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Low-Dose Urokinase in Massive Pulmonary Embolism When Standard Thrombolysis Is Contraindicated FREE TO VIEW

Pierre Bulpa, MD, FCCP; Guiseppe Carbutti, MD; Jean-Claude Osselaer, MD; Georges Lawson, MD; Alain Dive, MD, PhD; Patrick Evrard, MD
Author and Funding Information

Affiliations: From the ICU (Drs. Bulpa, Carbutti, Dive, and Evrard), the Laboratory (Dr. Osselaer), and the Ear-Nose-Throat Department (Dr. Lawson), Cliniques Universitaires de Mont-Godinne, Yvoir, Belgium; and the ICU (Dr. Carbutti), Cliniques du Sud Luxembourg, Arlon, Belgium.

Correspondence to: Pierre Bulpa, MD, FCCP, Intensive Care Unit, Mont-Godinne University Hospital, Université Catholique de Louvain, 5530 Yvoir, Belgium; e-mail: pierre.bulpa@uclouvain.be


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(4):1141-1143. doi:10.1378/chest.08-2583
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When acute massive pulmonary embolism is life threatening, thrombolysis could be a therapeutic option. However, lysis may be contraindicated once the risk of bleeding is high. We report on two patients who have massive pulmonary emboli complicated by severe hypotension, justifying thrombolytic treatment. Nevertheless, recent surgery in the first patient and a fresh hemorrhagic duodenal ulcer in the second patient precluded thrombolytic treatment at the usual dosage. Therefore, prolonged lysis with low-dose urokinase (1,000 units/kg/h) was initiated. After a few hours, the patients became hemodynamically stable and inotrope/vasopressor doses could be reduced and stopped. No major bleeding was observed. Consequently, prolonged thrombolysis with low-dose urokinase could be an alternative approach to therapy in patients with massive pulmonary emboli when recommended thrombolytic dosages are contraindicated.

Although the indications for thrombolysis in patients with pulmonary embolism are still subject to debate, thrombolytic therapy is commonly recommended when there is hemodynamic instability.1 However, contraindications like recent surgery or GI bleeding may preclude thrombolysis.1 Some reports2,3 suggest that low-dose thrombolysis could be an alternative to the standard dosage, with a lower risk of bleeding. We report on our experience with two patients, one with a history of recent surgery and the second with a recent bleeding duodenal ulcer. They both experienced a massive life-threatening pulmonary embolism and were treated with prolonged low-dose urokinase.

Case 1

A 76-year-old man with myoepithelioma of the parotid gland underwent a scheduled left parotidectomy. His medical history was characterized by moderate ischemic cardiomyopathy with no clinical signs of cardiac failure (left ventricular ejection fraction [LVEF] estimated at 30 to 35%, treated with angioplasty and stenting of the circumflex artery), dyslipidemia, and sporadic atrial fibrillation.

On the first postoperative day, severe dyspnea (classified as New York Heart Association class IV) associated with chest pain suddenly developed in the patient. The physical examination revealed tachypnea (respiratory rate, 26 breaths/min), with pallor, sweating, and cool extremities. Systolic arterial BP was < 80 mm Hg, but the patient responded well to a fluid challenge. He had a sinus tachycardia with a heart rate of 125 beats/min, a temperature of 36.9°C, and oxygen saturation of 98% while breathing 9 L/min oxygen. Chest auscultation was unremarkable. Bedside transthoracic echocardiography (TTE), performed soon after ICU admission, showed right-cavity enlargement (right ventricle [RV], 49 mm; right auricle, 50 mm), with severe RV hypokinesia, paradoxical septal motion, increased vena cava diameter (22 mm) without inspiratory collapse, calculated pulmonary hypertension of 75 mm Hg, LVEF of approximately 20%, and left wall motion similar to that described on previous echocardiographies. The ECG findings were similar to those of the preoperative ECG, with no evidence of acute cardiac ischemia, and the troponin level was normal. Hemodynamic data obtained through a Swan-Ganz catheter included the following: cardiac index, 0.74 L/min/m2; systolic pulmonary artery pressure, 63 mm Hg; diastolic pulmonary artery pressure, 40 mm Hg; mean pulmonary artery pressure, 50 mm Hg; central venous pressure, 28 mm Hg; and wedge pressure, and therefore pulmonary vascular resistance, could not be measured. As a result of these findings, therapy with dobutamine was started at 3 μg/kg/min, and inhaled nitric oxide (NO) at 10 ppm.

