Tissue-type plasminogen activator has high affinity for fibrin and is activated by fibrin. Because of these properties, t-PA was initially expected to cause minimal bleeding complications. This prediction has been only partially confirmed in major clinical trials in which t-PA was given in the doses necessary for effective coronary thrombolysis. The risk of bleeding in patients receiving t-PA is correlated with increased levels of fibrin degradation products and hypofibrinogenemia, consistent with a link between systemic plasminemia and hemorrhage. Limiting t-PA-associated bleeding may therefore require measures aimed at decreasing hyperplasminemia. These measures include a short infusion of a high t-PA dose. This article presents new experimental evidence that has confirmed our previous results showing that a short infusion of t-PA is an effective and safe thrombolytic treatment.

Recombinant tissue-type plasminogen activator (rt-PA), streptokinase (SK), and anisoylated plasminogen-streptokinase activator complex (APSAC) have salutary effects on mortality when administered to patients with evolving acute myocardial infarction (MI). Studies suggest that intravenous rt-PA is more effective in reperfusing occluded infarct-related arteries than SK, and the results of ongoing studies directly comparing the influence of SK and rt-PA on mortality are awaited. The clinical role of agents such as APSAC, urokinase, and pro-urokinase, used alone or in combination, remains to be determined. It is evident that a variety of thrombolytic agents will be effective, and variables such as ease of administration, pharmacokinetics, fibrin specificity, effects on blood viscosity, and incidence of adverse effects need to be assessed to determine which agents are the most suitable for clinical use. There is an increased risk of bleeding at vascular puncture sites with all thrombolytic agents. Current indications for thrombolytic therapy include ischemic chest pain of at least 30 min duration that is unrelieved by nitroglycerin and is associated with ST-segment elevations of at least 0.1 mV in two contiguous electrocardiographic leads. Such therapy is usually reserved for patients less than 75 years old who are not at increased risk for bleeding and whose chest pain began less than 4-6 prior to treatment. Trials are under way to determine whether patients with shorter pain duration, transient ST-segment changes (ie, unstable angina patients), chest pain associated with ST-segment depressions or T-wave inversions (ie, non-Q-wave infarction patients), or patients whose pain began more than 4 to 6 h earlier will benefit from early thrombolytic therapy. Other factors such as patient age, the likelihood of the diagnosis of MI, and the estimated risk of bleeding should also be considered. The findings of available major randomized trials indicate that early invasive procedures are generally unnecessary and that meticulous care must be exercised in the selection and management of patients subjected to thrombolytic therapy.

In most circumstances in health, efficient alveolar ventilation and alveolar-to-arterial exchange of O2 and CO2 are among the strongest of links in the gas-transport chain during maximal exercise. Indeed, in most instances, the metabolic cost of ventilation represents the only significant contribution of the pulmonary system to the limitation of O2 transport of locomotor muscles and thus to the limitation of maximum performance. Of the "weaknesses" inherent in the healthy pulmonary system response to exercise, the most serious one may well be its absence of structural adaptability to physical training or to the trained state. Thus, the lung's diffusion capacity and pulmonary capillary blood volume remain unaltered in the highly trained human or horse, while maximum pulmonary blood flow rises linearly with the enhanced max VO2. Similarly, ventilatory requirement rises markedly, with no alteration in the capability of the airways to produce higher flow rates or of the lung parenchyma to stretch to higher tidal volumes, and little or no change in the pressure-generating capability of inspiratory muscles. The case of the elderly athlete who remains capable of achieving high maximum pulmonary blood flows and ventilatory requirements and whose lung undergoes a normal aging process underscores the importance of deficits (from "normal") on the capacity end of this continuum of cost versus capacity in the pulmonary system. The asthmatic athlete may represent another such example of limited flow-generating capacity; and the healthy, young, highly fit athlete who shows marked reductions in SaO2 and in max VO2 at even moderately high altitudes demonstrates that, in many situations, precious little room can be added to the demand side or removed from the capacity side before signs of failure can be seen.

Breathing is controlled by an automatic brain-stem controller acted on by higher neural influences that stabilize breathing and compensate for neuromechanical abnormalities. Loss of this wakefulness-dependent descending influences during nonrapid eye movement (NREM) sleep results in the appearance of a hypocapnic apnea threshold, which is associated with periodic breathing when the gain of chemical feedback loops is high. In addition, loss of the descending wakefulness influence leads to loss of motor compensation that results in a rise in upper airway resistance, obstructive sleep apnea or hypoventilation in patients with kyphoskoliosis or thoracic neuromuscular disorders. REM sleep poses different problems for the respiratory control system owing to muscular atomia and suppression of chemical feedback. These changes are associated with respiratory deterioration in patients with compromised diaphragmatic function, eg, patients with chronic obstructive pulmonary disease.

We have reviewed evidence that hypoxic chemosensitivity is variable and that this variation may be both endowed, partly through genetic mechanisms, and acquired, and may reflect fundamental changes in carotid body function. This variation may influence the nature and effectiveness of adaptation to high altitude and to hypoxic disease states such as chronic obstructive pulmonary disease. High chemosensitivity seems to be the choice for coping with the casual exposure to hypoxia; but fundamental, highly effective adaptations, presumably at the level of peripheral tissue, seem to be the strategy of choice for professionally adapted species.

