The modern treatment of cardiopulmonary disease is increasingly predicated on the goal of dissolving the offending clot to establish vascular patency as rapidly as possible and then preventing rethrombosis. The availability of thrombolytic agents has made this therapeutic approach possible and the adjunctive use of heparin, coumarin, and aspirin has increased the efficacy of lytic drugs. The administration of any of these medications is associated with inherent risks, which are enhanced when they are used concomitantly. An understanding of coagulation and an appreciation of the pathophysiologic processes of the thrombotic events occurring in cardiopulmonary disease states are critical to the formulation of innovative therapeutic regimens that maximize efficacy and safety. Furthermore, knowledge of the comparative pharmacology of the various thrombolytic agents is useful in explaining the benefits and complications observed in clinical trials.

During the past year, there have been 2 major advances in the management of pulmonary embolism (PE). First, the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) investigators published the results of their comparison of ventilation-perfusion lung scanning and pulmonary angiography. This multimillion-dollar trial sponsored by the National Heart, Lung, and Blood Institute indicated that lung scanning is surprisingly insensitive to the diagnosis of PE. High-probability lung scanning detects fewer than half of the cases of PE that are found at pulmonary angiography. The PIOPED results force us to conclude that increased utilization of both ultrasonography of the deep leg veins and pulmonary angiography is warranted in order to detect the majority of cases of venous thromboembolism. Second, in June 1990, the Food and Drug Administration approved recombinant human tissue-type plasminogen activator (rt-PA) for use in the treatment of acute PE. The dosing regimen is 100 mg of rt-PA as a continuous peripheral intravenous infusion administered over 2 h. The convenience, rapid effect, and relative safety of this therapeutic approach may result in increased use of thrombolysis for management of PE.

The diagnosis of lower limb deep vein thrombosis can be made rapidly by compression ultrasound. This noninvasive test has almost completely replaced contrast phlebography in some major hospitals in North America. Compression ultrasound is well suited for making the diagnosis of deep vein thrombosis, measuring its extent, and monitoring the draining veins of the calf for evidence of spread of calf vein thrombosis. The nature of the deep vein thrombus, whether it is obstructing or nonobstructing, can be determined with the additional use of color Doppler mapping, a technique that displays flowing blood as a color overlay to the 2-dimensional real-time ultrasound image. Serial noninvasive determinations of the extent of thrombus in the lower-extremity deep veins is now possible with this combined sonographic imaging approach. Monitoring of possible changes in the extent of the thrombus burden can now be undertaken in patients enrolled in trials assessing the efficacy of different thrombolytic regimens.

A canine model of pulmonary embolism, induced by injection of autologous radioactive blood clots, was used to investigate principles of thrombolysis in pulmonary embolism. One study compared recombinant tissue plasminogen activator (rtPA) with heparin in the treatment of pulmonary embolism. This study also compared the efficacy of rtPA (1 mg/kg) given over 15 min (rtPA15) to the same total dose infused over 90 min. Compared with heparin, both rtPA regimens induced marked pulmonary thrombolysis. During drug infusion, the rate of thrombolysis was increased 2-fold with rtPA15. A 2nd canine study investigated the physiologic mechanism of the decrease in pulmonary artery pressure with rtPA. The pattern of hemodynamic improvement with rtPA indicated that pulmonary thrombolysis predominantly occurred in partially, rather than totally, obstructed vascular units. A 3rd canine study compared rtPA and high-dose urokinase (UK) in treatment of pulmonary embolism. Both rtPA regimens were superior to UK in inducing pulmonary thrombolysis and improving pulmonary hemodynamics. Most recently, the effects of flow dynamics on rtPA-induced pulmonary thrombolysis were investigated, and it was demonstrated that an increase in cardiac output markedly enhanced rtPA-induced pulmonary thrombolysis. Most likely, the increase in cardiac output increased thrombolysis by enhancing delivery of rtPA to thrombus in partially obstructed vascular units.

Emergency cardiac catheterization and coronary angioplasty for acute myocardial infarction (MI) have a continuing role in the thrombolytic era. Although thrombolytic therapy has revolutionized the treatment of MI, it has significant shortcomings: about 75% of patients with acute MI cannot be treated with thrombolytic agents, 25% of treated patients will have persistent occlusion of the infarct-related artery, 70% will have a residual stenosis greater than or equal to 70%, and 20% of treated patients will experience reocclusion. Cardiac catheterization identifies the coronary anatomy for mechanical revascularization and allows the unstable patient to receive special therapy, such as intra-aortic balloon pumping. Many large clinical studies have evaluated approaches to coronary angioplasty for acute MI. Deferred angioplasty has indisputable advantages over immediate routine angioplasty. Direct angioplasty without concomitant thrombolytic therapy has acceptable success and complication rates, so that it can be considered the treatment of choice for acute MI in centers with an angioplasty program if thrombolytic therapy is contraindicated. Patients at very low risk may not require cardiac catheterization routinely before discharge, since their good prognosis cannot be improved by invasive evaluation and intervention. Emergency surgical revascularization is indicated in a very small percentage of cases.