The chest radiograph findings were normal, but bedside perfusion pulmonary scintigraphy confirmed a massive embolism. The patient was first treated with unfractionated heparin and was considered for standard-dose thrombolysis (ie, urokinase at 4,400 units/kg/h), but the recent surgery precluded its use. After agreement with the ear-nose-throat surgeon, urokinase therapy was started, without a loading dose, at 1,000 units/kg/h (80,000 units/h) by a peripheral IV route, and heparin therapy was stopped. Under this treatment, systemic arterial pressure gradually stabilized. Hemodynamic data showed an improved cardiac index with normalization after 48 h (day 1, 1.62 L/min/m2; day 2, 3.58 L/min/m2), and decreased pulmonary artery pressures (day 1: systolic pulmonary artery pressure, 47 mm Hg; diastolic pulmonary artery pressure, 23 mm Hg; mean pulmonary artery pressure, 32 mm Hg; day 2: systolic pulmonary artery pressure, 39 mm Hg; diastolic pulmonary artery pressure, 11 mm Hg; mean pulmonary artery pressure, 23 mm Hg) such that the dobutamine administration could be stopped on day 2.

The only adverse event observed was mild hematuria from a urethral lesion caused during introduction of the urinary catheter, but no blood transfusion was required. Nevertheless, the urokinase dose was lowered to 60,000 units/h and then to 40,000 units/h. Any attempt to increase the dose was followed by hematuria, limiting further dose escalation. Even under these low doses of urokinase, thrombolytic activity was present as confirmed by decreased serum plasminogen (112 to 53%) and antiplasmin (108 to 40%).

A control TTE on day 1 showed a decrease in calculated pulmonary hypertension at 43 mm Hg and in right-cavity enlargement (RV, 42 mm) with normal motion. Four days later, the pulmonary hypertension and dilatation of the right cavities had disappeared and the vena cava diameter had returned to normal with inspiratory collapse, allowing the NO administration to be stopped. There was a slight improvement in the lung scintigraphy after 24 h, but, however better, it was still not at a normal level by day 4.

Urokinase was administered for 7 days. Further hospital stay was uneventful. The patient was discharged from the ICU after 7 days, and from the hospital 17 days later after adjustment to vitamin K antagonist treatment. Six months later, TTE findings were comparable to those from before the pulmonary embolism, and lung scintigraphy showed a nearly complete reperfusion of the vascular bed.

Case 2

An 80-year-old man with squamous cell carcinoma of the larynx underwent urgent tracheotomy. His medical history was unremarkable. During his hospitalization, a hemorrhagic ulcer of the posterior duodenal wall was discovered, and therapy with IV omeprazole was initiated. A few days later, just after mobilization, he experienced a cardiorespiratory arrest and needed resuscitation for 45 min. He was ventilated through the tracheotomy with a fraction of inspired oxygen of 100% and 10 ppm NO. At ICU admission, arterial BPs were 126/55/71 mm Hg while receiving epinephrine at a dose of 2.5 mg/h. He had atrial fibrillation with a heart rate of approximately 100 beats/min, and his temperature was 35.7°C. Chest auscultation revealed a few expiratory wheezes. Blood gas measurements showed severe lactic acidosis (pH, 7; Pco2, 36 mm Hg; Po2, 441 mm Hg; lactate concentration, 16.5 mmol). A bedside TTE, performed soon after ICU admission, showed right-cavity enlargement (RV, 43 mm), increased vena cava diameter (27 mm) without inspiratory collapse, a calculated pulmonary hypertension of 68 mm Hg, and normal LVEF. ECG showed left anterior hemi-bundle branch block and right bundle branch block but no evidence of acute cardiac ischemia. Bedside perfusion pulmonary scintigraphy confirmed a pulmonary embolism.

