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.

The postpneumonectomy syndrome is a rare complication occurring after right pneumonectomy and is seen mainly after pneumonectomy in childhood. The presenting symptoms are dyspnea, stridor, and recurrent pulmonary infections. The syndrome is caused by the shifting and rotation of the heart and mediastinum into the right hemithorax, and anterior herniation of the left lung. This causes tortuosity and stretching of the trachea and compression of the left main bronchus and left lower lobe bronchus, eventually resulting in secondary tracheobronchomalacia. This report reviews two cases of postpneumonectomy syndrome following pneumonectomy in adulthood. After implantation of an expandable prosthesis, an anatomic correction of the shifted mediastinum was achieved, which in both cases resulted in instantaneous and sustained relief.

The microscopic anatomy of the pulmonary circulation was reviewed, comparing the evidence for two competing models, the sheet-and-post paradigm and the tubular paradigm. Implications of the two paradigms were analyzed for function, including flow, recruitment, distension, and diffusion. We conclude that the pulmonary microcirculation is not essentially different from the systemic microcirculation except that two layers of tubular capillaries are arranged on a central layer of connective tissue, the alveolar wall. We find no morphologic basis or theoretic advantage for the sheet-and-post concept.

Large-scale, randomized clinical trials have produced over the last few years a wide consensus about the role of thrombolysis in the treatment of acute myocardial infarction (AMI). It has been estimated from the trials with broader inclusion criteria that about 40% of the patients admitted to coronary care units with AMI are eligible for fibrinolytic therapy and can benefit from it. On the other hand, drug utilization data suggest that only a fraction of eligible patients actually receive thrombolysis. A reason for this dissociation between knowledge and practice lies in the widespread assumption that thrombolysis is inefficacious in particular population subsets, as well as in the setting of a number of contraindications based on controversial evidence. Age per se does not represent a contraindication to thrombolysis, which could display a lifesaving potential two or three times that estimated for the general population of patients with AMI. Although it has been shown that the sooner thrombolytic treatment is provided after the onset of symptoms the more effective it is, the available evidence seems to indicate that the effect could well extend up to 12 h from the onset of symptoms. Patients with an inferior myocardial infarction should also receive thrombolytic treatment on the basis of the results of a meta-analysis carried out on 12,000 patients. Very misleading recommendations for practice can be produced by adjusting the main results so as to conveniently allow for subgroup findings, regardless of their degree of epidemiologic, biologic, and pathophysiologic consistency. For all categories of patients included in the population trials (with the exception of those with ST depression), thrombolysis should be considered a recommended treatment. From an epidemiologic perspective, the extension of the benefits of thrombolytic therapy to all AMI patients for whom the drug is not clearly contraindicated is a goal of primary importance.