The main hemodynamic abnormality in COPD is raised pulmonary vascular resistance and pulmonary hypertension. This is particularly evident when the vascular bed is stressed as in exercise; the absence of reserve collateral vessels prevents the normal reduction in pulmonary vascular resistance, and hence, pressure increases with flow. The increased afterload reduces right ventricular ejection fraction and stroke volume, but cardiac output is maintained by a relative tachycardia. Although most patients have a ventilatory limitation to exercise, in the later stages of the disease, hemodynamic factors may contribute. Studies of the effects of physical training on pulmonary hemodynamics have been few but none has shown any significant improvement. Occasionally there may be an increase in arteriovenous oxygen difference, accounting for the increase in symptom-limited oxygen consumption seen in some patients. The absence of hemodynamic effects of training may be due to insufficient training intensity. The often impressive increases in work tolerance after training may be due in part to an increase in muscular coordination and technique, as well as to metabolic training effects and psychologic factors.

In assessing the effectiveness of lower-limb and upper-limb nonspecific physical training, we have considered 3 objectives in this study: (1) determination of clinical and functional actual state in patients with chronic airway obstruction (CAO), before and after training; (2) determination of the tests, level of work, and duration of the session training as well as how to increase the training load throughout the training program; and (3) the "particular" upper-limb exercise training in patients with CAO. Many personal factors such as psychologic (personality, degree of patient motivation), alcohol and smoking habits, physical activity, malnutrition, as well as routine tests, at rest and maximal exercise, including the control of metabolic acidosis (lactate) and arterial blood gases (or at least of SaO2), should be considered. Exercise training has the potential to improve exercise tolerance in those who develop metabolic acidosis. The pattern of lactates during exercise represents a good criterion on the selection of patient's training. Two ergospirometric strategies, at high intensity exercise, established from the anaerobic threshold (AT) are described: (a) the above AT 45 min constant exercise (high work rate), at 60% of the difference between AT and maximum VO2 or 80% of the maximal tolerated power (MTP), and (b) the "45 min square-wave endurance exercise test" (SWEET), simulating an interval training session, established from the MTP and the AT. To the SWEET's base (% MTP from AT or aerobic training), a peak of 60 s at MTP (anaerobic training) is added every 5 min. While those 2 protocols, after 6 to 8 weeks of training, lactate and ventilation were lower for identical work rate. In addition, endurance (time in "a" and total physical work in "b") increased up to 60%. Further, maximal exercise ventilation and maximum VO2 increased after SWEET training. Roughly every 7 training sessions, a 10% to 15% reduction in heart rate (HR), during the training program, allows the patient to increase the work rate of the sessions. Evaluation of training the upper limb in patients with CAO requires measurements of MTP and maximum VO2. With the upper limb (wheelchair ergometer), Wmax, maximum VO2, and HR represent 30%, 65%, and 95%, respectively, of the lower limb (ergometer). Further, some expiratory and inspiratory accessory muscles show electromyographic fatigue at the MTP upper-limb level. This may contribute to the rationale for training respiratory muscles.(ABSTRACT TRUNCATED AT 400 WORDS)

Design of exercise programs that are part of pulmonary rehabilitation programs should be founded on an appreciation of the principles of exercise training of healthy subjects. Training produces structural and biochemical changes in the muscles that exercise which increase the ability of the trained muscle to perform aerobic exercise. After training, a given level of heavy exercise engenders lower levels of blood lactate. This is associated with a lower requirement for oxygen uptake, carbon dioxide output, and ventilation. Although the precise mechanism by which training produces changes in the exercising muscles is unknown, characteristics of an effective training program have been defined. Healthy subjects must train for at least 30 min per day, 3 to 5 days per week for 4 to 8 weeks to achieve a physiologic training effect. More controversial is whether a critical training intensity exists. Further, it is not clear which yardstick to apply to quantitate training intensity. Finally, after a training effect has been achieved, regular exercise must be continued or the gains will be lost.