Standard-dose thrombolysis was considered but not administered because of the duodenal ulcer (with recent bleeding) and the prolonged resuscitation. Instead, therapy with urokinase was started at a dose of 1,000 units/kg/h (100,000 units/h). With the low-dose thrombolysis, epinephrine administration could progressively be reduced and was stopped after 13 h, but norepinephrine had to be introduced (up to 7 μg/min) temporarily for 10 h. IV omeprazole (8 mg/h) was administered to prevent bleeding of the ulcer. A control TTE, 24 h later, showed a decrease in calculated pulmonary hypertension at 48 mm Hg and in vena cava diameter (24 mm). Urokinase administration was stopped after 48 h, and anticoagulation was started with nonfractionated heparin. The only adverse event observed was localized hematomas of the left flank and arm, and of the right thigh. There was no evidence of ulcer bleeding.

Further evolution was unremarkable. NO administration was stopped on day 2, and the patient was weaned from the ventilator on day 3. He was dialyzed temporarily, underwent total laryngectomy associated with thyroidectomy and parathyroidectomy after 15 days, and was discharged from the ICU on day 27 and from the hospital on day 70.

Although the indications for thrombolysis in patients with pulmonary embolism are still a subject of debate, its use in patients with life-threatening pulmonary embolism is widely accepted.1Three regimens have been approved by the US Food and Drug Administration for this purpose. One of these is urokinase at 4,400 units/kg/h for 24 to 48 h after a loading dose of 4,400 units/kg.1 However, there are some contraindications to this regimen,1 and, in such cases, no clear guidelines regarding alternative therapies are available. In our patients with massive pulmonary embolism, thrombolysis was indicated, but recent surgery or duodenal hemorrhage precluded its use. In view of the initial clinical instability in our patients, we decided to start prolonged low-dose thrombolysis with urokinase (1,000 units/kg/h), without a loading dose and concomitant heparin. The efficacy of this regimen was demonstrated by a dramatic clinical improvement within 24 h, allowing a progressive reduction in the dose of vasoactive drugs, which was associated with improved RV function. Although mild signs of bleeding were encountered, no transfusion was required. Interestingly, the urethral bleeding in the first patient disappeared when the urokinase dose was reduced, and no external blood loss was observed in the second patient.

Several approaches to acute life-threatening pulmonary embolism when standard thrombolysis is contraindicated have been described. Surgical or catheter thrombectomy may be considered but remains complex in this kind of patient, is especially effective in those with central embolism, and is only recommended when thrombolysis cannot be administered.4,5 Some reports6,7 have demonstrated the feasibility of full-dose thrombolysis soon after surgery but with the risk of massive blood transfusion. Another author8 reported a successful “watchful waiting” approach using just the administration of heparin; although no fatal embolism occurred in that case, this is the risk with that strategy. Others2,3,911 have proposed local low-dose infusion of thrombolytic agents with simultaneous systemic perfusion of heparin. This approach provides high drug levels directly into the clot and may reduce the risks of severe bleeding. However, catheterization of the pulmonary artery is required, increasing the risk of bleeding from vascular access sites.12,13 Because it was demonstrated that local infusion of a thrombolytic agent was not superior to systemic administration,14 some authors1517 had successfully administered a lower dose than usual by a peripheral vein with heparin. However, we chose to administer urokinase, without a loading dose and without heparin to minimize the bleeding risk, by a systemic route and did not observe any reduction in efficacy or any major hemorrhage. We selected urokinase because of its proven effectiveness,1 its nonantigenicity, and its short IV life, which allows rapid manipulation of the dose.

When the US Food and Drug Administration approved thrombolysis for pulmonary embolism, the dosing regimens were designed to activate fibrinolysis systematically in > 90% of patients and to achieve a rapid lysis throughout the body.18 The goal of these dosages was to dissolve the thrombus rapidly, but partial dissolution is the rule.19 Consequently, to diminish the risk of bleeding encountered with labeled dosages but to achieve the same effect, some authors15,17 have reported experiences with smaller doses. Although the efficacy seems comparable, the rate of bleeding was not lowered possibly due to the concurrent use of heparin. In our two cases, and due to the high hemorrhagic risk, we decided to perfuse urokinase without heparin but over a prolonged time. The lysis activation with this regimen was demonstrated by the decrease in concentrations of plasminogen and antiplasmin (two markers of thrombolytic activation12,20), even with urokinase doses as low as 500 units/kg/h. Therefore, these cumulative data suggest that lower than standard dosages are efficacious. Nonetheless, because labeled dosages have been studied more, they must be used if there is no contraindication. If that is the case, lower doses of a thrombolytic agent must be considered, but the best dosage remains to be determined.

