomenon

13 patients with various connective tissue diseases associated with Raynaud's phenomenon were studied with pulmonary physiologic techniques to see the alterations of lung functions and also whether spasm of pulmonary circulation occurs in these patients. We found that an increase in the dead space ventilation was common and associated with normal tidal volume. We interpreted this finding as evidence of redistribution of blood flow in the lung by spasm of blood vessels going to well-ventilated lung units generating a high dead space ventilation. We also found commonly that the distribution of inspired air in the lung was uneven, the diffusing capacity was reduced and the dynamic compliance decreased with increasing frequency of breathing suggestive of disease in small airways. The restrictive defect, the obstructive defect, the reduction of lung compliance and the arterial hypoxemia were relatively uncommon and probably occurred when the diseases were more advanced.     

Ventilatory mechanisms of exercise intolerance in chronic heart failure.

Mechanisms that have been suggested to underlie the abnormal ventilatory response to exercise in patients with chronic congestive heart failure (CHF) include high pulmonary pressures, ventilation-perfusion mismatching, early metabolic acidosis, and abnormal respiratory control. To evaluate the role that ventilation and gas exchange play in limiting exercise capacity in patients with CHF, data from 33 patients with CHF and 34 normal subjects of similar age who underwent maximal exercise testing were analyzed. Maximal oxygen uptake was higher among normal subjects (31.7 +/- 6 ml/kg/min) than among patients with CHF (17.7 +/- 4 ml/kg/min; p less than 0.001). The ventilatory equivalent for oxygen, expressed as a percentage of maximal oxygen uptake, was 25% to 35% higher among patients with CHF compared with normal subjects throughout exercise (p less than 0.01). A steeper component effect of ventilation on maximal oxygen uptake was observed among normal subjects compared with patients with CHF, which suggests that a significant portion of ventilation in CHF is wasted. Maximal oxygen uptake was inversely related to the ratio of maximal estimated ventilatory dead space to maximal tidal volume (VD/VT) in both groups (r = -0.73, p less than 0.001). Any given oxygen uptake at high levels of exercise among patients with CHF was accompanied by a higher VD/VT, lower tidal volume, and higher respiratory rate compared with normal subjects (p less than 0.01). Relative hyperventilation in patients with CHF started at the beginning of exercise and was observed both below and above the ventilatory threshold, which suggests that the excess ventilation was not directly related to earlier than normal metabolic acidosis. Thus abnormal ventilatory mechanisms contribute to exercise intolerance in CHF, and excess ventilation is associated with both a higher physiologic dead space and an abnormal breathing pattern. The high dead space is most likely due to ventilation-perfusion mismatching in the lungs, which is related to poor cardiac output, and the abnormal breathing pattern appears to be an effort to reduce the elevated work of breathing that is caused by high pulmonary pressures and poor lung compliance.     

Serial physiologic studies of a chronic obstructive pulmonary disease patient in acute respiratory failure: clues for weaning?

A patient with severe chronic obstructive pulmonary disease was studied during acute respiratory failure. On the day of intubation his respiratory rate was 42, the tidal volume 295 ml, and the maximal inspiratory pressure 8 cm H2O. These parameters improved with rest by mechanical ventilation to 16, 620 ml, and 30 cm H2O, respectively, on the day of successful weaning. Daily tidal volumes correlated significantly with maximal inspiratory muscle pressures (r = 0.936; p less than 0.001). Respiratory system compliances and resistances were measured by the inflation, the end-inspiratory occlusion, and the interrupter methods. In general, inflation compliance and occlusion compliance were comparable and significantly smaller than the interrupter compliance (p less than 0.002 and p less than 0.003, respectively), whereas inflation resistance and occlusion maximal resistance were also comparable but significantly smaller than the interrupter resistance (p less than 0.0008 and p less than 0.0006, respectively). The former was due to increased hysteresis of the pressure volume curves and the latter due to expiratory compression of airways. The compliance was low, and the resistance was high on the day of intubation and became much higher and lower, respectively, on the day of successful extubation. These physiological changes were associated with weaning difficulty. We conclude that respiratory failure and weaning are complex physiologic events under the influence of muscle strength, lung mechanics, gas exchange, and control of breathing. Therefore, prediction of weaning success based upon one or two measured parameters as has been done is probably inadequate in difficult patients.     