The beneficial effects of coronary thrombolytic therapy may be enhanced by certain adjunctive therapies. Some of these are of proven value, some appear to offer no benefit in spite of theoretical advantages, and some remain to be evaluated in clinical trials. Acetylsalicylic acid markedly enhances the mortality reduction of thrombolytic therapy and should be used routinely. There is a strong theoretical rationale for the use of heparin, but evidence for its benefit exists primarily in small angiographic trials, and convincing clinical benefit has not yet been demonstrated. Early intravenous beta-blockers were shown in the prethrombolysis era to confer modest benefit, but extensive data on their adjuvant use with thrombolysis are available from only one trial. Intravenous nitrates were demonstrated to reduce mortality in the prethrombolysis era, and are soon to be evaluated in trials employing thrombolytic therapy. The calcium channel blockers, in spite of a variety of theoretical benefits, have proved to be of no value acutely, and in the subacute setting, only diltiazem appears to confer benefit in the subgroup of patients with non-O-wave infarction. Angiotensin-converting enzyme inhibitors are likely to be of value in survivors of acute myocardial infarction with left ventricular dysfunction, and benefits observed with acute use in experimental infarction are now being evaluated in clinical trials.

Arrhythmias that may accompany myocardial reperfusion have generated significant clinical interest. First, there were concerns, based on animal studies, that high-grade ventricular tachyarrhythmias would pose a serious threat following thrombolytic therapy to treat an evolving myocardial infarction. Second, lower-grade arrhythmias, such as accelerated idioventricular rhythm, were cited as useful, noninvasive markers of successful reperfusion. Critical review of the current data, however, indicates that arrhythmias following thrombolytic therapy for acute myocardial infarction are usually neither dangerous clinical events nor consistent markers of reperfusion.

Thrombolytic therapy decreases mortality in patients with acute myocardial infarction and is now widely used in such patients. The choice of which thrombolytic agent to use in such patients, either streptokinase or recombinant tissue plasminogen activator (rt-PA), is based on regional preferences. The standard dose of streptokinase is 1.5 million units over 60 min, and the dose of rt-PA that is commonly used is 100 mg over 3 h. Experiments in animals have demonstrated that rt-PA produces continuing thrombolysis after it is cleared from the circulation and that thrombolysis is both increased and accelerated and bleeding is reduced when rt-PA is administered over a short time period. Based on these studies, there have been a number of recent trials examining alternative dosage regimens for rt-PA (bolus, front-loaded, and accelerated) in patients with myocardial infarction. To date, there is no convincing evidence that such regimens are superior to the more traditional rt-PA regimen. Future randomized trials will determine whether attempts to optimize rt-PA regimens will result in more efficacious treatment regimens. Interest in the use of thrombolytic therapy for patients with acute pulmonary embolism has been rekindled. The traditional 12- to 24-h regimens of streptokinase and urokinase are not optimal because of their logistic complexity and associated hemorrhagic complications. Clinical studies have demonstrated that rt-PA, 100 mg over 2 h, is an effective thrombolytic agent in patients with acute pulmonary embolism. In a recent double-blind trial in patients with acute pulmonary embolism, rt-PA, 0.6 mg/kg infused over 2 min, improved pulmonary perfusion. This bolus regimen is attractive because it is simple to administer. Future studies will compare the relative efficacy and safety of these two rt-PA regimens in patients with acute pulmonary embolism.

The 1980s has been a critical decade for the management of acute myocardial infarction (MI) because of the concentration in a very short time span of innovative results produced by a new generation of trials, in which thrombolysis has been the preeminent topic. The message coming from the results in the more than 50,000 patients included in the five key trials is simple and clear: thrombolysis, of any type, is the cornerstone of acute treatment of MI, and it works well to produce a very favorable epidemiologic picture. In the GISSI-2 trial, the nationwide adoption of a package of recommended treatments centered on thrombolysis for the overall population of patients with an acute MI has produced a relevant modification of the natural history of the disease, reducing the in-hospital mortality by about 40% in few years (from 13% to 8.8%). In particular, in the great majority of cases (patients aged less than 70 years in Killip class I with a first acute MI), the mortality has gone down to 3%, making a further reduction very hard to obtain with new drugs or strategies. In this context, we will discuss the concept of the relevance for clinical practice of obtaining even greater patency rates with new thrombolytic agents (hopefully more efficient and safe) or with new combinations of traditional agents.

Thrombolytic therapy is being used with increasing frequency in myocardial infarction (MI), pulmonary embolism, deep venous thrombosis (DVT), and peripheral arterial occlusion. Use of these agents, however, is hampered by concerns regarding safety and efficacy. Numerous laboratory parameters have been evaluated for monitoring the risk of bleeding complications, with levels of fibrinogen (and percentage of decrease) and fibrin/fibrinogen degradation products (FDPs) correlating to a variable extent with clinical bleeding. The bleeding time (BT) test has also been proposed as a potential predictor of bleeding during thrombolytic therapy. With respect to efficacy, the D-dimer fragment of FDPs, when corrected for soluble fibrin polymers, has been shown to correlate with clot lysis in venous thromboembolism but not MI. The BT also is being considered as a marker of lysis in patients with DVT. Given the increasing concomitant use of antiplatelet agents during thrombolytic therapy, the BT, as an in vivo test of hemostasis and platelet function, has potential utility as a noninvasive, adjunctive marker of thrombolytic efficacy.

Varicella pneumonia during pregnancy carries a significant mortality for both mother and fetus. The antiviral drug, acyclovir, appears to have decreased mortality in reported cases. We present a case report and review of the literature summarizing the experience to date with acyclovir in the treatment of varicella pneumonia during pregnancy.