Treatment of canine embolic pulmonary hypertension with recombinant tissue plasminogen activator. Efficacy of dosing regimes.

Abstract

We investigated effects of two dosing regimes of recombinant tissue plasminogen activator (rt-PA) and sodium heparin on pulmonary thrombolysis in a canine model of pulmonary hypertension, induced by injection of radioactive blood clots. By continuously counting over both lung fields with a mobile gamma camera, we correlated rate and extent of pulmonary thrombolysis with corresponding pulmonary hemodynamics. Treatment with heparin, over a 3-hour interval, did not result in significant thrombolysis or in a decrease in mean pulmonary artery pressure (PAP). In contrast, rt-PA caused marked pulironary thrombolysis. While total clot lysis was similar when 1 mg/kg rt-PA was infused over 15 (rt-PA15) or 90 (rt-PA90) minutes (47% and 42%, respectively), rate of lysis during infusion was markedly increased with rt-PA15 (56% vs. 27%/hr, p<O.OOl). Corresponding to the increased rate of thrombolysis with rt-PA15, relative PAP decrease was greater at 15 and 30 minutes. At 4 hours, PAP decreased most with rt-PA90. However, two of the six dogs given rt-PA15 had an increase in PAP and lung radioactivity 1 hour after rt-PA. This was associated with dislodgment of a previously trapped clot. These results suggest that rt-PA may be appropriate therapy for pulmonary embolism and support further studies designed to optimize dosing regimes. (Circulation 1988;19:214-220) R ecent clinicall-5 and basic6-8 studies have demonstrated the efficacy of recombinant tissue plasminogen activator (rt-PA) in inducing thrombolysis. Two prospective, randomized clinical studies demonstrated that rt-PA may be superior to streptokinase in treatment of coronary thrombosis. 12 In these two studies, while the decrease in systemic fibrinogen levels was greater with streptokinase, bleeding complications, usually at puncture sites, were similar with rt-PA and streptokinase.While numerous studies have investigated the effects of rt-PA in acute coronary occlusion due to thrombosis, only a few have studied the effects of rt-PA in pulmonary embolism.9"0 The present study was designed to assess the effect of rt-PA on pulmonary thrombolysis in a canine model of radioactive autologous clot embolization. By continuously imaging over both lung fields with a mobile gamma camera, we correlated rate and extent of clot lysis with corresponding pulmonary hemodynamics. Finally, because previous work has suggested that a given dose of rt-PA may be more effective in inducing thrombolysis when given over a short period of time,8 we compared the relative efficacy of rt-PA given over 15 minutes versus the same total dose infused over 90 minutes.Materials and Methods Eighteen dogs (15-27.5 kg) were anesthetized with pentobarbital (30 mg/kg i.v.) and supplemented as required to maintain apnea. Each dog was mechanically ventilated in the supine position via an endotracheal tube with 100% 02 at a tidal volume of 20 ml/kg. Rate

Recombinant tissue-type plasminogen activator in canine embolic pulmonary hypertension. Effects of bolus versus short-term administration on dynamics of thrombolysis and on pulmonary vascular pressure-flow characteristics.

“…As cited above, a recent study of embolic pulmonary hypertension demonstrated increased rate of clot lysis with rt-PA15 versus rt-PA90.5 To extend this work, the present study also tests the hypothesis that if the same total dose of rt-PA is given over 5 (rt-PA5) versus 15 (rt-PA15) minutes, the initial rate of thrombolysis and improvement in PAP would be most rapid with the former regimen.…”

Tissue Plasminogen Activator in Cardiac Arrest with Pulseless Electrical Activity

“…23 We chose to deliver the maximal amount of drug used in the treatment of myocardial infarction (100 mg) in the shortest period supported by the literature -15 minutes. 10,11,38 We also stipulated that patients receive a further 15 minutes of CPR after the infusion. We elected to leave the decision to administer heparin, aspirin, or both to the discretion of the attending physician and found that 5 of the 13 patients who were admitted were given heparin, 4 of whom also received aspirin.…”

“…Both theoretical reasoning and studies in laboratory animals support the hypothesis that fibrinolytic agents could be effective during CPR. [10][11][12][13][14] Many studies have suggested that the administration of fibrinolytic agents during CPR can have a dramatic effect, [15][16][17][18][19][20][21][22][23][24][25] but there have been no randomized trials of this approach. We undertook this study to evaluate the effect of the administration of tissue plasminogen activator (t-PA) during CPR in adults with undifferentiated pulseless electrical activity (i.e., with an unknown or presumed cardiovascular cause) that was not responsive to initial therapy.…”

Low-dose tenecteplase during cardiopulmonary resuscitation due to massive pulmonary embolism: a case report and review of previously reported cases

“…No animal experiments have been performed evaluating the dosing of tenecteplase in pulmonary embolism. Other thrombolytic agents have been evaluated in large animal models of acute pulmonary embolism, providing at least some guidance for human use [24,25]. We think it is important to assess the dosing of tenecteplase specifically for patients with pulmonary embolism.…”