Cardiopulmonary function in exercising bar-headed geese during normoxia and hypoxia

To investigate possible physiologic mechanisms that allow the bar-headed goose to perform strenuous physical activity when flying at high altitude (e.g., above 9,000 m), we measured cardiopulmonary variables during running exercise (treadmill; 0.6 m.sec-1; 2 degrees incline) while the bird breathed either normoxic (21% O2) or hypoxic (7% O2) gases via a face mask. 1. During normoxic exercise, O2 uptake rate doubled and both ventilation and cardiac output increased. Blood gases and pH in arterial, mixed venous and blood from the leg, however, remained virtually unaltered. 2. Hypoxia at rest stimulated ventilation to rise but not cardiac output. The birds reached a steady state with virtually unaltered O2 uptake. 3. Exercise during hypoxia further stimulated ventilation, resulting in elevated arterial PO2 and O2 content compared to hypoxia at rest. However, O2 uptake increased only slightly, and cardiac output did not rise over the resting hypoxic value. The hyperventilation resulted in respiratory alkalosis and increased CO2 output, with R values being as high as 2.0. 4. It is concluded that neither ventilation nor pulmonary gas transfer were the limiting step in supplying O2 to the working muscles during hypoxic exercise in our experiments. It is more likely that muscle blood flow or diffusion from muscle capillaries to mitochondria, or both, determined the aerobic capacity under these conditions.     

Skeletal muscle abnormalities in chronic heart failure patients: relation to exercise capacity and therapeutic implications

Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with chronic heart failure, might play an important role in the origin of symptoms and exercise intolerance in this condition. Biochemical and histologic changes in the skeletal muscles of chronic heart failure patients relate with the degree of exercise intolerance better than hemodynamics parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in chronic heart failure patients. The relationship between skeletal muscle changes and exercise intolerance suggests the possibility of modifying the peripheral changes in order to improve functional capacity in chronic heart failure patients. Recent studies have shown that the administration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles. Similarly, exercise training allows improvement in peak oxygen consumption, which parallels important biochemical and histologic changes in the skeletal muscles.     

Spectroscopy of phosphorus in nuclear magnetic resonance. General review of clinical applications to the study of human skeletal muscle]

Phosphorus nuclear magnetic resonance spectroscopy enables the energy metabolism of skeletal muscles to be studied non-invasively in vivo. Relative concentrations of phosphocreatine (PCr), inorganic phosphate (iP), monophosphoric sugars (mP) and ATP, as well as intracellular pH values, are directly accessible through the spectra. The striated muscle is continuously studied at rest, during exercise and during recovery. Exercise-induced changes in pH and mP provide indirect information on glycogenolysis and glycolysis. The speed of PCr resynthesis during post-exercise recovery and the PCr/iP ratio values at rest excellently reflect mitochondrial oxidative phosphorylations. Phosphorus NMR spectroscopy therefore is of interest not only to study the impact, through hypoxia, on muscle energy metabolism of such pathologies as cardiac or respiratory failure, or to study various acquired metabolic muscular diseases, but also and above all, to detect and locate muscular enzyme deficiencies involving glycogenolysis, glycolysis or mitochondrial metabolism, thereby pointing to the diagnosis of congenital, and mainly metabolic, myopathies.     