Right ventricular ejection fraction (RVEF), a measure of systolic pump performance of the right ventricle, is frequently depressed at rest or during exercise in patients with chronic obstructive pulmonary disease (COPD). The most common cause of reduced RVEF in COPD is augmentation of right ventricular afterload, namely an increase in pulmonary artery pressure and pulmonary vascular resistance. Therapy with agents that decrease the afterload on the right ventricle have the potential to improve the systolic performance of this chamber. Oxygen, vasodilators such as hydralazine and nifedipine, theophylline, and sympathomimetics all may augment RVEF in part by reducing pulmonary vascular resistance and, in some cases, pulmonary artery pressures in patients with COPD and cor pulmonale. However, only oxygen therapy has been shown to improve survival.

Because of the additive effects of impaired ventilatory muscle function on the one hand and the increased ventilatory load on the other, increasing attention is now directed at therapies to improve ventilatory muscle function. Three main approaches are being used: (1) reduction in load; (2) increase in intrinsic ventilatory muscle function; and (3) reduction in dyspnea perception. While promising results have been achieved, additional investigative work is required to resolve outstanding questions.

The measurement of dyspnea during an exercise task provides an opportunity to simulate daily physical activities that lead to breathing difficulty in patients with lung disease. Although the exact stimulus for the sensation of breathlessness is unknown, it is possible to measure dyspnea during exercise by applying the principles of psychophysics to the analysis of various stimulus-response relationships. It is logical to consider that the exercise task, ie, work or power production, causes both physiologic and perceptual responses. A 0 to 10 category scale with ratio properties developed by Borg and a visual analogue scale are the most commonly used instruments for rating the severity of dyspnea during exercise. The ratings of breathlessness are generally reliable over time and are sensitive to evaluate an acute intervention in patients with stable respiratory disease. The exercise intensity-dyspnea relationship appears to be the most appropriate stimulus-response relationship for quantifying dyspnea during exercise.

Both neural and humoral systems participate in the control of blood flow to various organs. Exercise places the greatest demands on the circulation. At rest, in humans, skeletal muscle receives somewhere between 15% and 20% of cardiac output, while during maximal exercise, this percentage reaches a value of 80% to 90%. The active human muscles have a high-flow capacity that exceeds the capacity of the heart to pump blood. Measurements in single human muscle have indicated that blood flow may be inhomogenous, that is, probably depending on variations of the vasomotor tone of the muscle mediated by humoral and neural factors. Exercise raises cardiac output and coronary blood flow, which rise linearly with increases in heart rate. In normal young men, coronary blood flow averages 280 ml/min/100 g of the left ventricle and reaches as high as 390 ml/min during moderately severe exercise, requiring about 85% of maximal heart rate. In nonexercising organs, the blood flow decreases at about 20% to 40% of the resting values, being the net result of competing vasoconstrictor and vasodilator drives.

We introduce our recent approach to study autonomic nervous system control of heart rate during exercise by means of heart rate variability (HRV) spectral analysis with special reference to its relationship to ventilatory threshold (Tvent). The rationale for the study was that HRV has been shown to reflect (cardiac) parasympathetic and sympathetic nervous system (PNS and SNS, respectively) activity, together with the underlying complexity of cerebral autonomic system in terms of fractal dimension (DF) of HRV time series. The experimental results showed that PNS was markedly reduced below Tvent, that the rate of change in sympathoadrenal activity indicators (plasma norepinephrine and epinephrine concentrations and SNS indicator) was enhanced above Tvent, and that these changes in PNS and SNS indicators were associated with the appearance of the low-dimensional (low DF) dynamics that might reflect less complex autonomic activity. These findings have been considered with respect to implication for clinical cardiology.

The weak relationship between left ventricular function and exercise capacity in heart failure has stimulated interest in neurohumoral mechanisms as possibly contributing to exercise intolerance. Although chronic activation of neuroendocrine systems is characteristic of heart failure and is accompanied by impaired reflex responsiveness to physiologic stimuli, data from clinical trials do not support the hypothesis that the abnormal neurohumoral state is directly related to exercise intolerance. Thus, these systems may play an important role in the natural history of the disease and its high mortality, but they may not be critical to the impaired exercise capacity.

A 19-year-old woman with a childhood history of cavitating left upper lobe pneumonia presented with persistent weight loss, fever, cough and roentgenographic evidence of right upper lobe pneumonia resistant to antibiotic therapy. An open lung biopsy led to the diagnosis of botryomycosis. Neutrophil function studies including flow cytometric evaluation of oxidative burst, bacterial killing and evaluation of neutrophil cytosolic proteins required for oxidase activation were consistent with chronic granulomatous disease. This is the first case report of primary pulmonary botryomycosis as a clinical manifestation of CGD. Other recent cases of immunodeficiency states associated with botryomycosis are reviewed.

