Pulmonary Thromboembolic Disease: Noninvasive Treatment

WILLIAM R. BELL

Treatment

Because pulmonary embolization occurs abruptly, often at the most inopportune times, when sophisticated diagnostic equipment and therapy are not immediately available, every effort must be made to sustain life. Critically important is the immediate correction of any aberrant cardiopulmonary hemodynamics. In this situation, blood flowing into the right side of the heart is retarded and inevitably inadequate. To augment blood flow through the pulmonary artery, the patient should be given intravenous saline to the tolerance of the right ventricle to move as much blood to all available gas-exchange units for maximal possible oxygenation. In certain patients, the additional use of vasopressor, inotropic agents, antiarrhythmic medications, and digitalis may be indicated. Oxygen should be given to improve any hypoxia that may exist.

Thrombolytic Therapy

Because thrombolytic agents are the only category of agents that can induce the resolution of endogenously formed thromboemboli and thereby permit the prompt return of normal blood flow to the pulmonary gas exchange units, this therapeutic strategy is the initial treatment of choice for most patients with pulmonary emboli. Thrombolytic agents are the initial treatment of choice in patients with massive emboli (greater than two lobar arteries obstructed or anything that totals an equal area of obstruction), massive emboli in shock, or submassive emboli superimposed on preexisting chronic cardiopulmonary disease that results in hemodynamic compromise. In patients who have minimal amounts of embolic material, who are without hemodynamic compromise, and who are relatively asymptomatic, anticoagulation with heparin may be equally efficacious as thrombolytic therapy.

All available thrombolytic agents interact directly or indirectly with plasminogen, with the resultant generation of plasmin, a proteolytic enzyme that has the capacity to degrade fibrin strands and induce the dissolution of thrombi and emboli; this is not achieved with heparin nor any other form of anticoagulation. Several reports have described more impressive and convincing improvement in pulmonary function and clinical status with the use of thrombolytic therapy compared with use of heparin alone in treatment of pulmonary emboli.¹^–¹⁷ A definitive, cooperative, randomized, controlled trial of patients with angiographically documented pulmonary emboli demonstrated accelerated angiographic resolution, improved perfusion by lung scan, lowering of pulmonary artery pressure, and statistical improvement in cardiac function in patients treated with thrombolytic therapy compared with patients treated with heparin alone.³^,⁴ These findings have been documented repeatedly by additional studies.¹¹^–¹⁷

The location of the infusion of the thrombolytic agent in relation to efficacy has been questioned. Studies in both animal models and humans with documented pulmonary emboli have found no difference in emboli resolution if any of the thrombolytic agents are infused directly into the main pulmonary artery rather than into a forearm vein.¹⁸ In a subpopulation of patients with pulmonary emboli who presented with chronic occlusion of the vasculature supply of one or more pulmonary segments, it may be advantageous to place an angiocatheter into the obstructing thromboemboli and to infuse the thrombolytic agent directly into the embolic material in an attempt to reperfuse oligemic pulmonary parenchyma.¹⁵

Four pharmacologic thrombolytic agents are currently available for the purpose of inducing thromboemboli dissolution. These agents are urokinase (UK) (Abbokinase, Abbott Laboratories, North Chicago, IL), streptokinase (SK) (Streptase, Astra Pharmaceuticals, Westboro, MA; and Kabikinase, Kabi Pharmacia, Piscataway, NJ), acetylated plasminogen streptokinase activator complex (APSAC) (anistreplase, Eminase, SmithKline–Beecham Pharmaceuticals, Philadelphia, PA; and recombinant tissue plasminogen activator (rTPA) (alteplase, Activase, Genentech Inc., South San Francisco, CA).

The two of these agents that have been available for the longest time are UK and SK, and they have been used frequently in the treatment of pulmonary thromboembolic disease. The success rate of these agents to induce resolution of pulmonary thromboemboli is about 75 to 93% of patients treated. UK is given in a loading dose of 4000 U/kg administered intravenously (i.v.) in 30 to 45 minutes and a maintenance i.v. dose of 4000 U/kg per hour. SK is initially given in a loading dose of i.v. 250,000 IU within 30 to 45 minutes, followed by a maintenance dose of 100,000 IU per hour. The optimal duration for infusion of these agents in the treatment of pulmonary thromboemboli is 24 to 48 hours. Some patients may require only 12 hours of therapy. Both agents can be given in larger doses: “Front loading,” UK 1,000,000 to 2,000,000 U and SK 1,000,000 IU in a semibolus manner within 5 to 15 minutes can be used in patients who are severely hemodynamically compromised and desperately in need of some degree of rapid resolution of emboli to maintain life,¹³^,¹⁷