Heart involvement in lamin A/C related diseases

The LMNA gene encodes lamins A and C, components of the nuclear envelope. Its mutations cause a wide range of diseases named laminopathies involving either specific tissues in isolated fashion (cardiac and skeletal muscles, peripheral nerve, adipose tissue) or several tissues in a generalized way (premature ageing syndromes and related disorders). The striated muscle laminopathies include a variety of well clinically characterized disorders where cardiac muscle involvement represents the common feature that coexists with or without skeletal muscle disease. The cardiac disease of LMNA mutated patients is classically defined by conduction system and rhythm disturbances occurring early in the course of the disease, followed by dilated cardiomyopathy and heart failure. These features are life threatening and often responsible of cardiac sudden death. When associated, the skeletal muscle involvement is characterized by muscle weakness and wasting of variable topography with or without early joint contractures and spinal rigidity. Specific management of the cardiac disease to includes antiarrhythmic drugs, cardiac devices such as implantable cardioverter for primary and secondary prevention of sudden death, and heart transplantation at the end stage of heart failure. A large number of LMNA mutations leading to striated muscle laminopathies have been reported without so far any clear and definite phenotype/genotype relation. Finally, among the diverse hypotheses for pathomechanisms of LMNA mutations, the structural hypothesis suggesting a defective role of lamins A/C in maintaining the structural integrity of the nuclear envelope in striated muscles under constant mechanical stress is highly attractive to link the LMNA mutations and the cardiac disease.     

Myasthenia gravis

Myasthenia gravis is an autoimmune disease, which leads to load-dependent weakness of voluntary skeletal muscles with recovery of function after resting. The disease is caused by autoantibodies directed against the postsynaptic nicotinic acetylcholine receptors (AChR) leading to a reduction of neuromuscular transmission. Muscles and nerves are not affected. Disorders of the thymus play a role in the pathogenesis of AChR antibody-positive myasthenia. The clinical symptoms include exercise-induced fatigue either of the ocular muscles alone (ocular myasthenia) or striated skeletal muscle and the ocular, facial and bulbar musculature (generalized myasthenia). Treatment of myasthenia gravis involves administration of acetylcholine esterase inhibitors and immunosuppressive drugs. A myasthenic crisis is characterized by life-threatening complications with severe weakness, swallowing difficulties and respiratory failure, which requires intensive care treatment.     

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure.

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.     

Role of respiratory function in exercise limitation in chronic heart failure

OBJECTIVE: To test the hypothesis that respiratory function contributes to limit maximal exercise performance in patients with chronic heart failure by using the technique of dead space loading during exercise. DESIGN: Blinded subjects underwent two maximal incremental exercise tests in random order on an upright bicycle ergometer: one with and one without added dead space. SETTING:: Tertiary-care university teaching hospital. SUBJECTS: Seven patients with stable chronic heart failure (mean +/- SEM left ventricular ejection fraction, 27 +/- 3%). RESULTS: Subjects were able to significantly increase their peak minute ventilation during exercise with added dead space when compared with control exercise (57.4 +/- 5.9 vs 50.0 +/- 5.6 L/min; p < 0.05). Peak oxygen uptake, workload, heart rate, and exercise duration were not significantly different between the added dead space and control tests. Breathing pattern was significantly deeper and slower at matched levels of ventilation during exercise with added dead space. CONCLUSION: Because patients with chronic heart failure had significant ventilatory reserve at the end of exercise and were able to further increase their maximal minute ventilation, we conclude that respiratory function does not contribute to limitation of exercise in patients with chronic heart failure.     

A critical threshold of exercise capacity in the ventilatory response to exercise in heart failure

During exercise patients with chronic left heart failure ventilate more than normal individuals at the same workload; the ratio of minute ventilation to minute production of carbon dioxide (VE/VCO2) is increased. The relation between increased VE/VCO2, severity of heart failure, and exercise capacity has not been defined. VE/VCO2 was measured in 47 patients with chronic left heart failure (New York Heart Association grades II and III) and in 1009 healthy controls. Exercise capacity was assessed by peak oxygen consumption (VO2max) during progressive exercise. In the controls VO2max ranged from 25 to 93 ml/kg/min; VE/VCO2 was 17-36 and did not correlate with VO2max. In chronic left heart failure the VO2max ranged from 9 to 29 ml/kg/min; VE/VCO2 was 22-42 and correlated strongly with VO2max. End tidal carbon dioxide and respiratory rate at peak exercise were similar in the controls and patients with chronic left heart failure. The increase in VE/VCO2 on exercise in chronic left heart failure indicates increased physiological dead space, presumably caused by a ventilation-perfusion mismatch. In the controls and patients with chronic left heart failure the relation of VE/VCO2 to VO2max was curvilinear with a threshold of VO2max below which VE/VCO2 started to rise above the normal range. This point of inflection may be explained by the existence of a critical level of cardiac function necessary to perfuse adequately all lung zones on exercise.     