Bronchopleural fistulas are associated with high morbidity and mortality and are particularly challenging in the ventilated patient. Familiarity with both basic and more technical medical management techniques may lessen morbidity and improve survival. Prompt recognition of BPFs and appropriate placement of a chest tube with an adequate suction device are crucial to prevent potential tension pneumothorax and to drain an infected pleural space. The chest tube may be used therapeutically to decrease BPF air leak and to promote fistula repair. Appropriate conventional ventilator manipulations aimed at decreasing fistula air leak and maintaining adequate oxygenation and ventilation may fail and necessitate a trial of HFV. Definitive therapy by the bronchoscopic application of a sealing agent to occlude the fistula site can be used, particularly in the poor surgical candidate.

Although commonly found at autopsy, leukemic infiltration of the lung is rarely recognized as a cause of respiratory symptoms or roentgenographic densities. Previously reported cases of patients who had symptomatic or roentgenographic acute leukemic lung diseases invariably presented with diffuse pulmonary infiltrates. We describe three patients with leukemic involvement of the lung who presented with cough, fever, and localized roentgenographic infiltrates suggestive of bacterial pneumonia. In each case, the diagnosis was made by transbronchial biopsy specimen and confirmed by complete response to chemotherapy. In common with the other reported cases, all of our patients had peripheral blast counts above 40 percent (greater than 6,000 blasts per ml3) at the time the pulmonary diagnosis was made. Leukemic invasion of the lung should be considered in patients with acute leukemia who develop lung infiltrates--whether diffuse or focal--in association with a high peripheral blast count.

Recent research suggests that anxiety disorders are more common in asthmatic patients than in the population as a whole. There are a variety of biologic, psychologic, and social factors that suggest that the disorder of asthma may in itself be anxiogenic and that simply having asthma may give patients an increased vulnerability toward the development of anxiety disorders. These issues are reviewed and emphasis is placed on the need for further research into the apparent biologic areas of overlap between psychiatric disorders and asthma. It is hypothesized that a "lactate challenge test" may be used in asthmatics to see if they are predisposed to panic and suggested that a therapeutic trial of tricyclic antidepressants in anxious asthmatics is indicated. Research into the psychobiologic aspects of asthma is likely to clarify the role of "emotional" factors in asthma and may well have significant implications for the management of this disorder.

Classification of chronic airflow obstruction may be based on the site of the obstructing lesions. It is seldom that only one type of lesion is present, but one may often dominate. In chronic bronchitis, the major disease of large airways, chronic mucus hypersecretion, is reflected by an increase in size of bronchial mucous glands. This may be a factor in airway narrowing, especially with coexisting edema of the airway wall. Excess intralumenal mucus compounds the obstruction. Increased airways reactivity is present in 15 to 70 percent of patients with chronic airflow obstruction. Increased airway muscle and cartilage atrophy are features of chronic bronchitis, but the association of increased muscle with increased airway reactivity is poor. Inflammation of the small airways (bronchiolitis) is a significant complication for cigarette smokers and is an important cause of mild chronic airflow obstruction. Goblet cell metaplasia is a reflection of chronic small airways inflammation and, together with intralumenal mucus, is an important feature. Permanent narrowing of the small airways presumably results from inflammation with consequent fibrosis, while functional narrowing results from release of mediators of inflammation. Increased muscle mass is present in some cases. Distortion and irregularity of small airways related to emphysema are major factors in severe obstruction. Lesser degrees of emphysema may be associated with a diminished number of alveolar attachments and mild chronic airflow obstruction. Emphysema, the dominant lesion in patients with severe chronic airflow obstruction, results from parenchymal lesions. Centrilobular emphysema, in which the respiratory bronchioles are selectively or dominantly involved, is the most common form.(ABSTRACT TRUNCATED AT 250 WORDS)

Medical views in the United States on the effects of smoking have shifted dramatically since the published evidence in 1958 established the link between smoking and fatal disease. Today's physician should be a nonsmoking role model, whose workplace both directly and indirectly teaches smoking cessation skills. Publications on smoking cessation techniques from the National Institutes of Health along with intervention tools such as patient smoking history questionnaires are available free of charge to physicians. Patient histories are critical to the intervention process, for they provide essential clues and information about which stage in cessation of smoking the patient has already reached: precontemplation, contemplation, action, and maintenance. Different approaches and techniques are required at each stage. The most important objective for the physician with a patient at the stage of contemplating quitting is to initiate a conversation leading to a directive to quit, with benefits of quitting stressed as reinforcement. Actively motivated patients committed to quit dates may need both educational and pharmacologic support; issues such as nicotine dependence and withdrawal symptoms must be addressed. Pharmacologic therapy at this time may consist of substitution of nicotine-containing gum (nicotine polacrilex) for cigarettes. Used in sufficient, regular dosages, the nicotine gum has been found to help diminish withdrawal symptoms following smoking cessation. Other drug therapies are currently under study. For now, nicotine replacement therapy (where indicated) is to be used for at least three months, the period of greatest chance of relapse. The physician should continue to encourage patients who have quit smoking to forestall relapses, while tacitly understanding that the incidence of relapse is high in first-time quitters. Hospital inpatients provide an opportunity to initiate bedside smoking cessation programs. The hope is that, in the future, hospitals will involve the entire health team in comprehensive smoking cessation programs.