Fibrinolytic therapy has an expanding role in the treatment of many thromboembolic disorders. Four fibrinolytic drugs are currently marketed: streptokinase, anisoylated plasminogen-streptokinase activator complex, urokinase, and recombinant human tissue-type plasminogen activator. All 4 of these drugs activate the fibrinolytic system by converting plasminogen to the active enzyme, plasmin. Plasmin present in the confines of a thrombus degrades fibrin and dissolves the thrombus. Plasmin free in the circulation degrades fibrinogen and other coagulation factors. All 4 of the currently available fibrinolytic agents are capable of initiating thrombus dissolution and, at doses currently recommended, cause degradation of fibrinogen and predispose to bleeding complications. Differences in the mechanisms of plasminogen activation among the available agents provide a theoretical basis for postulating the superiority of one agent over another in clinical practice. However, the relative roles of these agents in treatment of thromboembolic disorders depend on the outcome of properly designed and executed clinical trials.

Many clinicians who practiced in the early and mid-1970s remember PE thrombolysis as an extraordinary enterprise that consumed hospital resources and physicians' time around the clock for at least several days. Indeed, more than 1 in every 4 patients suffered a major hemorrhagic complication when a 24-h dosing regimen was utilized. This unfavorable experience soured some physicians, who have been reluctant to reconsider PE thrombolysis in the 1990s. Fortunately, recently completed clinical trials have taught us many ways to make thrombolytic therapy safer, more streamlined, and more economical (Fig 1).

Acute pulmonary thromboembolism produces a number of pathophysiologic derangements of pulmonary function. Foremost among these alterations is increased pulmonary vascular resistance. For patients without preexistent cardiopulmonary disease, increased pulmonary vascular resistance is directly related to the degree of vascular obstruction demonstrated on the pulmonary arteriogram. Vasoconstriction, either reflexly or biochemically mediated, may contribute to increased pulmonary vascular resistance. Acute pulmonary thromboembolism also disturbs matching of ventilation and blood flow. Consequently, some lung units are overventilated relative to perfusion (increased dead space), while other lung units are underventilated relative to perfusion (venous admixture). True right-to-left shunting of mixed venous blood can occur through the lungs (intrapulmonary shunt) or across the atrial septum (intracardiac shunt). In addition, abnormalities of pulmonary gas exchange (carbon monoxide transfer), pulmonary compliance and airway resistance, and ventilatory control may accompany pulmonary embolism. Thrombolytic therapy can reverse the hemodynamic derangements of acute pulmonary thromboembolism more rapidly than anticoagulant therapy. Limited data suggest a sustained benefit of thrombolytic treatment on the pathophysiologic alterations of pulmonary vascular resistance and pulmonary gas exchange produced by acute pulmonary emboli.

Imaging and Doppler echocardiography permits assessment of right ventricular size and systolic function and of pulmonary arterial pressures, and it may facilitate detection of thromboemboli within the heart or pulmonary artery. In patients with acute pulmonary embolism of sufficient severity to appreciably increase right ventricular afterload, the right ventricle becomes dilated and hypokinetic. Tricuspid regurgitation is generally apparent, but in the absence of preexisting pulmonary arterial or left heart pathology, the regurgitant flow velocity suggests only mild to mild-moderate elevation of pulmonary arterial systolic pressure. The absence of a greater degree of pulmonary hypertension reflects the inability of the previously normal, nonhypertrophied right ventricle to generate a mean pulmonary arterial pressure in excess of about 40 mm Hg. The echocardiographic abnormalities resolve during recovery from pulmonary embolism. Currently being investigated is the question of whether right heart abnormalities resolve more rapidly with thrombolytic therapy than with heparin therapy alone.