A critical threshold of exercise capacity in the ventilatory response to exercise in heart failure.

During exercise patients with chronic left heart failure ventilate more than normal individuals at the same workload; the ratio of minute ventilation to minute production of carbon dioxide (VE/VCO2) is increased. The relation between increased VE/VCO2, severity of heart failure, and exercise capacity has not been defined. VE/VCO2 was measured in 47 patients with chronic left heart failure (New York Heart Association grades II and III) and in 1009 healthy controls. Exercise capacity was assessed by peak oxygen consumption (VO2max) during progressive exercise. In the controls VO2max ranged from 25 to 93 ml/kg/min; VE/VCO2 was 17-36 and did not correlate with VO2max. In chronic left heart failure the VO2max ranged from 9 to 29 ml/kg/min; VE/VCO2 was 22-42 and correlated strongly with VO2max. End tidal carbon dioxide and respiratory rate at peak exercise were similar in the controls and patients with chronic left heart failure. The increase in VE/VCO2 on exercise in chronic left heart failure indicates increased physiological dead space, presumably caused by a ventilation-perfusion mismatch. In the controls and patients with chronic left heart failure the relation of VE/VCO2 to VO2max was curvilinear with a threshold of VO2max below which VE/VCO2 started to rise above the normal range. This point of inflection may be explained by the existence of a critical level of cardiac function necessary to perfuse adequately all lung zones on exercise.     

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.     

Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure

To determine the clinical value of respiratory gas analysis during exercise, oxygen consumption (VO2) at peak exercise and at lactate and ventilatory threshold was assessed in 34 patients with chronic heart failure who underwent maximal exercise testing with expiratory gas monitoring and serial determinations of mixed venous lactate and hemodynamics by Swan-Ganz catheterization. A lactate threshold, defined as the point of abrupt increment of blood lactate, could be identified in every patient; the ventilatory threshold, detected on the basis of the respiratory changes, was found in 26 patients (77%). Lactate and ventilatory thresholds were significantly related to each other (r = 0.94; p less than 0.001) and to peak VO2 (r = 0.89; p less than 0.001 in both). Among the resting hemodynamic measurements, peak VO2 was significantly related only to total pulmonary resistances (r = -0.35). Among the parameters at maximal exercise, it was positively related to cardiac index, stroke work, stroke volume index and mean arterial pressure (r = 0.89, 0.74, 0.74 and 0.56, respectively) and inversely related to systemic vascular and total pulmonary resistances (r = -0.74 and -0.63). Using multivariate stepwise regression analysis only maximal cardiac index and, to a lesser degree, total pulmonary resistance were related to peak VO2. Similar correlations were found between the hemodynamics and the lactate and ventilatory threshold. Thus, peak VO2, lactate and ventilatory thresholds can be detected in most patients with chronic heart failure. These parameters are highly correlated to each other and bear similar relations to the hemodynamic response to exercise. The cardiac index is the main central hemodynamic determinant of exercise capacity.     

Changes of Respiratory Mechanics in COPD Patients from Stable State to Acute Exacerbations with Respiratory Failure