Much less experience is available with the use of rTFA¹³^,¹⁷^,¹⁹^–²³ and APSAC in the treatment of patients with pulmonary thromboembolic disease.²⁴ rTPA has been used as a front-loading agent given i.v. at a dose of 100 mg i.v. within 2 hours. This agent can provide excellent prompt resolution (as with large doses of UK and SK) and may provide immediate improvement in hemodynamics. If treatment is given only for 2 hours, the degree of resolution is incomplete.

It must be made clear that the use of front-loading doses per se for the treatment of pulmonary thromboemboli is inadequate for thorough resolution of this disease regardless of the agent used. For excellent resolution of the embolic thrombotic material, all “frontloading” regimens, whichever agent is used, must be followed by standard maintenance thrombolytic therapy given for 24 to 48 hours in most patients.

Because of the potency of these thrombolytic agents, patient selection should be exercised. These agents should not be administered to any patient with any degree of active bleeding, or to any patient with a recent (1 to 2 months) central nervous system (CNS) event. With respect to r-TPA, if the patient has experienced a CNS event anytime in his or her life, this agent should not be used.

Thrombolytic therapy, regardless of the agent used, for the time required to treat pulmonary thromboembolic disease, (i.e., 24 to 48 hours) should be monitored. Although a universally accepted method for monitoring thrombolytic therapy does not exist, the optimal technique is the thrombin time (TT).²⁵ This test should be used before (in the absence of heparin) the institution of thrombolytic therapy, at 4 to 5 hours after initiation of continuous infusion of the thrombolytic agent, and every 12 hours thereafter for the duration of therapy. At the end of the infusion, anticoagulation therapy must be used, first with heparin (without a loading dose), followed by warfarin for 6 weeks to 6 months, depending on the clinical situation.

Anticoagulation Therapy

The initial anticoagulant of choice for treatment of pulmonary thromboembolic disease, be it primary or secondary therapy, is heparin given intravenously. This agent should be given initially in the form of a 5000 U loading dose, given slowly by i.v. push, followed by a continuous infusion with a mechanical infusion pump. The kinetics of heparin disappearance favor the use of a continuous infusion,²⁶ particularly in pulmonary embolism, in which the disappearance of heparin is accelerated compared with both deep vein thrombosis and the normal state.²⁷

The argument that hemorrhagic complications of heparin therapy, particularly in high-risk patients, are reduced by continuous infusion as opposed to intermittent injection has been supported by two controlled trials²⁸ but not by two others.²⁹ Despite this controversy, complications probably can be reduced by continuous infusion, especially because the total daily dose of the drug can be lower with continuous infusion than with intermittent injection, and patients who bleed on intermittent therapy can be switched successfully to i.v. therapy without further bleeding. For intermittent therapy, in most patients with submassive pulmonary embolism 5000 U intravenously every 4 hours has been adequate. After approximately 48 hours, oral anticoagulant therapy can be started, using at least a 6-day overlap of the two anticoagulants. In massive pulmonary embolism, larger doses are recommended, at least for the first 24 hours of treatment (approximately 10,000 U every 4 hours).³⁰ With the continuous infusion program, one would start with either the medium or the large dose, depending on apparent clinical severity, beginning with an infusion of 25 units/kg per hour.

The need for laboratory monitoring of dosage is unresolved. Monitoring therapy by coagulation tests was not shown to effective when intermittent heparin was used.²⁸ Two studies, however suggested a benefit when continuous infusion has been used.³⁰ The Lee–White clotting time done as a bedside test worked well, but some investigators reject it as being too time consuming and difficult to standardize.³ The thrombin clotting time with or without dilution has been used successfully by several groups to control heparin therapy.³¹ One or another modification of the whole-blood recalcification time, which is a test-tube adaption of the Lee-White clotting time, was sufficiently sensitive and reproducible in the hands of several groups.³² The activated partial thromboplastin time (APTT), attractive for relative linearity between that test result and heparin concentration over the therapeutic range, can be done on either whole blood or plasma.³³

Only gold members can continue reading. Log In or Register to continue