When thrombolysis was first investigated in patients with pulmonary embolism, the efficacy of the fibrinolytic system (the “lytic state”) was monitored with prolongation of activated thromboplastin or thrombin time to at least 1.5 times baseline.18 Yet, further investigations demonstrated little correlation between blood tests and the efficacy of thrombolysis.19 Therefore, thrombolytic treatment could only be evaluated on clinical clues.

In conclusion, prolonged systemic low-dose thrombolysis with urokinase could be an effective and safe therapeutic approach in patients with life-threatening pulmonary embolism when full-dose thrombolysis is required but contraindicated. Further studies are needed to confirm these preliminary data.

LVEF

left ventricular ejection fraction

NO

nitric oxide

RV

right ventricle

TTE

transthoracic echocardiography

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We acknowledge the help of François Primosig in reviewing the manuscript.

Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence. Chest. 1999;115:1695-1707. [PubMed] [CrossRef]
 
Nakao M. Local low-dose infusion of streptokinase for massive pulmonary embolism when systemic thrombolysis is contraindicated. N Y State J Med. 1990;90:32-33. [PubMed]
 
Leeper KV Jr, Popovich J Jr, Lesser BA, et al. Treatment of massive acute pulmonary embolism: the use of low doses of intrapulmonary arterial streptokinase combined with full doses of systemic heparin. Chest. 1988;93:234-240. [PubMed]
 
Digonnet A, Moya-Plana A, Aubert S, et al. Acute pulmonary embolism: a current surgical approach. Interact Cardiovasc Thorac Surg. 2007;6:27-29. [PubMed]
 
Kucher N. Catheter embolectomy for acute pulmonary embolism. Chest. 2007;132:657-663. [PubMed]
 
Klaus S, Bahlmann L, Mierisch C, et al. Early postoperative thrombolytic therapy after laparotomy. Resuscitation. 2001;50:353-355. [PubMed]
 
Sayeed RA, Nashef SA. Successful thrombolysis for massive pulmonary embolism after pulmonary resection. Ann Thorac Surg. 1999;67:1785-1787. [PubMed]
 
Maier LS, Hermann H-P, Scholz KH. Massive pulmonary embolism with large floating thrombus in the truncus of the pulmonary artery. Intensive Care Med. 2001;27:1674-1676. [PubMed]
 
Spöhr F, Rehmert GC, Böttiger BW, et al. Successful thrombolysis after pulmonary embolectomy for persistent massive postoperative pulmonary embolism. Resuscitation. 2004;62:113-118. [PubMed]
 
Vujic I, Young JW, Gobien RP, et al. Massive pulmonary embolism: treatment with full heparinization and topical low-dose streptokinase. Radiology. 1983;148:671-675. [PubMed]
 
Molina JE, Hunter DW, Yedlicka JW, et al. Thrombolytic therapy for postoperative pulmonary embolism. Am J Surg. 1992;163:375-380. [PubMed]
 
Bell R. Present-day thrombolytic therapy: therapeutic agents; pharmacokinetics and pharmacodynamics. Rev Cardiovasc Med. 2002;3suppl:S34-S44. [PubMed]
 
Meyer G, Gisselbrecht M, Diehl J-L, et al. Incidence and predictors of major hemorrhagic complications from thrombolytic therapy in patients with massive pulmonary embolism. Am J Med. 1998;105:472-477. [PubMed]
 
Verstraete M, Miller GA, Bounameaux H, et al. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation. 1998;77:353-360
 
Laaban JP, Poubeau P, Horellou MH, et al. Value of moderate doses of urokinase combined with heparin in the treatment of massive pulmonary embolism: a retrospective study of 33 cases. Ann Med Interne (Paris). 1989;140:551-556. [PubMed]
 
Tilsner V. Thrombolytic therapy in fulminant pulmonary thromboembolism. Thorac Cardiovasc Surg. 1991;39:357-359. [PubMed]
 