Symptoms, clinical course, functional and biological data during an exacerbation of chronic obstructive pulmonary disease (EXCOPD) have been investigated, but data on physiological changes of respiratory mechanics during a severe exacerbation with respiratory acidosis requiring noninvasive mechanical ventilation (NIMV) are scant. The aim of this study was to evaluate changes of respiratory mechanics in COPD patients comparing data observed during EXCOPD with those observed during stable state in the recovery phase. In 18 COPD patients having severe EXCOPD requiring NIMV for global respiratory failure, we measured respiratory mechanics during both EXCOPD (T0) and once the patients achieved a stable state (T1). The diaphragm and inspiratory muscles effort was significantly increased under relapse, as well as the pressure-time product of the diaphragm and the inspiratory muscle (PTPdi and PTPes). The resistive loads to breathe (i.e., PEEPi,dyn, compliance and inspiratory resistances) were also markedly increased, while the maximal pressures generated by the diaphragm and the inspiratory muscles, together with forced expired volumes were decreased. All these indices statistically improved but with a great intrasubject variability in stable condition. Moreover, tension-time index (TTdi) significantly improved from the EXCOPD state to the condition of clinical stability (0.156 ± 0.04 at T0 vs. 0.082 ± 0.02 at T1 p < 0.001). During an EXCOPD, the load/capacity of the respiratory pump is impaired, and although the patients exhibit a rapid shallow breathing pattern, this does not necessarily correlate with a TTdi ≥ 0.15. These changes are reverted once they recover from the EXCOPD, despite a large variability between patients.     

Hemodynamic determinants of exercise capacity in chronic heart failure.

PURPOSE: To synthesize information on hemodynamic determinants of exercise capacity in patients with chronic heart failure. DATA IDENTIFICATION: Relevant studies published from the mid-1960s to the present were identified by a manual search of the English-language literature and by bibliographic review of pertinent articles. STUDY SELECTION: Both controlled and observational studies that reported measures of either exercise time or oxygen uptake and hemodynamic variables in patients with heart failure were reviewed for quality and included when relevant to the discussion. DATA EXTRACTION: Key conclusions or data, or both, were extracted from each article and described. DATA SYNTHESIS: Exercise intolerance is a hallmark of chronic congestive heart failure. Studies have emphasized central factors and indices of systolic ventricular function, but poor relations have been consistently found between these measurements and exercise capacity. Recent data suggest that diastolic function (that is, ventricular filling and compliance) is an important factor affecting the ability to increase cardiac output and determining exercise capacity, but this issue needs further study. A clearer picture of histologic and biochemical abnormalities in skeletal muscle has recently emerged; patients with heart failure show greater glycolysis, reduced oxidative phosphorylation, and reduced oxidative enzyme activity. Vasodilatory abnormalities in heart failure were first described more than 20 years ago, and such abnormalities may underlie recently reported reductions in skeletal muscle blood flow during exercise. Relative hyperventilation is commonly observed during exercise in patients with heart failure and is related to ventilation-perfusion mismatching in the lung due to a higher-than-normal fraction of physiologic dead space. Neurohumoral abnormalities include reductions in beta-receptor density and sensitivity and contribute to reduced inotropic and chronotropic responses to exercise. CONCLUSIONS: Systolic function and exercise capacity are unrelated in patients with chronic heart failure, but many hemodynamic abnormalities (including those in the heart, lung, and skeletal muscle) overlap, which leads to exercise intolerance in these patients.     

Cardiopulmonary interaction in heart failure

In heart failure lung dysfunction is frequent and is greater the greater the heart failure severity. It can be evaluated in terms of lung mechanics and gas diffusion. Indeed heart-lung interaction is related to heart dimensions and lung fluid content; furthermore heart-lung interaction is influenced by the body position. Lung diffusion is also altered in patients with chronic heart failure, and a low gas diffusion is associated with a reduced performance. During exercise, heart-lung interaction becomes more evident. Heart failure patients show an abnormal hyperventilation due to a progressively increased respiratory rate, and a lower tidal volume; hyperventilation is due to different causes including enhanced responses from chemo- and metabolo-receptors, increased CO(2) production and increased dead space ventilation. Several drugs affect the ventilatory pattern in heart failure patients: ACE-inhibitors and anti-aldosteronic drugs improve lung diffusion and ventilatory efficiency during exercise; beta-blockers reduce exercise-induced hyperventilation. Furthermore, ultrafiltration improves lung mechanics, both at rest and during exercise, through body fluid content reduction.