The reduction in morbidity and mortality associated with thrombolytic therapy in patients with acute myocardial infarction was initially attributed to early restoration of arterial patency, salvage of ischemic myocardium, and preservation of left ventricular function. Recombinant tissue plasminogen activator (rt-PA) was initially the favored thrombolytic agent because of selected studies showing superior early patency rates. Interestingly, averaged results of studies using conventional dosing regimens show 90-min patency rates for streptokinase, rt-PA, and anisoylated plasminogen streptokinase activator complex (APSAC) to be 53%, 68%, and 72%, respectively, suggesting that previous claims exaggerated differences in early patency. More recently, it was found that administering the full 100-mg dose of rt-PA within 90 min increased 90-min patency rates to approximately 85% and that infusing rt-PA plus urokinase or streptokinase halved reocclusion rates. These results again suggest the unrealized potential of rt-PA to offer a unique clinical benefit. However, three important recent trials have challenged the concept that early patency conveys a survival benefit by showing no difference in mortality in patients treated with different thrombolytic agents. Other trials have shown survival benefit in patients in whom patency of the infarct artery was achieved in a time frame beyond that in which myocardial salvage could be expected. The "open-artery hypothesis" suggests that survival may be more dependent on improved left ventricular remodeling and healing, increased electrical stability, and better myocardial perfusion than on infarct size reduction. In an attempt to determine whether 90-min patency or 24-h patency is more predictive of survival, the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial will randomize approximately 40,000 patients to (1) streptokinase and subcutaneous heparin; (2) streptokinase and intravenous heparin; (3) front-loaded, weight-adjusted rt-PA and intravenous heparin; or (4) the combination of streptokinase and rt-PA and intravenous heparin.

Although the benefits of coronary thrombolysis are well established, the optimal therapeutic strategy for ensuring rapid and sustained coronary artery patency remains controversial. The available data suggest that the success of coronary thrombolysis depends not only on the induction of clot lysis, but also on the extent to which procoagulant activity that promotes recurrent thrombosis is inhibited. Procoagulant activity increases almost immediately in patients treated with fibrinolytic agents, and persistent increases in thrombin activity have been associated with recurrent coronary thrombosis. Heparin administered intravenously appears to markedly attenuate the thrombin activity associated with thrombolysis and, in patients treated with tissue plasminogen activator (t-PA), prevents early recurrent coronary thrombosis. The results of clinical trials of coronary thrombolysis indicate that conjunctive treatment of patients with heparin improves survival compared with treatment with fibrinolytic agents alone. Although recent clinical trials in which patients were treated with streptokinase suggested that 12,500 units of heparin administered subcutaneously twice daily decreases mortality, this dosage regimen does not induce therapeutic levels of anticoagulation within the first 24 h in most patients. The failure to achieve early therapeutic anticoagulation may account for the lack of mortality benefit in trials in which patients given t-PA were treated with conjunctive subcutaneous heparin therapy. Thus, the available experimental and clinical data suggest that intravenous heparin should be given to patients treated with fibrinolytic agents for acute myocardial infarction.

The occurrence of various forms of severe neurologic events has been increasingly reported in acute myocardial infarction patients receiving thrombolytic therapy. Strokes have long been known to complicate acute myocardial infarction. The recent attention on severe neurologic events has focused primarily on probable cerebral bleeds. The various forms of severe neurologic events that clinicians are confronted with have unique features and characteristics that will be delineated. The incidence of these events and patient risk factors for cerebral ischemia and cerebral hemorrhage will be outlined. Guidelines that should be adopted to minimize the chance of a patient's suffering a severe neurologic event while at the same time maximizing the number of patients who receive this lifesaving therapy are summarized.

Changes in the economic and therapeutic environment have altered the time frame in which an accurate diagnosis of acute myocardial infarction (AMI) must be made. The advent of effective reperfusion therapies and the increasing emphasis on reducing cost produce an environment in which rapid diagnosis can reduce morbidity and mortality while simultaneously reducing overall cost by avoiding unnecessary hospitalization and intervention. The first element of a diagnostic strategy remains a brief, directed history and physical examination. The orientation of this phase is to identify important causes of symptoms other than AMI, while rapidly leading to more definitive evaluation for myocardial ischemia when another diagnosis is not found. The ECG provides the most rapid definitive diagnosis, but the diagnosis remains equivocal in many patients with nondiagnostic ECGs. In this group, the use of cardiac enzyme measurements early in the course holds promise in directing intensive care at high-risk patients while avoiding unnecessary intervention in low-risk patients. A protocolized approach to patient evaluation should become a part of standard practice patterns in every hospital.