Schulman S, Lockner D, Granqvist S, et al. A comparative randomized trial of low-dose versus high-dose streptokinase in deep vein thrombosis of the thigh. Thromb Haemost. 1984;51:261-265. [PubMed]
 
Hyers T, Hull R, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 1992;102suppl:408S-425S. [PubMed]
 
Hyers T, Agnelli G, Hull R, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119suppl:176S-193S. [PubMed]
 
Perler B. Thrombolytic therapies: the current state of affairs. J Endovasc Ther. 2005;12:224-232. [PubMed]
 

Figures

Tables

References

Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence. Chest. 1999;115:1695-1707. [PubMed] [CrossRef]
 
Nakao M. Local low-dose infusion of streptokinase for massive pulmonary embolism when systemic thrombolysis is contraindicated. N Y State J Med. 1990;90:32-33. [PubMed]
 
Leeper KV Jr, Popovich J Jr, Lesser BA, et al. Treatment of massive acute pulmonary embolism: the use of low doses of intrapulmonary arterial streptokinase combined with full doses of systemic heparin. Chest. 1988;93:234-240. [PubMed]
 
Digonnet A, Moya-Plana A, Aubert S, et al. Acute pulmonary embolism: a current surgical approach. Interact Cardiovasc Thorac Surg. 2007;6:27-29. [PubMed]
 
Kucher N. Catheter embolectomy for acute pulmonary embolism. Chest. 2007;132:657-663. [PubMed]
 
Klaus S, Bahlmann L, Mierisch C, et al. Early postoperative thrombolytic therapy after laparotomy. Resuscitation. 2001;50:353-355. [PubMed]
 
Sayeed RA, Nashef SA. Successful thrombolysis for massive pulmonary embolism after pulmonary resection. Ann Thorac Surg. 1999;67:1785-1787. [PubMed]
 
Maier LS, Hermann H-P, Scholz KH. Massive pulmonary embolism with large floating thrombus in the truncus of the pulmonary artery. Intensive Care Med. 2001;27:1674-1676. [PubMed]
 
Spöhr F, Rehmert GC, Böttiger BW, et al. Successful thrombolysis after pulmonary embolectomy for persistent massive postoperative pulmonary embolism. Resuscitation. 2004;62:113-118. [PubMed]
 
Vujic I, Young JW, Gobien RP, et al. Massive pulmonary embolism: treatment with full heparinization and topical low-dose streptokinase. Radiology. 1983;148:671-675. [PubMed]
 
Molina JE, Hunter DW, Yedlicka JW, et al. Thrombolytic therapy for postoperative pulmonary embolism. Am J Surg. 1992;163:375-380. [PubMed]
 
Bell R. Present-day thrombolytic therapy: therapeutic agents; pharmacokinetics and pharmacodynamics. Rev Cardiovasc Med. 2002;3suppl:S34-S44. [PubMed]
 
Meyer G, Gisselbrecht M, Diehl J-L, et al. Incidence and predictors of major hemorrhagic complications from thrombolytic therapy in patients with massive pulmonary embolism. Am J Med. 1998;105:472-477. [PubMed]
 
Verstraete M, Miller GA, Bounameaux H, et al. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation. 1998;77:353-360
 
Laaban JP, Poubeau P, Horellou MH, et al. Value of moderate doses of urokinase combined with heparin in the treatment of massive pulmonary embolism: a retrospective study of 33 cases. Ann Med Interne (Paris). 1989;140:551-556. [PubMed]
 
Tilsner V. Thrombolytic therapy in fulminant pulmonary thromboembolism. Thorac Cardiovasc Surg. 1991;39:357-359. [PubMed]
 
Schulman S, Lockner D, Granqvist S, et al. A comparative randomized trial of low-dose versus high-dose streptokinase in deep vein thrombosis of the thigh. Thromb Haemost. 1984;51:261-265. [PubMed]
 
Hyers T, Hull R, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 1992;102suppl:408S-425S. [PubMed]
 
Hyers T, Agnelli G, Hull R, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119suppl:176S-193S. [PubMed]
 
Perler B. Thrombolytic therapies: the current state of affairs. J Endovasc Ther. 2005;12:224-232. [PubMed]
 
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