The use of thrombolytic therapy has increased considerably in the past five years, particularly in patients with acute myocardial infarction. The agents that have been used in humans thus far include streptokinase and urokinase, as well as tissue-type plasminogen activator and, most recently, single-chain urokinase-type plasminogen activator or pro-urokinase. Each of these agents works by very different mechanisms to activate plasminogen and, as a result, to lyse fibrin clots. This article reviews the mechanisms by which pathophysiologic thrombi develop, the pharmacologic agents available to lyse thrombi, and the mechanisms of action of these agents.

The long-term CVC allows patients with a variety of diseases to lead a more normal and pain-free life. The use of these catheters has become commonplace in most hospitals, and the physician caring for patients in the ICU will be caring for increasing numbers of patients with an indwelling long-term CVC. Infections of these catheters can be manifested in many different ways: tunnel infections, exit site infections, catheter-related bacteremia, and septic thrombophlebitis. The overwhelming majority of these infections are caused by coagulase-negative staphylococci, but physicians should be aware of the wide variety of organisms that can infect the long-term CVC. The diagnosis of long-term CVC sepsis can be difficult, but the use of quantitative blood cultures for catheters left in place and the Maki method for culturing those catheters that are removed will aid physicians in their quest for diagnostic certainty. The great majority of catheter infections will resolve with antibiotic therapy alone without the need for catheter removal, but there are important exceptions to this general rule. Tunnel infections and fungal long-term CVC infections often require catheter removal for their resolution; septic thrombophlebitis and CR-SCVT require the addition of anticoagulation or fibrinolytic therapy to antibiotic regimens for resolution of the infection, and surgical debridement may be warranted if these modalities fail to resolve the infection.

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.